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Abstract

Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood–brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood–brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer’s disease, Parkinson’s disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood–brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood–brain barrier in brain disorders.

Keywords

Blood–brain barrier inflammation multiple sclerosis intracranial aneurysm stroke epilepsy Alzheimer’s Parkinson’s disease neurodegeneration

Introduction

Matrix metalloproteinases

Matrix metalloproteinases (MMPs) are calcium-dependent zinc-endopeptidases of the metzincin superfamily.¹ Structurally, MMPs contain a conserved Zn²⁺-binding motif in the catalytic domain and several conserved protein domains (Figure 1).² MMPs are expressed as inactive zymogens with a pro-peptide domain (pro-MMPs) that must be removed for MMP activation. The pro-peptide is part of the “cysteine switch,” which is an intramolecular complex between a single cysteine in the pro-peptide domain and the zinc in the active site. Through cleavage of the pro-peptide, the cysteine dissociates from the complex, which activates the MMP enzyme and allows binding and cleavage of MMP substrates. MMPs also contain an amino-terminal signal sequence directing the peptide to the endoplasmic reticulum. In addition, all MMPs, except MMP-7 and MMP-26, have a hemopexin-like domain that is connected to the catalytic domain and is responsible for MMP interactions with substrates, endogenous inhibitors, and cell-surface molecules.

Figure 1.

Matrix metalloproteinase structure. MMPs are divided into distinct structural groups: minimal-domain MMPs, hemopexin-domain-containing MMPs, gelatinases, and membrane-type MMPs. Minimal-domain MMPs contain an amino-terminal signal sequence (S) that directs them to the endoplasmic reticulum, a pro-peptide (Pro) that maintains them as inactive zymogens, and a catalytic domain with a zinc-binding site (Zn²⁺). In addition to the domains found in the minimal domain MMPs, hemopexin-domain-containing MMPs have a hemopexin-like domain that is connected to the catalytic domain via a hinge (h). This hinge region mediates the interactions with substrates, TIMPs, and cell-surface molecules. Gelatinase-type MMPs contain inserts that resemble collagen-binding type II repeats of fibronectin (FN). Membrane-type MMPs (MT-MMPs) have a domain that interacts with the membrane. Some MMPs also have a furin-cleavage site (F). MMPs found in the brain are highlighted in red.

History

The first MMP (MMP-1) was identified by Jerome Gross and Charles Lapiere in 1962 in tadpole.³ In 1968, the first human MMP was discovered in skin tissue.⁴ Since then, a large family of MMPs has been described in various species.¹ In 1971, MMPs were shown to be biosynthesized as inactive precursors (zymogens) that require activation.⁵ The first endogenous MMP inhibitor, tissue inhibitor of metalloproteinse-1 (TIMP-1), was identified in 1975 and as of today, four TIMPs (TIMP-1-4) have been described.^6,7 In 1990, the “cysteine switch” MMP activation mechanism was discovered.⁸ Since then our understanding of MMP biology has increased tremendously. Through the unraveling of the MMP catalytic cycle, we now know that MMPs also digest non-extracellular matrix proteins and contribute to the fine-tuning of cellular processes. In addition, new MMPs – MMP-20, MMP-26, and MMP-28 – have been identified over the last 25 years.^9–11

Classification

Currently, 24 human MMP homologues have been described and are categorized into six sub-families: collagenases (MMPs-1, -8, and -13), gelatinases (MMPs-2 and -9), stromelysins (MMPs-3, -10, and -11), matrilysins (MMPs-7 and -26), membrane-type metalloproteinases (MT1-6-MMPs, also referred to as MMPs-14, -15, -16, -17, -24, and -25), and other MMPs (MMPs-12, -18, -19, -20, -21, -22, -23, -27, and -28; Table 1).^12–14

Table 1.

MMPs in CNS disease.

Nomenclature	Class/trivial or alternative name	Involvement in CNS diseases
MMP-1	Collagenase-1/interstitial collagenase	Neuroinflammation^b, epilepsy^a, AD^a, brain cancer
MMP-2	Gelatinase A/72 kDa gelatinase	Neuroinflammation, MS, cerebral aneurysms, stroke, epilepsy^a, AD^a, PD^a, brain cancer
MMP-3	Stromelysin-1	Neuroinflammation, MS, cerebral aneurysms, stroke, epilepsy^a, AD^a, PD, brain cancer
MMP-7	Matrilysin-1/PUMP-1	Neuroinflammation^b, stroke, epilepsy^a, AD^a
MMP-8	Collagenase-2/neutrophil collagenase	Neuroinflammation, brain cancer^b
MMP-9	Gelatinase B/92 kDa gelatinase	Neuroinflammation, MS, cerebral aneurysms, stroke, epilepsy, AD^a, PD^a, brain cancer
MMP-10	Stromelysin-2	Stroke, epilepsy^b, brain cancer
MMP-11	Stromelysin-3	MS, stroke, brain cancer
MMP-12	Macrophage metalloelastase	Neuroinflammation, MS, AD^b
MMP-13	Collagenase-3	Neuroinflammation, brain cancer
MMP-14	Membrane-type-1 MMP (MT1-MMP)	Neuroinflammation, cerebral aneurysms, MS, PD^a, brain cancer
MMP-15	Membrane-type-2 MMP (MT2-MMP)	MS, brain cancer
MMP-16	Membrane-type-3 MMP (MT3-MMP)	MS, brain cancer
MMP-17	Membrane-type-4 MMP (MT4-MMP)	Neuroinflammation^a, MS^a, AD^b, brain cancer^a
MMP-18	Collagenase 4, xCol4, Xenopus Collagenase
MMP-19	RASI-1 (Stromelysin-4)	Brain cancer^b
MMP-20	Enamelysin
MMP-21	X-MMP	MS^a
MMP-23	CA-MMP
MMP-24	Membrane-type-5 MMP (MT5-MMP)	MS^a, brain cancer^a
MMP-25	Membrane-type-5 MMP (MT6-MMP)	MS^a, brain cancer^a
MMP-26	Matrilysin-2, Endometase	Brain cancer^b
MMP-27	MMP-22, C-MMP
MMP-28	Epilysin	MS^a

MMP mRNA, protein and/or activity levels are elevated but involvement in disease is unclear.

Limited literature (one to two publications) available to support MMP involvement in the disorders.

Function and role

MMPs play a role in normal physiological processes including tissue morphogenesis, cell migration, and angiogenesis. MMPs are also involved in pathophysiological processes including wound healing, inflammation, and cancer. Some speculate that MMPs cleave extracellular matrix (ECM) proteins to allow infiltrating cells, including leukocytes, metastatic, and transformed cells, to penetrate ECM barriers.^14,15 However, this is controversial since the first in vitro studies that associated MMPs with the cleavage of ECM molecules were based on experiments using excessive amounts of MMPs. Today, evidence suggests that ECM cleavage is not a main function of MMPs in vivo.¹⁶

Studies using mass spectrometry indicate that ECM molecules are MMP substrates and other studies show that blocking MMPs (e.g., MT1-MMP) prevents leukocytes from crossing artificial collagen and ECM layers.^15,17,18 In these studies, it was demonstrated that fibroblasts and tumor cells tunnel through dense barriers of cross-linked type I collagen in vitro or in vivo via a virtually indistinguishable proteolytic process that requires MMPs. Furthermore, Ota et al.¹⁹ showed that cancer cells utilize an MT1- and MT2-MMP-dependent basement membrane transmigration program to intravasate into the vasculature in vivo.

Other studies using MMP knockout (KO) mice and novel mass spectrometry techniques that allowed improved tissue analysis revealed a wide MMP substrate spectrum that includes cell surface molecules and soluble factors such as chemokines, cytokines, and cytokine receptors.¹⁸ MMP-mediated cleavage of these substrates modulates their activity and represents an important mechanism of fine tuning cellular processes such as inflammation.^18,20–22 In essence, MMPs are critical for remodeling processes in developing and regenerating tissues.^15,18

Expression, activation, and regulation

All MMPs, with the exception of MMP-28, are ubiquitously expressed in mammalian organisms. MMP expression levels are generally low and only increase when needed,²³ except MMP-2 and MT1-MMP (and to a lesser extent MMP-9), which are constitutively expressed in the brain in both their pro- and activated forms.^24,25 MMPs are generated and then secreted into the extracellular space in an inactive, latent pro-form (zymogen), which is activated through proteolysis of the N-terminal pro-domain (Figure 1). This process allows rapid regulation of MMP activity, and thus, controls the availability of cytokines and chemokines. Consequently, MMPs are pivotal in controlling fast cellular responses, such as cell migration during inflammation.

Under physiological conditions, most MMPs are activated by other MMPs or proteases in the extracellular space, but some MMPs are activated intracellularly by the enzyme furin, or by other mechanisms (e.g., phosphorylation). MMP inhibition, on the other hand, is mediated by tissue inhibitors of metalloproteinases, TIMPs, that coexist with MMPs.^7,26 TIMPs inactivate MMP activity by binding to them, which under physiological conditions prevents excessive tissue degradation and injury. Under pathophysiological conditions, MMPs can be activated by reactive oxygen species and other factors (e.g., NO, hypoxia, pH) through a mechanism that likely involves auto-catalytic activation.^27–29

Little is known about transcriptional MMP regulation and what is known involves inflammatory signaling. Tumor necrosis factor-α (TNF-α) and interleukin-17 both stimulate MMP-9 transcription through the transcription factors activator protein-1 (AP-1) and nuclear factor-κB (NF-κB).^30–32 This effect can be blocked with interferon-γ through NF-κB inhibition.³³ The endotoxin lipopolysaccharide (LPS) triggers reactive oxygen species production and p38 kinase phosphorylation, which activates AP-1 and induces MMP-9 transcription.³⁴ Figure 2 shows the MMP-9 promotor with one NF-κB and two AP-1 binding sites. MMP-2, on the other hand, is regulated by TNF-α and p38-MAPK acting through NF-κB, but not AP-1 (Figure 2), and a caspase 8-dependent pathway.³⁵ Together, MMP regulation is not fully understood and varies between cell types in a context-dependent manner.^36,37

Figure 2.

MMP-2 and MMP-9 promoter region with putative transcription factor binding sites. The boxes represent binding sites for the corresponding transcription factors. TSS: transcription start site; AP-1: activator protein 1; AP-2: activator protein 2; GATA-1: GATA-binding factor 1, erythroid transcription factor, globin transcription factor 1; SP-1: specificity protein 1; NF-κB: nuclear factor-κB, CREB: cyclic AMP response-element binding protein; p53: tumor protein p53 (modified after Peters et al.³⁸ and Rosenberg³⁹).

MMPs in brain and blood–brain barrier

MMPs participate in many physiological and pathological processes in the brain and at the blood–brain barrier (Table 2). The blood–brain barrier is the capillary endothelium that separates blood from brain.⁴⁰ Physical barrier function is localized to three structures that are critical for barrier integrity: the brain capillary endothelium, the tight junctions between the endothelial cells, and the basement membrane (Figure 3).⁴⁰ First, the brain capillary endothelium is a barrier for small hydrophilic compounds. Second, tight junctions seal the clefts between adjacent endothelial cells, which prevents uncontrolled paracellular passage of solutes and makes the brain endothelium a low-permeability barrier.^41–43 The major tight junction proteins in the brain endothelium are claudin-1, claudin-5, occludin, and zonula occludens-1. Third, the basement membrane, which is a specialized ECM, connects endothelial cells with pericytes and astrocytes to form the neurovascular unit and facilitates communication between the cells within this unit through receptors such as integrins and dystroglycans.^44,45

Figure 3.

Blood–brain barrier anatomy. The blood–brain barrier is formed by capillary endothelial cells that are linked by tight junctions, surrounded by a basement membrane, and astrocytic endfeet. Astrocytes provide the cellular link to neurons; pericytes are embedded in the basement membrane. In disease, MMP protein expression and activity levels are increased, which is thought to result in blood–brain barrier leakage, possibly through degradation of tight junction and basement membrane proteins.

Table 2.

MMP effects in the brain and blood–brain barrier.

MMPs in physiological processes	MMPs in pathophysiological processes
CNS development^46,47	Involvement in CNS injuries and diseases^48–52,53
CNS survival⁵⁴	Blood–brain barrier leakage^55–57
Angiogenesis⁵⁸	Neuroinflammation^59–65
Neurogenesis^66,67	Neurotoxicity^68–77
Cell fate determintion⁷⁸	Demyelination^79–82
Proliferation and migration of cell precursors^17,83	Tumor angiogenesis^58,84–87
Axonal growth and regeneration^88–91	Tumor metastasis^82,93
Myelinogenesis and remyelination^47,94
Terminate neuroinflammation^95,96

Endothelial cells, tight junctions, and basement membrane are critical for proper barrier function, and thus, for brain homeostasis and overall brain health. In turn, pathological disruption of the endothelium, tight junctions, or the basement membrane impairs barrier integrity, which can have severe consequences for the brain and contribute to disease progression.^97,98 In this regard, it has been proposed that MMPs digest tight junctions and basement membrane proteins, and thus, are critical contributors to brain disease and directly affect brain health.^99,100 However, little data exist to support this since it is technically challenging to demonstrate MMP activity in vivo. For example, Gu et al.¹⁰¹ show increased MMP activity and higher permeability at the blood–brain barrier in stroke during reperfusion in vivo. Yang et al.¹⁰² show increased MMP-2 and MMP-9 mRNA and activity levels after reperfusion in spontaneously hypertensive rats with middle cerebral artery occlusion (MCAO). The authors also observed blood–brain barrier leakage in the piriform cortex and disrupted tight junction proteins. Inhibiting MMPs prevented the loss of tight junction proteins, indicating that MMPs disturb barrier integrity by degrading tight junction proteins.¹⁰² Thus, while technically challenging, first evidence showing that MMPs digest tight junctions and ECM proteins in vivo is emerging.

Methods and techniques to study MMPs

MMPs are mostly studied at the mRNA, protein, and activity levels. MMP mRNA expression has been demonstrated in several studies using real-time quantitative PCR and microarray analysis.^103,104 MMP protein expression is usually determined by Western blotting, ELISA, or by immunohistochemistry. To detect MMP activity in vitro, a widely used technique – substrate zymography – is employed. Substrate zymography identifies MMPs by the degradation of their substrate and by their molecular weight.^105,106 This method allows determining if the MMP is active or latent. All types of substrate zymography originate from gelatin zymography, which is used to detect the gelatinases MMP-2 and MMP-9.¹⁰⁷ To detect other MMPs, gelatin is replaced with another substrate such as collagen, carboxymethylated transferrin, or casein.^{104,108–111} Another method to detect MMP activity in vitro is by using fluorogenic MMP substrates. These artificial MMP substrates are composed of a fluorescent dye that is connected via a peptide to a quencher. Active MMP cleaves the peptide, and thus, removes the quencher resulting in fluorescence, which is a direct measure of MMP activity.¹¹²

Currently, it is not possible to localize activity of most MMPs in tissues due to a lack of suitable reagents. An exception to this is gelatin in situ zymography, a method that allows detecting MMP-2 and MMP-9. Gelatin in situ zymography is a modification of substrate zymography in frozen tissue sections. In this method, an MMP substrate is transferred onto a frozen section of an unfixed tissue sample. The substrate is digested by active MMPs in a time- and dose-dependent manner, which is visualized with microscopy.¹¹³ A further development of this method is in vivo zymography,¹¹⁴ where substrates are used in a live animal to detect MMP activity in vivo.¹¹⁵

MMPs in central nervous system disease

Neuroinflammation

Neuroinflammation is defined as an unspecific inflammatory event in the brain. All central nervous system (CNS) disorders discussed here – multiple sclerosis (MS), cerebral aneurysm, stroke, epilepsy, Alzheimer’s disease (AD), Parkinson’s disease (PD), and brain cancer – have a neuroinflammatory component that involves MMPs.

MMPs contribute to neuroinflammation through four mechanisms (Figure 4). First, MMPs activate neuroinflammatory pathways. This is done indirectly by activating enzymes that act on signaling molecules such as cytokines, cell surface receptors, cell–cell adhesion molecules, or clotting factors.^59,60 Alternatively, MMPs directly activate neuroinflammatory pathways. For example, MT4-MMP has TNF-α-convertase activity through which transmembrane TNF-α is proteolytically converted into soluble, active TNF-α (Figure 4(1)).^61,62 Second, MMPs themselves act as neuroinflammatory signaling molecules. Upon stimulation with LPS, apoptotic signals, or in PD, neurons secrete active MMP-3 into the interstitium, which triggers microglial activation and production and secretion of pro-inflammatory cytokines (Figure 4(2)).^63–65 Third, MMPs contribute to neuroinflammation-mediated neurotoxicity by shedding death molecules like the Fas ligand, by affecting GABA and glycine levels, which modulate chloride channel activity, by stimulating glutamate receptor-mediated excitotoxicity, or by altering cell–ECM interaction.^68–72 However, the exact mechanisms through which MMPs exert neurotoxicity are not fully understood (Figure 4(3)).^73–77 And lastly, neuroinflammation-induced MMPs may proteolyze cerebrovascular basement membrane and tight junction proteins, which could compromise vascular integrity resulting in barrier leakage and extravasation (Figure 4(4)).^55–57,79

Figure 4.

MMPs in neuroinflammation. MMPs contribute to neuroinflammation through four mechanisms. (1) MMPs activate neuroinflammatory pathways and/or neurosignaling components. (2) MMPs act as signaling molecules themselves. (3) MMPs contribute to neuroinflammation-mediated neurotoxicity. (4) MMPs compromise vascular integrity resulting in blood–brain barrier leakage.

Together, MMPs are induced by and contribute to neuroinflammation through various mechanisms. MMPs also contribute to inflammation-induced barrier dysfunction and leakage. The combination of both – neuroinflammation and barrier dysfunction – promotes progression of several CNS disorders (MS, cerebral aneurysms, stroke, epilepsy, AD, PD, and brain cancer), which are discussed in the following sections.

Multiple sclerosis

MS is a neuroinflammatory auto-immune disease that affects about 1.3 million people worldwide.¹¹⁶ In MS, the myelin sheaths that cover neuronal axons and nerve fibers in the brain and spinal cord are damaged, which disrupts communication and causes a wide range of disease symptoms.¹¹⁷

The role of MMPs in MS has been studied extensively in animal models and human tissue.^118–122 These studies revealed that MMPs digest myelin basic protein, which causes demyelination and drives MS progression (Figure 5(a)).^79,81,82 Using the experimental autoimmune encephalomyelitis (EAE) animal model of MS, several groups analyzed MMPs in brain, brain capillary endothelial cells, spinal cord, lymph nodes, and spleen and showed that multiple MMPs were elevated during the EAE peak stage.^{119,123–128} Specifically, in EAE mouse and rat models, mRNA, and protein levels were increased for MMPs-2, -3, -7, -8, -9, -10, -11, -12, -13, -28, MT1-MMP, and MT6-MMP. In contrast, mRNA and protein levels for MT2-5-MMP and MMP-21 were decreased in lumbar and sacral spinal cord tissue of EAE mice.¹²⁹ While the consequence of decreased MMP levels, particularly those of MT-MMPs, is unclear, it is well established that increased MMP levels aggravate disease severity in EAE rodent models.^{118,119,125,127,128,130,131}

Figure 5.

MMPs in multiple sclerosis. (a) Brain endothelial cells and leukocytes secrete MMPs, which are thought to degrade tight junction and extracellular matrix proteins leading to extravasation of immune cells. (b) Leukocytes, microglia, neurons, and reactive astrocytes secrete MMPs, which demyelinate neuronal axons.

One characteristic of MS is leukocyte extravasation and transmigration across the brain endothelium into the CNS. MMPs may facilitate this process by activating adhesion molecules and degrading the basement membrane that surrounds blood vessels (Figure 4(1) and (4)). However, this is controversial since there is no conclusive evidence. Agrawal et al.¹¹⁸ show selective MMP-2- and MMP-9-mediated cleavage of dystroglycan, which is a linker between astrocyte endfeet and parenchymal basement membrane molecules. This process is located at postcapillary venules, where extravasation occurs.¹¹⁸ But this and other studies, for example, the study by Buhler et al.¹¹⁹ suggest that MMPs are involved in immune cell extravasation into the brain during EAE.

Studies using brain tissue, serum, and cerebrospinal fluid (CSF) samples from MS patients consistently found increased protein levels for MMPs-2, -3, -7, -9, -12, -13, and MT1-MMP.^{80,120,132–138} In these studies, leukocytes were identified as a main source of MMPs, the best-studied of which in MS is MMP-9. MMP-9 mRNA, protein, and activity levels are increased in mononuclear blood cells, serum, and CSF, and correlate with barrier leakage and disease progression.^{121,139–143}

Immune cells from the blood can cross the blood–brain barrier via a transcellular (likely no MMPs involved) or a paracellular (MMPs involved) pathway. For the latter, it has been reported that T cells, monocytes, and dendritic cells express and release active MMP-2 and MMP-9, which open the brain endothelial tight junctions to cross the barrier and migrate into the brain.^{118,144–149} After passing the tight junctions, MMP-2 and MMP-9 cleave the transmembrane receptor β-dystroglycan, which anchors astrocytic endfeet to the basement membrane.¹¹⁸ In addition, in lesional MS tissue, MMPs-1, -2, -3, -9, and -19 have been detected in microglial nodules and microglial-like cells where they contribute to inflammation and further destabilize the blood–brain barrier.^150,151

One MMP that currently gets attention in the MS field is MMP-12. MMP-12, also called macrophage metalloelastase, is assumed to be essential in the pathogenesis of MS, most likely due to its primary myelin- or oligodendrocyte-toxic potential and its role in macrophage extravasation. At the same time, MMP-12 does not seem to damage the blood–brain barrier or alter ECM remodeling and deposition.^138,152 In contrast, data from other studies show that MMP-12 KO mice with EAE had a significantly worse maximum severity and disease burden compared with EAE wild-type control mice, suggesting that increased MMP-12 expression levels are protective in MS.¹²⁷ An additional study showed that wild-type and MMP-12 KO mice with EAE followed a relapsing-remitting course.¹⁵³ Although both mouse groups had a similar clinical onset, relapses in MMP-12 KO mice with EAE were more severe and their residual disability at remission was higher.

Thus, while it is clear that MMPs contribute to MS, it is less clear if this occurs by degrading the endothelial basement membrane, which would facilitate leukocyte extravasation and migration into the brain (Figure 5(a)). In the brain, leukocytes then release more MMPs that contribute to the overall MMP effect of axonal demyelination and neuronal cell death.

Cerebral aneurysms

An aneurysm is a blood-filled balloon-like bulge in the wall of an artery. The causes of brain aneurysms are manifold and include aging, atherosclerosis, hypertension, and severe head injury, all of which are accompanied by neuroinflammation.¹⁵⁴ Most cerebral aneurysms remain undetected until they rupture, which is life-threatening.¹⁵⁵ Therefore, it is critical to prevent rupture by securing intracranial aneurysms, which is accomplished by invasive brain surgery.¹⁵⁶ A less invasive approach would be to prevent aneurysms from forming, which requires understanding of aneurysm pathology. One theory states that MMPs degrade the vascular ECM, thereby contributing to localized ballooning of a blood vessel and leading to aneurysm formation and growth.^157–159 For example, in human brain samples, protein expression levels of plasmin, MMP-2, MMP-9, and MT1-MMP were increased in the aneurysmal wall compared to normal cerebral arteries and overall MMP-2/MMP-9 proteolytic activity was higher in aneurysm tissue compared to control arteries.¹⁵⁷

Recent reports also indicate that MMPs are involved in vascular calcification,^160,161 which could be another negative effect MMPs contribute to the pathological outcome of cerebral aneurysms. In a retrospective review, the authors showed that the presence of calcification in an aneurysm was the sole marker of adverse outcome.¹⁶² Larger aneurysms tended to be more likely to be calcified, while size by itself did not have an adverse effect on outcome. Furthermore, in surgically securing intracranial aneurysms, calcified aneurysms are a significant source of morbidity.¹⁶²

One possibility to limit aneurysm progression and growth is through MMP inhibition, which could potentially reduce the need for invasive treatment.^163,164 Pre-clinical studies show that MMP inhibitors block aneurysm formation and growth.^164–166 Xiong et al.¹⁶⁶ demonstrated in a mouse model of Marfan syndrome that inhibiting MMP-2 and MMP-9 protein expression with doxycycline blocked ECM degradation, which significantly delayed aneurysm rupture. Nuki et al.¹⁶⁵ used a mouse model, where 70% of animals develop brain aneurysms and demonstrated that doxycycline reduced the incidence of aneurysms to 10%. The authors also showed a reduced incidence (40%) of intracranial aneurysms in MMP-9 KO mice, whereas over 60% of MMP-2 KO mice still developed cerebral aneurysms, suggesting that MMP-9 is critical for aneurysm formation. Aoki et al.^167,168 used statins in rats, where cerebral aneurysms were induced by unilateral ligation of the common carotid artery and hypertension. Statin treatment decreased aneurysm size by 30–40% within one month likely through a mechanism that lowered MMP levels, which is thought to delay aneurysm formation and growth.¹⁶⁴ The therapeutic benefit of statins is attributed to their cholesterol-lowering, anti-inflammatory, and anti-NF-κB effects, which lower MMP activity.¹⁶⁴ Statins have also been studied in humans. Yoshimura et al.¹⁶⁹ conducted a retrospective study analyzing data from 117 patients with ruptured brain aneurysms and 304 patients with unruptured brain aneurysms to assess if statins prevent rupture. In this study, 9% of patients with ruptured cerebral aneurysms used statins, whereas 26% of patients with unruptured aneurysms used statins, which indicates that statins lower the risk of brain aneurysms to rupture.

Together, MMPs contribute to formation, growth, and rupture of cerebral aneurysms by digesting the ECM, which leads to ballooning of blood vessels. This suggests that inhibition of MMPs, especially MMP-9, could potentially prevent cerebral aneurysms.

Stroke

In 2012, stroke accounted for about seven million deaths worldwide, which is 12% of all deaths and makes stroke the number two killer.¹⁷⁰ With an additional 10 million people surviving a stroke each year, over 30 million people altogether survived a previous stroke.¹⁷¹ Stroke is characterized by a loss in brain function due to limited cerebral blood flow (ischemic) caused by a blocked blood vessel, or due to bleeding into the brain parenchyma or subarachnoid space (hemorrhagic).

In stroke, MMPs have detrimental effects in the acute phase and beneficial effects in the post-stroke phase.¹⁷² Detrimental effects are mediated by dysregulated MMPs and include neurovascular disruption and brain parenchymal damage (Figure 6(a)). Various studies in human and rat brains show that protein and activity levels of MMPs-2, -3, and -9 are increased after stroke and MCAO compared to control tissue.^173,174 These changes in MMP protein and activity levels result in aberrant proteolysis that contributes to blood–brain barrier dysfunction and in part determines the extent of the infarct.^{132,173–177} In addition, studies using rat stroke models suggest that by degrading the basal lamina, MMPs predispose brain capillaries to rupture and hemorrhagic transformations after stroke.^178–180 Other examples of detrimental MMP effects in stroke were shown in studies using rodent models of focal cerebral ischemia. In these studies, increased MMP-9 protein levels were detected in the acute phase (2–24 h) after stroke that coincided with an opening of the blood–brain barrier. In contrast, MMP-2 protein levels were increased several days after stroke,^181,182 during which barrier leakage is presumably restored.

Figure 6.

MMP-9 in stroke. (a) acute phase: endothelial cells and recruited leukocytes secrete MMP-9, which degrades the blood–brain barrier, the neurovascular basement membrane, and the ECM. (b) remodeling phase: astrocytes and neurons secrete MMP-9, which contributes to remodeling of the ECM in the neurovascular unit.

While most MMP research in stroke is focused on MMP-2 and MMP-9,^183,184 other MMPs also have detrimental effects. Suzuki et al.¹⁸⁵ treated mice after thrombotic MCAO with tissue-type plasminogen activator (tPA) and observed an increased incidence of intra-cranial bleeding compared to mice not treated with tPA. The authors showed increased MMP-3 mRNA and protein levels in the capillary endothelium in the infarct region of tPA-treated mice compared to tPA-untreated control mice. Suzuki et al.^185,186 concluded that in tPA-treated mice, MMP-3 digests the neurovascular basal lamina, thereby opening the endothelial barrier and contributing to intra-cranial bleeding. These findings suggest that MMP-3 has detrimental effects during tPA treatment or is induced by tPA, which is unfortunate since tPA is currently the only FDA-approved treatment for ischemic stroke.

However, MMPs also have beneficial effects during the recovery phase after stroke (Figure 6(b)).¹⁸⁷ Studies suggest that MMP-9, MMP-2, and MMP-7 remodel lesional ischemic and infarct tissue and participate in angiogenesis, vasculogenesis, and neurogenesis.^{17,83,94,188–190} Two mechanisms have been identified by which MMPs exert these effects. First, during tissue remodeling in the post-stroke recovery and healing phase, MMPs digest old ECM so that new ECM and tissue can be generated.^2,187,191 Second, during ECM digestion, MMPs (mainly MMP-7 and MMP-9, but also MMPs-1, -2, -3, -10, and -11) increase the availability of growth factors (e.g., nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3/-4, and vascular endothelial growth factor). This occurs through cleaving inactive growth factor precursors into their active form or through releasing active growth factors by ECM proteolysis.^54,188 Increased levels of growth factors support tissue remodeling by stimulating angiogenesis, vasculogenesis, and neurogenesis, all of which are critical in stroke recovery. These findings suggest that during the remodeling and healing process, MMPs are involved in the migration of neuronal precursor cells to areas damaged by stroke.^17,83

Together, MMPs are essential in stroke in both the acute phase and the post-stroke phase (Figure 6). In the acute phase, MMPs impair barrier integrity and damage the parenchymal tissue, whereas in the post-stroke phase MMPs contribute to the recovery process by remodeling lesional ischemic and infarct tissue and by participating in angiogenesis, vasculogenesis, and neurogenesis.

Epilepsy

The World Health Organization estimates that at least 65 million people worldwide suffer from epilepsy.^192–194 Epilepsy describes various diseases and seizure syndromes, and patients are diagnosed with epilepsy after recurring, unprovoked seizures.¹⁹⁵

The role MMPs have in epilepsy is still unclear, but studies suggest MMPs contribute to epileptogenesis, epilepsy progression, and brain remodeling after seizures. For example, MMP-9 KO mice are less sensitive to chemically-induced seizures compared to wild-type mice, and conversely, human MMP-9-overexpressing rats are more sensitive to chemical seizure induction, suggesting MMP-9 affects epileptogenesis and/or seizure genesis.^196,197

MMP levels are increased in the epileptic brain. In chemically induced animal seizure models and patients with temporal lobe epilepsy, MMP-9 protein and activity levels are increased in neurons of the parietal and frontal cortex, as well as the thalamus, the regions where the seizures originated.^73,197–200 Li et al.²⁰¹ detected increased MMP-9 protein and activity levels in CSF from adult epilepsy patients with generalized tonic–clonic seizures compared to age-matched non-epileptic individuals. MMP-9 levels were also increased in serum from patients after seizures. Suenaga et al.²⁰² detected threefold higher MMP-9 protein levels in serum from children with encephalopathy after prolonged febrile seizures compared to serum from healthy children. The authors also found higher serum MMP-9 levels in children with prolonged febrile seizures but no encephalopathy, in children with simple febrile seizures, and in children with convulsive status epilepticus compared to healthy children.²⁰² Research suggests that increased MMP-9 protein and activity levels mainly serve two functions: first, MMP-9 contributes to seizure-induced neuronal cell death; and second, MMP-9 is critical in remodeling neuronal networks after seizures. Jourquin et al.⁷⁵ and Hoehna et al.⁷³ demonstrated neuronal cell death in areas with increased MMP-9 levels after seizures and showed that inhibiting MMP-9 reduced cell death. Other studies show that MMP-9 is involved in structural remodeling, mossy fiber sprouting, diminished seizure-induced pruning of dendritic spines, and decreased aberrant synaptogenesis.^197,199,203

MMP-2 function in the epileptic brain is less understood than that of MMP-9. Jourquin et al.⁷⁵ demonstrated that MMP-2 does not contribute to neuronal cell death in epilepsy. However, it is conceivable that MMP-2 contributes to structural remodeling in epileptogenesis since MMP-2 mRNA, protein, and activity are increased after seizures.^197,199,204

Several studies demonstrate blood–brain barrier dysfunction in epilepsy and seizure-induced barrier leakage.^205–210 Additionally, barrier leakage itself triggers seizures, suggesting a pernicious feedback loop contributing to epilepsy progression.^210–212 In this regard, MMPs most likely degrade tight junction and ECM proteins, which potentially contribute to barrier leakage after seizures.^98–100 Li et al.²⁰¹ showed that increased MMP-9 protein and activity levels in serum and CSF of patients with generalized tonic–clonic seizures correlate with barrier leakage. Furthermore, barrier leakage is associated with leukocyte extravasation into the brain after seizures. Leukocyte extravasation is a complex, multi-step process that requires MMPs, in particular MMP-2 and MMP-9, both from the endothelium as well as from activated T cells and macrophages.^{188,147,149,213} Li et al.²⁰¹ demonstrated in patients with generalized tonic–clonic seizures that increased CSF leukocyte counts correlated with increased MMP-9 levels in CSF and the degree of barrier leakage.²⁰¹

Thus, MMP-2 and MMP-9 seem to contribute to seizure- and/or epileptogenesis, neuronal network remodeling, neuronal cell death, and barrier leakage after seizures. Little is known about other MMPs in epilepsy.

Alzheimer’s disease

AD is a neurodegenerative disorder that affects more than 20 million patients globally.^214,215 Disease projections are grim and predict up to 100 million AD patients by 2050.²¹⁶ Despite all research efforts, AD etiology and progression are not well-understood and a cure or prevention is currently not available. AD pathology is characterized by brain accumulation of amyloid-β (Aβ), development of Aβ plaques, formation of neurofibrillary tangles, and neuroinflammation, all of which contribute to neurodegeneration.^217,218 In this section, we first describe what is currently known about MMPs in AD and then describe the relationship between Aβ and MMPs.

Several groups have reported that MMP levels in rodent AD models are increased compared to control animals. Yan et al.²¹⁹ detected increased MMP-9 protein levels in brain slices from transgenic APPsw and amyloid precursor protein (APP)/PS1 mice compared to wild-type mice. Using 5xFAD mice, Py et al.²²⁰ found increased MMP-2, MMP-9, and MT1-MMP protein levels in the hippocampus compared to control mice. MMP-2 and MMP-9 were primarily expressed in astrocytes; MT1-MMP was localized to neurons; MMP-9 and MT1-MMP were also detected in amyloid plaques. Consistent with these findings, several groups found overexpression of MMP-2, -3, and -9 mRNA and protein in postmortem brains from AD patients.^221–224 Horstmann et al.²²⁵ used zymography and detected MMP-2, -3, -9, and -10 activity levels in serum and CSF from AD patients and compared them to gender- and age-matched healthy control individuals. The authors found that MMP-3 activity was elevated by 40% in plasma and 60% in CSF from AD patients compared to control individuals. MMP-2 activity in the CSF of AD patients was decreased by 32% compared to CSF samples from healthy individuals, while activity levels in plasma remained unchanged. MMP-9 and MMP-10 activity were undetectable in CSF, MMP-10 activity was unchanged in plasma, and MMP-9 activity in plasma was decreased by 41% compared to healthy individuals. Lorenzl et al.²²⁶ detected higher levels of proMMP-9 protein in plasma samples from AD patients compared to control individuals.

Some research aimed at clarifying the relationship between MMPs and Aβ. Deb and Gottschalk²²⁷ observed in rat hippocampal and astrocyte cultures that Aβ₄₀ induced protein expression and proteolytic activity of MMPs-2, -3, and -9. We demonstrated that exposing isolated rat brain capillaries to Aβ₄₀ ex vivo increased MMP-2 and MMP-9 protein and activity levels.²²⁸ We made similar observations in a transgenic mouse AD model (Tg2567 hAPP mice), where MMP-2 and MMP-9 levels in brain capillaries were elevated compared to capillaries from wild-type mice. Yin et al.²²⁹ observed in APP/PS1 mice that astrocytes surrounding amyloid plaques secrete more MMP-2 and MMP-9. They also demonstrated that breeding APP/PS1 mice with MMP-2 or MMP-9 KO mice, or pharmacologically inhibiting MMP-2 or MMP-9 in APPsw mice increased Aβ brain levels by 1.5-fold compared to controls and increased Aβ half-life by about 50%.²²⁹ Additionally, Yin et al. observed in the phosphate buffer-soluble fraction of cortex and hippocampus of MMP-2 KO mice increased murine Aβ₄₀ and Aβ₄₂ compared to age-matched wild-type mice, whereas Aβ₄₀ and Aβ₄₂ were unchanged in the phosphate buffer-insoluble fraction. In the cortex and hippocampus of MMP-9 KO mice, murine Aβ₄₂ levels were increased in the phosphate buffer-soluble fraction of hippocampus and cerebral cortex compared to age-matched wild-type mice, while they remained unchanged in the phosphate buffer-insoluble fraction. These effects were due to decreased Aβ proteolysis and not to increased Aβ production. These findings suggest that MMPs potentially contribute to Aβ clearance. In this regard, MMPs-2, -3, and -9 proteolytically degrade Aβ.^{219,230,231,232} Ridnour et al.²³³ showed that levels of Aβ_1–16, a product of Aβ metabolism by MMP-9, and MMP-9 activity were decreased in brain lysates of hAPPSwDI mice lacking nitric oxide synthase compared to their littermates expressing nitric oxide synthase. Based on these data, the authors concluded that nitric oxide is potentially involved in clearing plaques through increasing MMP-9 activity. Yan et al.²¹⁹ demonstrated in brain slices of APP/PS1 mice in situ that MMP-9 digests both fibrillary Aβ₄₂ as well as compact amyloid plaques. In another study, Wang et al.²³⁴ examined in vivo the relationship between MMP-9 protein expression and Aβ plaques by deleting the MMP-9 gene in APP/PS1 mice. In the cortex and hippocampus of these APP/PS1 MMP-9 KO mice, Aβ plaques were larger in size and number compared to APP/PS1 mice with functional MMP-9. Finally, Liao et al.²³⁵ demonstrated that MT1-MMP degrades both soluble and fibrillary Aβ peptide in a time-dependent manner in vitro and this effect is inhibited by the MMP inhibitors GM6001 and TIMP-2. The authors also showed that MT1-MMP degrades brain fibrillary amyloid plaques in another AD mouse model (hAPPSwDI mice) in situ.

These findings suggest an inverse relationship between MMP-2/MMP-9 and Aβ, where one would expect low MMP levels in the AD brain with high Aβ load. However, MMPs are upregulated in the AD brain, which is counterintuitive considering the above-mentioned findings. One explanation for this could be that MMP-mediated Aβ degradation is too low to prevent Aβ brain accumulation. While MMPs might be involved in processing Aβ and clearing plaques, they are likely not major players in this process.^219,229

Thus, MMPs are increased in the AD brain, but the role of MMPs in AD is unknown. The current literature is unclear on whether changes in MMP levels contribute to AD progression or might have beneficial effects on the disease. While it is possible that MMPs play no major role in AD, studies show that MMPs could potentially be involved in processing Aβ and AD progression.

Parkinson’s disease

PD is a neurodegenerative movement disorder with more than six million patients worldwide.²³⁶ PD was first described by James Parkinson²³⁷ in 1817, but to this day, many aspects of the disease are unknown. At the molecular level, PD is characterized by accumulation of α-synuclein in dopaminergic neurons, resulting in the formation of Lewy bodies, cell damage, and neuronal death of dopaminergic neurons. PD is also accompanied by neuroinflammation aggravating the disease.^238,239

In recent years, MMPs have received some attention in the PD field. Lorenzl et al.²⁴⁰ determined protein expression and activity levels of MMPs-1, -2, and -9 in postmortem brain tissue from PD patients and age-matched control individuals. While the authors observed no change in MMP-1 and MMP-9, they detected a 50% reduction in MMP-2 activity levels in the substantia nigra of PD patients compared to control individuals. The authors suggested reduced MMP-2 activity could help neurite outgrowth of surviving dopaminergic neurons in the substantia nigra.²⁴⁰

In addition to MMPs-1, -2, and -9, PD research has focused mainly on MMP-3. Three mechanisms have been suggested on how MMP-3 could be involved in PD. First, using in vitro cell lines and primary cultures of dopaminergic neurons from rat, Choi et al.²⁴¹ observed that active MMP-3 is released from apoptotic dopaminergic neurons and that MMP-3 protein levels are higher compared to healthy, non-apoptotic dopaminergic neurons. Using the MTPT mouse PD model, Chung et al.²³⁸ found increased MMP-3 protein and activity levels compared to control mice resulting in apoptosis and cell death. MMP-3 was also involved in caspase-3 activation, specifically in apoptotic signaling upstream of caspase-3 and downstream of c-Jun N-terminal kinases.^{238,241–244}

Second, MMP-3 might potentially be involved in α-synuclein cleavage. Sung et al.²⁴⁵ showed that MMP-3 cleaves purified α-synuclein in vitro and that α-synuclein aggregation increased in the presence of MMP-3-cleaved α-synuclein fragments compared to a solution without these fragments. Furthermore, aggregates of α-synuclein fragments were more toxic in cell viability assays compared to aggregates of non-fragmented α-synuclein. Sung et al.²⁴⁵ also demonstrated that MMPs-1, -2, -9, and MT1-MMP cleave purified α-synuclein as well, however, they were less effective than MMP-3. Moreover, Kim et al.²⁴⁶ showed in microglia cultures and in a 6-OHDA mouse PD model that α-synuclein-induced MT1-MMP expression supports cell migration of reactive microglia into the pathological region, which accelerated PD pathogenesis.

Third, recent data indicate involvement of neuroinflammatory events such as microglial activation, T-leukocyte infiltration, and blood–brain barrier dysfunction in PD.^{238,247–249} This is consistent with data from Chung et al.,²³⁸ who showed infiltration of peripheral immune cells and brain uptake of FITC-albumin (70 kDa) in the MPTP mouse PD model, indicating neuroinflammation and barrier leakage. The authors showed in MMP-3 KO mice that barrier leakage was attenuated and the number of immune cells infiltrating the substantia nigra was decreased, demonstrating MMP-3 involvement in the MPTP mouse model.

In conclusion, MMP-3 seems to be involved in dopaminergic neurodegeneration, neuroinflammation, and barrier leakage in PD. More research will have to clarify the role MMPs play in PD and if MMP inhibition could be a valid therapeutic strategy.

Brain cancer

In 2012, more than 250,000 people were newly diagnosed with brain cancer and nearly 190,000 patients died worldwide.^250,251 Survival rates for adult brain cancer patients are low. Even with aggressive therapy, median survival of patients with glioblastoma multiforme, the most common and deadliest malignant brain cancer, is only 12–17 months.^252–254 Thus, to effectively treat brain cancer, new approaches and interventions are desperately needed.

MMPs are potential therapeutic targets in cancer because they play a role in cancer biology. In this regard, mRNA and protein overexpression of MMPs-1, -2, -3, -7, -8, -9, -13, and MT1-MMP has been observed in many malignant peripheral and CNS tumors, and a correlation between MMP expression, tumor aggressiveness, tumor stage, and prognosis has been demonstrated.^255,256 Indeed, secreted MMPs (MMPs-1, -2, -3, 7-, -8, -9, -10, -11, -13) as well as membrane-bound MT-MMPs are critical for the formation of cancer metastases, their invasion into the brain, and the formation of secondary tumors, and MMPs participate in most of the steps of the metastasis process (Figure 7).^84,92

Formation of metastatic cells at the primary tumor: Ii et al.²⁵⁶ showed in primary tumors that MMP-7 converts the transmembrane cell–cell adhesion protein E-cadherin into a soluble protein resulting in ineffective binding between tumor cells, which allows cancer cells to split from the primary tumor and form metastases that can enter the bloodstream.

Intravasation of metastatic cells into the blood circulation: Juncker-Jenson et al.²⁵⁷ found that MMP-1 participates in the intravasation of metastatic cells from a human HEp3 epidermoid carcinoma graft in chick embryos. The authors showed that MMP-1 regulating endothelial permeability and transendothelial migration supported tumor invasion by activating the endothelial non-tumor/non-matrix receptor PAR1. The authors also used grafts with naturally acquired or experimentally induced MMP-1 deficiency and found that intravasation was decreased by more than 80%.²⁵⁷

Metastatic cell adhesion to the brain capillary endothelium: it is unclear if MMPs participate in this step of the metastasis process but given the various functions MMPs have it is conceivable. Hummel et al.²⁵⁸ showed that MMPs-2, -3, -9, and -12 are involved in the shedding of cell adhesion molecules (e.g., vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1) from the plasma membrane of human brain endothelial cell cultures after TNF-α-induced MMP upregulation. MMPs might also contribute to shedding CD44 in metastatic cell adhesion to the capillary endothelium.²⁵⁹ This is particularly interesting since CD44 is a cell-surface glycoprotein in endothelial cells, leukocytes, and many metastatic cancer cells, where it presents selectins thereby facilitating adhesion of the host cell to the brain capillary endothelium.^260–262

Metastatic cell extravasation: MMPs contribute to metastatic cell extravasation and facilitate paracellular transmigration of tumor cells across brain capillary endothelial cells in vitro and the blood–brain barrier in vivo.^{183,263–265} Lee et al.²⁶⁴ showed that MMP-2 contributes to the migration of breast cancer cells across the cell monolayer of an in vitro human blood–brain barrier model. Lorger and Felding-Habermann²⁶⁵ demonstrated in vivo that breast cancer cells injected into the left internal carotid artery of BALB/c mice resulted in brain metastases. For paracellular extravasation, endothelial cell–cell contacts have to be loosened so that metastatic cells can migrate across the endothelium. This requires junction proteins to be degraded. Indeed, MMPs proteolyze tight junction and adherence junction proteins, thereby opening the paracellular route.^{99,100,255,263} Feng et al.⁹⁹ demonstrated in leukemic BALB/c nu/nu mice that leukemic cells secrete MMP-2 and MMP-9, which degraded the tight junction proteins zonula occludens-1, claudin-5, and occludin. Thus, MMPs are critical for leukemic and other cancer cells to cross the capillary endothelium and access the brain.

Metastatic cell adhesion to the ECM: several membrane-type MMPs (MT1-, 2-, 3-, 5-MMP) shed the cell-surface glycoprotein CD44, which is critical in metastatic cell adhesion to the luminal endothelial membrane and the ECM on the basolateral side of the endothelium.^{259,266–268} CD44 is involved in presenting cytokines, chemokines, cell adhesion molecules, growth factors, and other proteins such as MMP-2 and MMP-9 to receptors on metastatic and endothelial cells and mediates signaling that regulates metastatic cell migration and invasion.^267,269 CD44 also interacts with ECM proteins like fibronectin, thereby supporting metastatic cell adhesion to the ECM.²⁷⁰

MMPs in ECM proteolysis: localized opening of the ECM (Figure 7) is necessary for metastatic cells to bypass it and MMP-2 and MMP-9 seem to support this process through ECM proteolysis. Wang et al.²⁷¹ compared MMP-2 and MMP-9 levels in human glioma samples with those from control individuals and showed that MMP-2 and MMP-9 levels in gliomas were increased and correlated with the degree of glioma malignancy. The authors also showed that MMP-2 and MMP-9 staining in gliomas was localized to the cytoplasm of tumor cells, endothelial cells, and their ECM. They concluded that by degrading the ECM, MMP-2 and MMP-9 are determining factors of glioma invasiveness and angiogenesis.²⁷¹ Other studies in cancer cells showed that CD44 captures MMP-2 and MMP-9 at the tumor cell surface, where MMPs then locally digest the ECM surrounding the tumor cells during extravasation.^272,273 Other MMPs might also contribute to ECM proteolysis. While conclusive in vivo proof in support of this is still missing, there are many findings that point in this direction. Shiomi et al.²⁷⁶ reported increased MT1-MMP mRNA and protein levels in resected glioblastoma tissue compared to non-tumor control tissue. MT1-MMP levels correlated with pro-MMP-2 activation and tumor malignancy and the authors speculated that MMP-2 and MT1-MMP likely contribute to glioma invasion through degrading brain ECM proteoglycans and glia limitans. Nakada et al.²⁷⁴ observed increased MT1-MMP and MT2-MMP mRNA and protein levels in astrocytomas compared to control brain tissue and concluded that both activate MMP-2, which then degrades the ECM. Other groups detected that MT3-MMP directly cleaves ECM components such as type III collagen, proteoglycan, and interstitial collagens.^275,276 These findings are key for cancer metastasis and invasion since they result in ECM digestion.

Figure 7.

MMPs in cancer metastasis. MMPs participate in most steps of the cancer metastasis process. (1) Formation of metastatic cells at the primary tumor. (2) Intravasation of metastatic cells into the blood circulation. (3–6) Extravasation of metastatic cells across the blood–brain barrier into the brain. (7) Tumor cell migration in the brain. (8) MMPs contribute to the tumor microenvironment and tumor angiogenesis.

Metastatic cell migration: for a secondary tumor to form, cancer cells require space when settling in new tissues. This space is likely generated through MMP-mediated ECM degradation and remodeling. In this context, Belien et al.²⁷⁷ showed MT1-MMP digesting axonal myelin proteins that inhibit cell migration and neurite outgrowth. Given that invasive glioma cells preferentially migrate along white matter fiber tracts and that MT1-MMP degrades cell migration-inhibiting proteins that are embedded within white matter fiber tracts, these observations suggest that MT1-MMP facilitates cancer cell migration, thereby increasing glioma malignancy.

MMPs in the tumor microenvironment and tumor angiogenesis: increasing evidence suggests MMPs establish and maintain a microenvironment that supports tumor survival and growth. MMPs facilitate cancer cell proliferation by regulating cytokines, growth factors, and cell adhesion molecules that attract tumor cells and support metastatic cell spreading.²⁵⁵ Thus, increased MMP levels are considered to correlate with increased tumor malignancy, and studies report that MMP mRNA, protein, and activity levels are increased in cancer.^255,256 Xu et al.²⁷⁸ observed increased MMP-1 protein levels in gliomas compared to levels in resected brain tissue from epilepsy patients. Levels of MMPs-1, -2, -3, -7, -8, -9, -13, MT1-, 2-, 3-, 5-, and MT6-MMP were also increased in brain tumors compared to non-cancerous brain tissue.^{253,274,279,280} The same MT-MMPs activate proMMP-2 and proMMP-13, and activity and protein expression levels of those MT-MMPs correlate with pro-MMP-2 activation in gliomas, and thus, with tumor malignancy.^256,279,280 MMPs also contribute to angiogenesis, which is critical for the tumor microenvironment because blood vessels supply tumors with oxygen and nutrients, thereby supporting tumor survival, growth, and increasing tumor malignancy.^58,110,281 Angiogenesis is based on endothelial cell migration into surrounding connective tissues and MMPs are critical in this process.^282,283 MMPs degrade the ECM, release ECM-sequestered pro-angiogenic compounds such as vascular endothelial growth factor, process growth factors, integrins, and adhesion molecules, thereby balancing pro- and anti-angiogenesis.^58,110,281 Tumor-induced angiogenesis is important to sustain growth of solid tumors and the functional roles of MMPs in tumor angiogenesis are well established.^85,93 For example, MMPs help recruit pericytes, which are localized in tumor blood vessels and are critical for the development of a functional vascular network. MMPs participate in several steps of the pericyte recruitment process. First, MMPs degrade the ECM to allow pericyte invasion. Second, MMPs stimulate pericyte proliferation and protect pericytes from apoptosis. Third, MMPs help recruit bone marrow-derived stem cells, which differentiate into pericytes.⁸⁶ Angiogenesis is essential for tumor growth and blocking angiogenesis is considered a valid strategy to control malignant tumors. Thus, MMPs can be beneficial in cancer due to their anti-angiogenic effect that is based on processing growth factors, integrins, and adhesion molecules. For example, tumor angiogenesis is reduced in integrin-α1-null mice compared to wild-type mice.⁸⁷ Integrin-α1-null mice overexpress MMP-9, which cleaves angiostatin from plasminogen, and angiostatin inhibits endothelial cell growth, resulting in tumor growth inhibition.⁸⁷ MMPs also influence the tumor microenvironment by increasing the permeability of the vascular endothelium in brain tumors, which is then referred to as “blood-tumor barrier”. Thus, the blood-tumor barrier is leaky compared to the healthy, intact blood–brain barrier, which helps supply the tumor with an increasing demand of nutrients.^284,285 Noell et al.²⁸⁶ showed increased MMP-2, -3, and -9 immunoreactivity in brain slices of human primary glioblastomas compared to non-tumor brain tissue and assumed blood–brain barrier leakage in this area. Studies from other groups detected increased proMMP-2 and proMMP-9 levels in the CSF of dogs with intracranial tumors compared to healthy dogs.^287,288 Turba et al.²⁸⁸ attributed increased CSF proMMP-9 levels to the recruitment of leukocytes by the tumors and speculated that MMP-9 likely facilitated leukocytes bypassing the blood–brain barrier in order to reach the tumor, and that those leukocytes secreted MMP-9 into the CSF.

In conclusion, MMPs are critical in many aspects of brain cancer. Their main role lies in facilitating metastasis and angiogenesis, which makes them interesting targets for brain cancer treatment and prevention of secondary brain tumors.

MMP inhibition as a therapeutic strategy

Pharmacological inhibition of MMPs is a potential therapeutic strategy for the treatment of CNS disorders. MMP inhibitors such as marimastat, batimastat, and doxycycline could potentially be used in patients. Currently, however, the only FDA-approved MMP inhibitor is the tetracycline analogue doxycycline (Periostat®) for the treatment of periodontal disease.^289–291 The major obstacle hindering the development of MMP inhibitors for clinical use in patients is our lack of knowledge and understanding of the complex MMP biology and the role MMPs play in CNS disorders such as cerebral aneurysm, epilepsy, AD, and PD. Nonetheless, there is a wealth of preclinical data that support MMP inhibition as a treatment strategy in MS, stroke, and brain cancer.

First, a number of MMP inhibitors decrease the incidence and severity of EAE in animal MS models.^{145,292–295} The MMP inhibitor Ro31-9730 suppressed EAE in rats,²⁹⁵ and minocycline reduced MMP-9 protein and activity in T cells and suppressed EAE in mice.²⁹² Second, preclinical data from various mouse and rat cancer models including colon and breast cancer showed that batimastat reduced tumor growth, number, and occurrence of secondary lung and lymphatic metastases.^296–299 Third, MMP inhibition with GM6001 or BB-94 in rodent stroke models shortly (hours) after stroke reduced edema, infarct size, and the number of hemorrhagic events.^{180,185,300,301} Long-term (days) MMP inhibition with the MMP-inhibitor BB-1101 for up to 48 h after stroke in rats reduced barrier leakage, but function in neurologic and behavioral tests did not improve.³⁰² Inhibiting MMPs with FN-439 or BB-94 in a rat stroke model for one week even aggravated ischemic brain injury and seemed to halt functional recovery.¹⁹¹

Even though MMP inhibition seems promising in animal models, this has not or only partially been demonstrated in clinical studies. In an MS trial, 16 patients with relapsing-remitting MS were treated with a doxycycline/interferon combination for 4 months (NCT00246324³⁰³). Doxycycline/interferon treatment reduced brain lesions, which correlated with reduced MMP-9 serum levels and improved posttreatment EDDS values with only one patient relapsing. Overall, doxycycline/interferon treatment was considered effective, safe, and well-tolerated; it was concluded that a trial with a larger patient cohort should be conducted. However, a report on a follow-up trial has thus far not been published.

In a stroke trial, minocycline was given with/without tPA to 60 patients within 6 h after acute ischemic stroke (NCT00630396³⁰⁴). The mean baseline NIH Stroke Scale score was 8.5 ± 5.8 (moderate stroke). Minocycline did not cause severe hemorrhages in tPA-treated patients, was concluded to be safe and well-tolerated up to 10 mg/kg, i.v. alone and in combination with tPA, and was considered ideal for a tPA combination therapy. In another clinical study, Lampl et al.³⁰⁵ showed that minocyclin significantly improved patient outcomes. Specifically, NIH Stroke Scale and Rankin Scale scores were significantly lowered, and the Barthel Index was significantly increased. Moreover, participants are currently being recruited for a study testing the safety and efficacy of minocycline in acute cerebral hemorrhage (MACH trial; NCT01805895).

Lastly, several clinical studies testing MMP inhibition in brain cancer have been conducted. In two phase-II trials, a combination of marimastat and temozolomide was tested in recurrent GBM and gliomas.^306,307 These trials showed that maristamat/temozolomide appears to increase progression-free survival (PFS): at six months, PFS was 39% for GBM (target PFS: 10%) and 54% for glioma (target PFS: 40%) compared to temozolomide treatment alone. Other brain cancer trials with MMP inhibitors showed no improvement. Prinomastat/temozolomide compared to temozolomide alone did neither improve the one-year survival rate nor PFS (NCT00004200, Pfizer). Likewise, phase I and II trials with the MMP inhibitor COL-3 in recurrent high-grade gliomas do not warrant further studies (NCT00004147^308,309). In addition, clinical trials testing more than 50 MMP inhibitors for the treatment of cancer have all failed.^310–322 Vandenbrouke and Libert³¹⁹ summarized the reasons for failure, which included the complexity of MMP biology and lack of MMP knowledge. The authors also listed suboptimal trial design, inadequate clinical endpoints, use of metabolically unstable MMP inhibitors, poor oral bioavailability, no effect, toxic adverse effects, and discrepancies between pre-clinical animal models and human patients.³¹⁹

In summary, while much effort has gone into MMP research over the decades, the field is still far away from a therapeutic breakthrough. Thus, more work remains to be done to test if MMP inhibition is a viable therapeutic strategy.

Conclusion and future perspectives

Here, we review and summarize current knowledge and understanding of the role MMPs play in health and disease in the brain, particularly the blood–brain barrier. While we know that MMPs participate in important neurophysiological functions and have basic understanding of their role in pathological conditions such as neuroinflammation, MS, stroke, and brain cancer, we know little about MMPs in other CNS disorders such as cerebral aneurysms, epilepsy, AD, and PD.

The picture that emerges is complex: a large number of diverse MMPs covers a broad spectrum of different functions in various physiological and pathophysiological processes resulting in a wide range of effects with varying impact. These MMP effects can be both beneficial and detrimental in the same disease depending on location, time point, and other factors. Thus, MMP expression and functional activity vary significantly and are context-dependent. However, one pattern all the diseases mentioned here have in common is neuroinflammation that involves MMPs.

From what we know today, MMP inhibition as an (additional) therapeutic option is problematic and has a history of failure, but is still discussed for the treatment of CNS disorders. Considering the knowledge gap in MMPs, more research needs to be done while avoiding the mistakes of the past. Specifically, research mainly focused on MMP-2 and MMP-9 needs to be expanded to other MMPs to understand the role each MMP plays in health and disease and to gain better insight into MMP biology in general. For example, elucidating the mechanisms responsible for MMP regulation could provide new opportunities for therapeutic intervention. In addition, specific and selective MMP inhibitors that can be used safely with no or only minor adverse effects need to be identified.

Clearly, we are only beginning to understand MMP biology in the larger context of health and disease. In the future, it will be critical to assess if MMPs can be attractive therapeutic targets to advance the treatment of neurodegenerative diseases.

Footnotes

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute of Neurological Disorders and Stroke: NINDS/NIH R01NS079507 (PI: BB, Co-I: AMSH) and the National Institute on Aging: NIA/NIH R01AG039621 (PI: AMSH, Co-I: BB) of the National Institutes of Health.

Acknowledgements

We thank Ms Paula Thomason for editorial assistance and Mr Tom Dolan for graphical assistance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author’s contributions

RGR and BB wrote the manuscript; AMSH contributed to the content of the manuscript and critically revised the text, tables and figures for scientific content.

References

Stocker

Grams

Baumann

. The metzincins – topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci 1995; 4: 823–840.

Page-McCaw

Ewald

Werb

. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 2007; 8: 221–233.

Gross

Lapiere

. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci U S A 1962; 48: 1014–1022.

Eisen

Jeffrey

Gross

. Human skin collagenase. Isolation and mechanism of attack on the collagen molecule. Biochim Biophys Acta 1968; 151: 637–645.

Harper

Bloch

Gross

. The zymogen of tadpole collagenase. Biochemistry 1971; 10: 3035–3041.

Bauer

Stricklin

Jeffrey

. Collagenase production by human skin fibroblasts. Biochem Biophys Res Commun 1975; 64: 232–240.

Woessner

. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991; 5: 2145–2154.

Van Wart

Birkedal-Hansen

. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 1990; 87: 5578–5582.

Benoit de Coignac

Elson

Delneste

. Cloning of MMP-26. Eur J Biochem 2000; 267: 3323–3329.

10.

Llano

Pendas

Knauper

. Identification and structural and functional characterization of human enamelysin (MMP-20). Biochemistry 1997; 36: 15101–15108.

11.

Lohi

Wilson

Roby

. Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 2001; 276: 10134–10144.

12.

Nagase

Visse

Murphy

. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69: 562–573.

13.

Paiva

Granjeiro

. Bone tissue remodeling and development: focus on matrix metalloproteinase functions. Arch Biochem Biophys 2014; 561: 74–87.

14.

Sternlicht

Werb

. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17: 463–516.

15.

Sabeh

Ota

Holmbeck

. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J Cell Biol 2004; 167: 769–781.

16.

Song

Zhang

. In vivo processing of CXCL5 (LIX) by matrix metalloproteinase (MMP)-2 and MMP-9 promotes early neutrophil recruitment in IL-1beta-induced peritonitis. J Immunol 2013; 190: 401–410.

17.

Lee

Kim

Rogowska

. Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 2006; 26: 3491–3495.

18.

Rodríguez

Morrison

Overall

. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta 2010; 1803: 39–54.

19.

Ota

X-Y

. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci U S A 2009; 106: 20318–20323.

20.

Cauwe

Van den Steen

Opdenakker

. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 2007; 42: 113–185.

21.

Morrison

Butler

Rodriguez

. Matrix metalloproteinase proteomics: substrates, targets, and therapy. Curr Opin Cell Biol 2009; 21: 645–653.

22.

Van Lint

Libert

. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol 2007; 82: 1375–1381.

23.

Manicone

Harju-Baker

Johnston

. Epilysin (matrix metalloproteinase-28) contributes to airway epithelial cell survival. Respirat Res 2011; 12: 144.

24.

Yong

Power

Forsyth

. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2001; 2: 502–511.

25.

Schubert-Unkmeir

Konrad

Slanina

. Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: a role for MMP-8. PLoS Pathog 2010; 6: e1000874.

26.

Hartmann

El-Gindi

Lohmann

. TIMP-3: a novel target for glucocorticoid signaling at the blood–brain barrier. Biochem Biophys Res Commun 2009; 390: 182–186.

27.

Deem

Cook-Mills

. Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species. Blood 2004; 104: 2385–2393.

28.

Park

Matrisian

Kells

. Mutational analysis of the transin (rat stromelysin) autoinhibitor region demonstrates a role for residues surrounding the “cysteine switch”. J Biol Chem 1991; 266: 1584–1590.

29.

Rajagopalan

Meng

Ramasamy

. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 1996; 98: 2572–2579.

30.

Moon

S-K

Cha

B-Y

Kim

C-H

. ERK1/2 mediates TNF-α-induced matrix metalloproteinase-9 expression in human vascular smooth muscle cells via the regulation of NF-κB and AP-1: involvement of the ras dependent pathway. J Cell Physiol 2004; 198: 417–427.

31.

Cheng

Wei

Xiurong

. IL-17 Stimulates migration of carotid artery vascular smooth muscle cells in an MMP-9 dependent manner via p38 MAPK and ERK1/2-dependent NF-κB and AP-1 activation. Cell Mol Neurobiol 2009; 29: 1161–1168.

32.

Wang

. Interleukin 17A promotes gastric cancer invasiveness via NF-?B mediated matrix metalloproteinases 2 and 9 expression. PloS ONE 2014; 9: e96678.

33.

Balasubramanian

Fan

Messmer-Blust

. The interferon-γ-induced GTPase, mGBP-2, inhibits tumor necrosis factor α (TNF-α) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-κB and Rac protein. J Biol Chem 2011; 286: 20054–20064.

34.

Woo

C-H

Lim

J-H

Kim

J-H

. Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in raw 264.7 cells. J Immunol 2004; 173: 6973–6980.

35.

Green

Dholakia

Janczar

. Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFalpha, NFkappaB, p38 and caspase 8 dependent pathways. J Neuroinflamm 2011; 8: 46.

36.

Chakraborti

Mandal

Das

. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 2003; 253: 269–285.

37.

Yan

Boyd

. Regulation of matrix metalloproteinase gene expression. J Cell Physiol 2007; 211: 19–26.

38.

Peters

Kassam

St Jean

. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke 1999; 30: 2612–2616.

39.

Rosenberg

. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 2009; 8: 205–216.

40.

Abbott

Ronnback

Hansson

. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7: 41–53.

41.

Martin

Mansel

Jiang

. Antagonistic effect of NK4 on HGF/SF induced changes in the transendothelial resistance (TER) and paracellular permeability of human vascular endothelial cells. J Cell Physiol 2002; 192: 268–275.

42.

Romero

Radewicz

Jubin

. Changes in cytoskeletal and tight junctional proteins correlate with decreased permeability induced by dexamethasone in cultured rat brain endothelial cells. Neurosci Lett 2003; 344: 112–116.

43.

Zlokovic

. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008; 57: 178–201.

44.

Cambier

Gline

. Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes. Am J Pathol. 166: 1883–1894.

45.

Liebner

Czupalla

Wolburg

. Current concepts of blood-brain barrier development. Int J Dev Biol 2011; 55: 467–476.

46.

Verslegers

Van Hove

Dekeyster

. MMP-2 mediates Purkinje cell morphogenesis and spine development in the mouse cerebellum. Brain Struct Funct 2015; 220: 1601–1617.

47.

Larsen

DaSilva

Conant

. Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice. J Neurosci 2006; 26: 2207–2214.

48.

Amalinei

Caruntu

Giusca

. Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol 2010; 51: 215–228.

49.

Candelario-Jalil

Yang

Rosenberg

. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 2009; 158: 983–994.

50.

Rosenberg

. Matrix metalloproteinases in neuroinflammation. Glia 2002; 39: 279–291.

51.

Rosenberg

. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 2009; 8: 205–216.

52.

Yang

Rosenberg

. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res 2015; 1623: 30–38.

53.

Zhang

Kojic

Tsang

. Distinct roles for metalloproteinases during traumatic brain injury. Neurochem Int 2016; 96: 46–55.

54.

Lee

Kermani

Teng

. Regulation of cell survival by secreted proneurotrophins. Science 2001; 294: 1945–1948.

55.

Gurney

Estrada

Rosenberg

. Blood–brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol Dis 2006; 23: 87–96.

56.

Rosenberg

Estrada

Dencoff

. Tumor necrosis factor-α-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res 1995; 703: 151–155.

57.

Rosenberg

Kornfeld

Estrada

. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res 1992; 576: 203–207.

58.

Rundhaug

. Matrix metalloproteinases and angiogenesis. J Cell Mol Med 2005; 9: 267–285.

59.

Ethell

Kinloch

Green

. Metalloproteinase shedding of Fas ligand regulates beta-amyloid neurotoxicity. Curr Biol 2002; 12: 1595–1600.

60.

Stamenkovic

. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 2003; 200: 448–464.

61.

Black

Rauch

Kozlosky

. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997; 385: 729–733.

62.

English

Puente

Freije

. Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. J Biol Chem 2000; 275: 14046–14055.

63.

Kim

Choi

Block

. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB J 2007; 21: 179–187.

64.

Kim

Cho

. Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. J Neurosci 2005; 25: 3701–3711.

65.

Woo

Park

Choi

. Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem 2008; 106: 770–780.

66.

Barkho

Munoz

. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells 2008; 26: 3139–3149.

67.

Sîrbulescu

Ilieş

Zupanc

GKH

. Matrix metalloproteinase-2 and -9 in the cerebellum of teleost fish: functional implications for adult neurogenesis. Mol Cell Neurosci 2015; 68: 9–23.

68.

Chen

Moulder

Tenkova

. Excitotoxic cell death dependent on inhibitory receptor activation. Exp Neurol 1999; 160: 215–225.

69.

Chen

Strickland

. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 1997; 91: 917–925.

70.

Duszyk

Shu

Sawicki

. Inhibition of matrix metalloproteinase MMP-2 activates chloride current in human airway epithelial cells. Can J Physiol Pharmacol 1999; 77: 529–535.

71.

Giancotti

Ruoslahti

. Integrin signaling. Science. 1999; 285: 1028–1032.

72.

Powell

Fingleton

Wilson

. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 1999; 9: 1441–1447.

73.

Hoehna

Uckermann

Luksch

. Matrix metalloproteinase 9 regulates cell death following pilocarpine-induced seizures in the developing brain. Neurobiol Dis 2012; 48: 339–347.

74.

Johnston

Zhang

Silva

. HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Ann Neurol 2001; 49: 230–241.

75.

Jourquin

Tremblay

Decanis

. Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate. Eur J Neurosci 2003; 18: 1507–1517.

76.

Kim

Cho

. The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus. Neurobiol Dis 2009; 36: 169–180.

77.

Vos

Sjulson

Nath

. Cytotoxicity by matrix metalloprotease-1 in organotypic spinal cord and dissociated neuronal cultures. Exp Neurol 2000; 163: 324–330.

78.

Shi

Y-B

Hasebe

. Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development. Pharmacol Therap 2007; 116: 391–400.

79.

Chandler

Miller

Clements

. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J Neuroimmunol 1997; 72: 155–161.

80.

Cossins

Clements

Ford

. Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions. Acta Neuropathol 1997; 94: 590–598.

81.

Matyszak

Perry

. Delayed-type hypersensitivity lesions in the central nervous system are prevented by inhibitors of matrix metalloproteinases. J Neuroimmunol 1996; 69: 141–149.

82.

Opdenakker

Van Damme

. Cytokine-regulated proteases in autoimmune diseases. Immunol Today 1994; 15: 103–107.

83.

Wang

Zhang

. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 2006; 26: 5996–6003.

84.

Folgueras

Pendas

Sanchez

. Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 2004; 48: 411–424.

85.

Handsley

Edwards

. Metalloproteinases and their inhibitors in tumor angiogenesis. Int J Cancer 2005; 115: 849–860.

86.

Chantrain

Henriet

Jodele

. Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer 2006; 42: 310–318.

87.

Pozzi

LeVine

Gardner

. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene 2002; 21: 272–281.

88.

Andries L, Van Hove I, Moons L, et al. Matrix metalloproteinases during axonal regeneration, a multifactorial role from start to finish. Mol Neurobiol. Epub ahead of print 29 February 2016. DOI: 10.1007/s12035-016-9801-x.

89.

Hayashita-Kinoh

Kinoh

Okada

. Membrane-type 5 matrix metalloproteinase is expressed in differentiated neurons and regulates axonal growth. Cell Growth Differ 2001; 12: 573–580.

90.

Tonge

Zhu

Lynham

. Axonal growth towards Xenopus skin in vitro is mediated by matrix metalloproteinase activity. Eur J Neurosci 2013; 37: 519–531.

91.

Vaillant

Meissirel

Mutin

. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum. Mol Cell Neurosci 2003; 24: 395–408.

92.

Deryugina

Quigley

. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 2006; 25: 9–34.

93.

Fingleton

. Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci 2006; 11: 479–491.

94.

Larsen

Wells

Stallcup

. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J Neurosci 2003; 23: 11127–11135.

95.

Ito

Mukaiyama

Itoh

. Degradation of interleukin 1β by matrix metalloproteinases. J Biol Chem 1996; 271: 14657–14660.

96.

McQuibban

Gong

J-H

Tam

. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 2000; 289: 1202–1206.

97.

Baeten

Akassoglou

. Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev Neurobiol 2011; 71: 1018–1039.

98.

Rascher

Fischmann

Kroger

. Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol 2002; 104: 85–91.

99.

Feng

Cen

Huang

. Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PloS ONE 2011; 6: e20599.

100.

Lischper

Beuck

Thanabalasundaram

. Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions. Brain Res 2010; 1326: 114–127.

101.

Zheng

. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood–brain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem 2012; 120: 147–156.

102.

Yang

Estrada

Thompson

. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007; 27: 697–709.

103.

Gorter

Van Vliet

Rauwerda

. Dynamic changes of proteases and protease inhibitors revealed by microarray analysis in CA3 and entorhinal cortex during epileptogenesis in the rat. Epilepsia 2007; 48(Suppl. 5): 53–64.

104.

Nishikawa

Yamaguchi

Yoshitake

. Effects of TNFα and prostaglandin E2 on the expression of MMPs in human periodontal ligament fibroblasts. J Period Res 2002; 37: 167–176.

105.

Hawkes

Taniguchi

. Zymography and reverse zymography for detecting MMPs and TIMPs. Methods Mol Biol 2010; 622: 257–269.

106.

Leber

Balkwill

. Zymography: a single-step staining method for quantitation of proteolytic activity on substrate gels. Analytic Biochem 1997; 249: 24–28.

107.

Kleiner

Stetlerstevenson

. Quantitative zymography: detection of picogram quantities of gelatinases. Analytic Biochem 1994; 218: 325–329.

108.

Chin

Murphy

Werb

. Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates. J Biol Chem 1985; 260: 12367–12376.

109.

Hao

Lopez-Campistrous

. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor–receptor pathway. Circ Res 2004; 94: 68–76.

110.

Stamenkovic

. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000; 14: 163–176.

111.

W-H

Woessner

McNeish

. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 2002; 16: 307–323.

112.

C-J

Liu

Chen

. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. Am J Pathol 2013; 182: 1552–1562.

113.

Yan

Blomme

EAG

. In situ zymography: a molecular pathology technique to localize endogenous protease activity in tissue sections. Veterinary Pathol Online 2003; 40: 227–236.

114.

Keow

Herrmann

Crawford

. Differential in vivo zymography: a method for observing matrix metalloproteinase activity in the zebrafish embryo. Matrix Biol 2011; 30: 169–177.

115.

Bell

Winkler

Singh

. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 2012; 485: 512–516.

116.

WHO. Atlas: Multiple sclerosis resources in the world 2008, Geneva: WHO, 2008.

117.

Compston

Coles

. Multiple sclerosis. Lancet 2008; 372: 1502–1517.

118.

Agrawal

Anderson

Durbeej

. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 2006; 203: 1007–1019.

119.

Buhler

Samara

Guzman

. Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis. BMC Neurosci 2009; 10: 17.

120.

Galboiz

Shapiro

Lahat

. Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclerosis patients. Ann Neurol 2001; 50: 443–451.

121.

Lee

Palace

Stabler

. Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain 1999; 122(Pt 2): 191–197.

122.

Leppert

Leib

Grygar

. Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae. Clin Infect Dis 2000; 31: 80–84.

123.

Guo

Lin

. Evaluation of a rat model of experimental autoimmune encephalomyelitis with human MBP as antigen. Cell Mol Immunol 2004; 1: 387–391.

124.

Kieseier

Kiefer

Clements

. Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis. Brain 1998; 121(Pt 1): 159–166.

125.

Nygardas

Hinkkanen

. Up-regulation of MMP-8 and MMP-9 activity in the BALB/c mouse spinal cord correlates with the severity of experimental autoimmune encephalomyelitis. Clin Exp Immunol 2002; 128: 245–254.

126.

Pagenstecher

Stalder

Kincaid

. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states. Am J Pathol 1998; 152: 729–741.

127.

Weaver

Goncalves da Silva

Nuttall

. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization. FASEB J 2005; 19: 1668–1670.

128.

Werner

Dotzlaf

Smith

. MMP-28 as a regulator of myelination. BMC Neurosci 2008; 9: 83.

129.

Toft-Hansen

Babcock

Millward

. Downregulation of membrane type-matrix metalloproteinases in the inflamed or injured central nervous system. J Neuroinflammation 2007; 4: 24.

130.

Dubois

Masure

Hurtenbach

. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J Clin Invest 1999; 104: 1507–1515.

131.

Esparza

Kruse

Lee

. MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity. FASEB J 2004; 18: 1682–1691.

132.

Anthony

Ferguson

Matyzak

. Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathol Appl Neurobiol 1997; 23: 406–415.

133.

Bar-Or

Nuttall

Duddy

. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 2003; 126: 2738–2749.

134.

Kanesaka

Mori

Hattori

. Serum matrix metalloproteinase-3 levels correlate with disease activity in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2006; 77: 185–188.

135.

Kouwenhoven

Ozenci

Gomes

. Multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes. J Autoimmun 2001; 16: 463–470.

136.

Lindberg

De Groot

Montagne

. The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis. Brain 2001; 124: 1743–1753.

137.

Zeng

Zhao

. Glatiramer acetate inhibits degradation of collagen II by suppressing the activity of interferon regulatory factor-1. Biochem Biophys Res Commun 2014; 448: 323–328.

138.

Vos

van Haastert

de Groot

. Matrix metalloproteinase-12 is expressed in phagocytotic macrophages in active multiple sclerosis lesions. J Neuroimmunol 2003; 138: 106–114.

139.

Leppert

Ford

Stabler

. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 1998; 121(Pt 12): 2327–2334.

140.

Lichtinghagen

Seifert

Kracke

. Expression of matrix metalloproteinase-9 and its inhibitors in mononuclear blood cells of patients with multiple sclerosis. J Neuroimmunol 1999; 99: 19–26.

141.

Liuzzi

Trojano

Fanelli

. Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis. Mult Scler 2002; 8: 222–228.

142.

Waubant

Goodkin

Bostrom

. IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS. Neurology 2003; 60: 52–57.

143.

Waubant

Goodkin

Gee

. Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 1999; 53: 1397–1401.

144.

Alvarez

Teale

. Multiple expression of matrix metalloproteinases in murine neurocysticercosis: implications for leukocyte migration through multiple central nervous system barriers. Brain Res 2008; 1214: 145–158.

145.

Graesser

Mahooti

Madri

. Distinct roles for matrix metalloproteinase-2 and alpha4 integrin in autoimmune T cell extravasation and residency in brain parenchyma during experimental autoimmune encephalomyelitis. J Neuroimmunol 2000; 109: 121–131.

146.

Liu

Hendren

Qin

. Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem 2009; 108: 811–820.

147.

Reijerkerk

Kooij

van der Pol

. Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells. FASEB J 2006; 20: 2550–2552.

148.

Rosenberg

Yang

. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 2007; 22: E4.

149.

Zozulya

Reinke

Baiu

. Dendritic cell transmigration through brain microvessel endothelium is regulated by MIP-1alpha chemokine and matrix metalloproteinases. J Immunol 2007; 178: 520–529.

150.

Maeda

Sobel

. Matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions. J Neuropathol Exp Neurol 1996; 55: 300–309.

151.

van Horssen

Vos

Admiraal

. Matrix metalloproteinase-19 is highly expressed in active multiple sclerosis lesions. Neuropathol Appl Neurobiol 2006; 32: 585–593.

152.

Hansmann

Herder

Kalkuhl

. Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis. Acta Neuropathol 2012; 124: 127–142.

153.

Goncalves DaSilva

Liaw

Yong

. Cleavage of osteopontin by matrix metalloproteinase-12 modulates experimental autoimmune encephalomyelitis disease in C57BL/6 Mice. Am J Pathol 2010; 177: 1448–1458.

154.

Keedy

. An overview of intracranial aneurysms. McGill J Med 2006; 9: 141–146.

155.

Novitzke

. The basics of brain aneurysms: a guide for patients. J Vasc Intervent Neurol 2008; 1: 89–90.

156.

Kaku

Watarai

Kokuzawa

. Treatment of cerebral aneurysms: surgical clipping and coil embolization. Intervent Neuroradiol 2007; 13: 68–72.

157.

Bruno

Todor

Lewis

. Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 1998; 89: 431–440.

158.

Chyatte

Lewis

. Gelatinase activity and the occurrence of cerebral aneurysms. Stroke 1997; 28: 799–804.

159.

Kim

Singh

Huang

. Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 1997; 41: 642–666. discussion 6–7.

160.

Perrotta

Sciangula

Aquila

. Matrix metalloproteinase-9 expression in calcified human aortic valves: a histopathologic, immunohistochemical, and ultrastructural study. Appl Immunohistochem Mol Morphol 2016; 24: 128–137.

161.

Zhao

Y-G

Meng

F-X

B-W

. Gelatinases promote calcification of vascular smooth muscle cells by up-regulating bone morphogenetic protein-2. Biochem Biophys Res Commun 2016; 470: 287–293.

162.

Bhatia

Sekula

Quigley

. Role of calcification in the outcomes of treated, unruptured, intracerebral aneurysms. Acta Neurochirurg 2011; 153: 905–911.

163.

Thompson

Baxter

. MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial. Ann N Y Acad Sci 1999; 878: 159–178.

164.

Tsuji

Aoki

Fukuda

. Statins as a candidate of drugs for intracranial aneurysm treatment. Health 2014; 6: 1459–1466.

165.

Nuki

Tsou

Kurihara

. Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension 2009; 54: 1337–1344.

166.

Xiong

Knispel

Dietz

. Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome. J Vasc Surg 2008; 47: 166–172; discussion 72.

167.

Aoki

Kataoka

Ishibashi

. Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor kappaB pathway. Neurosurgery 2009; 64: 357–365. discussion 65–66.

168.

Aoki

Kataoka

Ishibashi

. Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke 2008; 39: 1276–1285.

169.

Yoshimura

Murakami

Saitoh

. Statin use and risk of cerebral aneurysm rupture: a hospital-based case–control study in Japan. J Stroke Cerebrovasc Dis 2014; 23: 343–348.

170.

WHO. The top 10 causes of death – fact sheet N°310, 2014.

171.

Feigin

Forouzanfar

Krishnamurthi

. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383: 245–254.

172.

Zlokovic

. Remodeling after stroke. Nat Med 2006; 12: 390–391.

173.

Clark

Krekoski

Bou

. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett 1997; 238: 53–56.

174.

Sole

Petegnief

Gorina

. Activation of matrix metalloproteinase-3 and agrin cleavage in cerebral ischemia/reperfusion. J Neuropathol Exp Neurol 2004; 63: 338–349.

175.

Wang

Cuzner

. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J Neurosci Res 2002; 69: 1–9.

176.

Rosell

Ortega-Aznar

Alvarez-Sabin

. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006; 37: 1399–1406.

177.

Rosenberg

Navratil

Barone

. Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 1996; 16: 360–366.

178.

Hamann

Liebetrau

Martens

. Microvascular basal lamina injury after experimental focal cerebral ischemia and reperfusion in the rat. J Cereb Blood Flow Metab 2002; 22: 526–533.

179.

Kelly

Shuaib

Todd

. Matrix metalloproteinase activation and blood–brain barrier breakdown following thrombolysis. Exp Neurol 2006; 200: 38–49.

180.

Sumii

. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002; 33: 831–836.

181.

Gasche

Fujimura

Morita-Fujimura

. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab 1999; 19: 1020–1028.

182.

Planas

Sole

Justicia

. Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. Neurobiol Dis 2001; 8: 834–846.

183.

Gidday JM, Gasche YG, Copin J-C, et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia, 2005; 289(2): H558–H568.

184.

Ludewig

Sedlacik

Gelderblom

. Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke. Circ Res 2013; 113: 1013–1022.

185.

Suzuki

Nagai

Umemura

. Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J Thromb Haemost 2007; 5: 1732–1739.

186.

Suzuki

Nagai

Yamakawa

. Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. Blood 2009; 114: 3352–3358.

187.

Rosell

. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 2008; 8: 82–89.

188.

Bergers

Brekken

McMahon

. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2: 737–744.

189.

Hsu

McKeon

Goussev

. Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J Neurosci 2006; 26: 9841–9850.

190.

Nagy

Bozdagi

Matynia

. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 2006; 26: 1923–1934.

191.

Zhao

Wang

Kim

. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 2006; 12: 441–445.

192.

Ngugi

Bottomley

Kleinschmidt

. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 2010; 51: 883–890.

193.

WHO. Epilepsy Fact sheet N°999, http://www.who.int/mediacentre/factsheets/fs999/en/2012.

194.

Shafer

. About epilepsy: The basics, Landover, MD: Epilepsy Foundation, 2014.

195.

Bazil

Morrell

Pedley

Epilepsy. In: Rowland

(ed). Merritt’s neurology, 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005, pp. 990–1008.

196.

Mizoguchi

Nakade

Tachibana

. Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J Neurosci 2011; 31: 12963–12971.

197.

Wilczynski

Konopacki

Wilczek

. Important role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol 2008; 180: 1021–1035.

198.

Quirico-Santos

Nascimento Mello

Casimiro Gomes

. Increased metalloprotease activity in the epileptogenic lesion – lobectomy reduces metalloprotease activity and urokinase-type uPAR circulating levels. Brain Res 2013; 1538: 172–181.

199.

Szklarczyk

Lapinska

Rylski

. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J Neurosci 2002; 22: 920–930.

200.

Takacs

Nyilas

Szepesi

. Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: a possible role in homeostatic synaptic plasticity. Neurochem Int 2010; 56: 799–809.

201.

Wang

Zhang

. Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels. J Neuroinflammation 2013; 10: 80.

202.

Suenaga

Ichiyama

Kubota

. Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures. J Neurol Sci 2008; 266: 126–130.

203.

Konopka

Grajkowska

Ziemianska

. Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia. Epilepsy Res 2013; 104: 45–58.

204.

Zhang

Deb

Gottschall

. Regional and age-related expression of gelatinases in the brains of young and old rats after treatment with kainic acid. Neurosci Lett 2000; 295: 9–12.

205.

Alonso-Nanclares

DeFelipe

. Alterations of the microvascular network in the sclerotic hippocampus of patients with temporal lobe epilepsy. Epilepsy Behav 2014; 38: 48–52.

206.

Kastanauskaite

Alonso-Nanclares

Blazquez-Llorca

. Alterations of the microvascular network in sclerotic hippocampi from patients with epilepsy. J Neuropathol Exp Neurol 2009; 68: 939–950.

207.

Marchi

Oby

Batra

. In vivo and in vitro effects of pilocarpine: relevance to ictogenesis. Epilepsia 2007; 48: 1934–1946.

208.

Rigau

Morin

Rousset

. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 2007; 130: 1942–1956.

209.

Tomkins

Shelef

Kaizerman

. Blood–brain barrier disruption in post-traumatic epilepsy. J Neurol Neurosurg Psychiatry 2008; 79: 774–777.

210.

van Vliet

da Costa Araújo

Redeker

. Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 2007; 130: 521–534.

211.

Marchi

Angelov

Masaryk

. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 2007; 48: 732–742.

212.

Marchi

Teng

Ghosh

. Blood-brain barrier damage, but not parenchymal white blood cells, is a hallmark of seizure activity. Brain Res 2010; 1353: 176–186.

213.

Harkness

Adamson

Sussman

. Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium. Brain 2000; 123(Pt 4): 698–709.

214.

WHO and International AsD. Dementia: a public health priority, http://www.who.int/mental_health/publications/dementia_report_2012/en/2012 (2012, accessed 3 June 2016).

215.

Prince

Bryce

Albanese

. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013; 9: 63e2–75e2.

216.

Brookmeyer

Johnson

Ziegler-Graham

. Forecasting the global burden of Alzheimer’s disease. Alzheimer Dement 2007; 3: 186–191.

217.

Eikelenboom

Bate

Van Gool

. Neuroinflammation in Alzheimer’s disease and prion disease. Glia 2002; 40: 232–239.

218.

Tiraboschi

Hansen

Thal

. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 2004; 62: 1984–1989.

219.

Yan

Song

. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 2006; 281: 24566–24574.

220.

Bonnet

Bernard

. Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer’s disease: evidence for a pro-amyloidogenic role of MT1-MMP. Front Aging Neurosci 2014; 6: 247.

221.

Asahina

Yoshiyama

Hattori

. Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer’s disease brain. Clin Neuropathol 2001; 20: 60–63.

222.

Backstrom

Lim

Cullen

. Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1–40). J Neurosci 1996; 16: 7910–7919.

223.

Bruno

Mufson

Wuu

. Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J Neuropathol Exp Neurol 2009; 68: 1309–1318.

224.

Yoshiyama

Asahina

Hattori

. Selective distribution of matrix metalloproteinase-3 (MMP-3) in Alzheimer’s disease brain. Acta Neuropathol 2000; 99: 91–95.

225.

Horstmann

Budig

Gardner

. Matrix metalloproteinases in peripheral blood and cerebrospinal fluid in patients with Alzheimer’s disease. Int Psychogeriatr 2010; 22: 966–972.

226.

Lorenzl

Albers

Relkin

. Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer’s disease. Neurochem Int 2003; 43: 191–196.

227.

Deb

Gottschall

. Increased production of matrix metalloproteinases in enriched astrocyte and mixed hippocampal cultures treated with beta-amyloid peptides. J Neurochem 1996; 66: 1641–1647.

228.

Hartz

Bauer

Soldner

. Amyloid-beta contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke 2012; 43: 514–523.

229.

Yin

Cirrito

Yan

. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 2006; 26: 10939–10948.

230.

Molecular cell biology of the endothelium in development and diseases. In: Abstracts of the 4th symposium on the biology of endothelial cells, Munich, 18–20 July 2003 (Angiogenesis 2002; 5: 281–354).

231.

Caragounis

Filiz

. Differential modulation of Alzheimer’s disease amyloid beta-peptide accumulation by diverse classes of metal ligands. Biochem J 2007; 407: 435–450.

232.

White

Laughton

. Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J Biol Chem 2006; 281: 17670–17680.

233.

Ridnour

Dhanapal

Hoos

. Nitric oxide-mediated regulation of beta-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem 2012; 123: 736–749.

234.

Wang

Lee

. Mmp-9 attenuates amyloid plaque pathogenesis in APP/PS1 Mice. Am J Pathol 2011; 6(4): S261.

235.

Liao

Van Nostrand

. Degradation of soluble and fibrillar amyloid beta-protein by matrix metalloproteinase (MT1-MMP) in vitro. Biochemistry 2010; 49: 1127–1136.

236.

European Parkinson’s Disease Association (EPDA). Life with Parkinson’s Part 1, Brussels: EPDA, 2014.

237.

Parkinson

. An essay on the shaking palsy, London: Printed by Whittingham and Rowland for Sherwood, Neely and Jones, 1817.

238.

Chung

Kim

Bok

. MMP-3 contributes to nigrostriatal dopaminergic neuronal loss, BBB damage, and neuroinflammation in an MPTP mouse model of Parkinson’s disease. Mediators Inflamm 2013; 2013: 370526.

239.

Van der Perren

Macchi

Toelen

. FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an alpha-synuclein-based rat model for Parkinson’s disease. Neurobiol Aging 2015; 36: 1559–1568.

240.

Lorenzl

Albers

Narr

. Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson’s disease. Exp Neurol 2002; 178: 13–20.

241.

Choi

Kim

Son

. A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. J Neurochem 2008; 106: 405–415.

242.

Cho

Son

Kim

. Doxycycline is neuroprotective against nigral dopaminergic degeneration by a dual mechanism involving MMP-3. Neurotox Res 2009; 16: 361–371.

243.

Kim

Choi

. Matrix metalloproteinase-3 contributes to vulnerability of the nigral dopaminergic neurons. Neurochem Int 2010; 56: 161–167.

244.

Shin

Kim

Lee

. Matrix metalloproteinase-3 is activated by HtrA2/Omi in dopaminergic cells: relevance to Parkinson’s disease. Neurochem Int 2012; 60: 249–256.

245.

Sung

Park

Lee

. Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. J Biol Chem 2005; 280: 25216–25224.

246.

Kim

Cho

Kim

. Alpha-synuclein induces migration of BV-2 microglial cells by up-regulation of CD44 and MT1-MMP. J Neurochem 2009; 109: 1483–1496.

247.

Monahan

Warren

Carvey

. Neuroinflammation and peripheral immune infiltration in Parkinson’s disease: an autoimmune hypothesis. Cell Transplant 2008; 17: 363–372.

248.

Reale

Iarlori

Thomas

. Peripheral cytokines profile in Parkinson’s disease. Brain Behav Immun 2009; 23: 55–63.

249.

Rite

Machado

Cano

. Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. J Neurochem 2007; 101: 1567–1582.

250.

Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer, 2013. Available from: http://globocan.iarc.fr (accessed 17 March 2016).

251.

World Health Organization (WHO). World cancer report 2014, Geneva: WHO, 2014.

252.

Holland

. Glioblastoma multiforme: the terminator. Proc Natl Acad Sci U S A 2000; 97: 6242–6244.

253.

Krex

Klink

Hartmann

. Long-term survival with glioblastoma multiforme. Brain 2007; 130: 2596–2606.

254.

Ohgaki

Kleihues

. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005; 64: 479–489.

255.

Yamamoto

Adachi

. Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med (Maywood) 2006; 231: 20–27.

256.

Shiomi

Okada

. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev 2003; 22: 145–152.

257.

Juncker-Jensen

Deryugina

Rimann

. Tumor MMP-1 activates endothelial PAR1 to facilitate vascular intravasation and metastatic dissemination. Cancer Res 2013; 73: 4196–4211.

258.

Hummel

Kallmann

Wagner

. Production of MMPs in human cerebral endothelial cells and their role in shedding adhesion molecules. J Neuropathol Exp Neurol 2001; 60: 320–327.

259.

Nakamura

Suenaga

Taniwaki

. Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase. Cancer Res 2004; 64: 876–882.

260.

Hanley

Napier

Burdick

. Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells. FASEB J 2006; 20: 337–339.

261.

Napier

Healy

Schnaar

. Selectin ligand expression regulates the initial vascular interactions of colon carcinoma cells – the roles of CD44V and alternative sialofucosylated selectin ligands. J Biol Chem 2007; 282: 3433–3441.

262.

Thomas

Zhu

Schnaar

. Carcinoembryonic antigen and CD44 variant isoforms cooperate to mediate colon carcinoma cell adhesion to E- and L-selectin in shear flow. J Biol Chem 2008; 283: 15647–15655.

263.

Fazakas

Wilhelm

Nagyoszi

. Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE 2011; 6: e20758.

264.

Lee

Kim

Yoo

. Human brain endothelial cell-derived COX-2 facilitates extravasation of breast cancer cells across the blood-brain barrier. Anticancer Res 2011; 31: 4307–4313.

265.

Lorger

Felding-Habermann

. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 2010; 176: 2958–2971.

266.

Eibl

Pietsch

Moll

. Expression of variant CD44 epitopes in human astrocytic brain tumors. J Neurooncol 1995; 26: 165–170.

267.

Naor

Nedvetzki

Golan

. CD44 in cancer. Crit Rev Cl Lab Sci 2002; 39: 527–579.

268.

Suenaga

Mori

Itoh

. CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase. Oncogene 2005; 24: 859–868.

269.

Lesley

Hyman

Kincade

. CD44 and its interaction with extracellular matrix. Adv Immunol 1993; 54: 271–335.

270.

Jalkanen

. Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. J Cell Biol 1992; 116: 817–825.

271.

Wang M, Wang T, Liu S, et al. The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol 2003 (Biochim Biophys Acta 20: 65–72).

272.

Annabi

Bouzeghrane

Currie

. A PSP94-derived peptide PCK3145 inhibits MMP-9 secretion and triggers CD44 cell surface shedding: implication in tumor metastasis. Clin Exp Metastasis 2005; 22: 429–439.

273.

Bauvois

. New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 2012; 1825: 29–36.

274.

Nakada

Nakamura

Ikeda

. Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol 1999; 154: 417–428.

275.

Matsumoto

Katoh

Saito

. Identification of soluble type of membrane-type matrix metalloproteinase-3 formed by alternatively spliced mRNA. Biochim Biophys Acta 1997; 1354: 159–170.

276.

Shimada

Nakamura

Ohuchi

. Characterization of a truncated recombinant form of human membrane type 3 matrix metalloproteinase. Eur J Biochem 1999; 262: 907–914.

277.

Belien

Paganetti

Schwab

. Membrane-type 1 matrix metalloprotease (MT1-MMP) enables invasive migration of glioma cells in central nervous system white matter. J Cell Biol 1999; 144: 373–384.

278.

Sun

Bao

. MMP-1 overexpression induced by IL-1beta: possible mechanism for inflammation in degenerative lumbar facet joint. J Orthop Sci 2013; 18: 1012–1019.

279.

Pei

. Leukolysin/MMP25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage. Cell Res 1999; 9: 291–303.

280.

Velasco

Cal

Merlos-Suarez

. Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors. Cancer Res 2000; 60: 877–882.

281.

Sounni

Devy

Hajitou

. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 2002; 16: 555–564.

282.

Birbrair

Zhang

Wang

. Type-1 pericytes participate in fibrous tissue deposition in aged skeletal muscle. Am J Physiol Cell Physiol 2013; 305: C1098–C1113.

283.

Stetler-Stevenson

. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Investigat 1999; 103: 1237–1241.

284.

Bronger

Konig

Kopplow

. ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res 2005; 65: 11419–11428.

285.

Groothuis

. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. NeuroOncology 2000; 2: 45–59.

286.

Noell

Wolburg-Buchholz

Mack

. Dynamics of expression patterns of AQP4, dystroglycan, agrin and matrix metalloproteinases in human glioblastoma. Cell Tissue Res 2012; 347: 429–441.

287.

Mariani

Boozer

Braxton

. Evaluation of matrix metalloproteinase-2 and -9 in the cerebrospinal fluid of dogs with intracranial tumors. Am J Vet Res 2013; 74: 122–129.

288.

Turba

Forni

Gandini

. Recruited leukocytes and local synthesis account for increased matrix metalloproteinase-9 activity in cerebrospinal fluid of dogs with central nervous system neoplasm. J Neurooncol 2007; 81: 123–129.

289.

Ashley

. Clinical trials of a matrix metalloproteinase inhibitor in human periodontal disease. SDD Clinical Research Team. Ann N Y Acad Sci 1999; 878: 335–346.

290.

Golub

Lee

Ryan

. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998; 12: 12–26.

291.

Preshaw

Hefti

Novak

. Subantimicrobial dose doxycycline enhances the efficacy of scaling and root planing in chronic periodontitis: a multicenter trial. J Periodontol 2004; 75: 1068–1076.

292.

Brundula

Rewcastle

Metz

. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002; 125: 1297–1308.

293.

Gijbels

Galardy

Steinman

. Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J Clin Invest 1994; 94: 2177–2182.

294.

Graesser

Mahooti

Haas

. The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the pathogenesis of experimental autoimmune encephalomyelitis. Lab Invest 1998; 78: 1445–1458.

295.

Hewson

Smith

Leonard

. Suppression of experimental allergic encephalomyelitis in the Lewis rat by the matrix metalloproteinase inhibitor Ro31-9790. Inflamm Res 1995; 44: 345–349.

296.

Eccles

Box

Court

. Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). Cancer Res 1996; 56: 2815–2822.

297.

Sledge

Jr Qulali

Goulet

. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 1995; 87: 1546–1550.

298.

Watson

Morris

Parsons

. Therapeutic effect of the matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model. Br J Cancer 1996; 74: 1354–1358.

299.

Watson

Morris

Robinson

. Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Res 1995; 55: 3629–3633.

300.

Asahi

Jung

. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 2000; 20: 1681–1689.

301.

Pfefferkorn

Rosenberg

. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 2003; 34: 2025–2030.

302.

Sood

Taheri

Candelario-Jalil

. Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. J Cereb Blood Flow Metab 2008; 28: 431–438.

303.

Minagar

Alexander

Schwendimann

. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol 2008; 65: 199–204.

304.

Fagan

Waller

Nichols

. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 2010; 41: 2283–2287.

305.

Lampl

Boaz

Gilad

. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007; 69: 1404–1410.

306.

Groves

Puduvalli

Conrad

. Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: a relationship among efficacy, joint toxicity and anticonvulsant status. J Neurooncol 2006; 80: 83–90.

307.

Groves

Puduvalli

Hess

. Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J Clin Oncol 2002; 20: 1383–1388.

308.

New

Mikkelsen

Phuphanich

. A phase I/II study of COL-3 administered on a continuous oral schedule in patients with recurrent high grade glioma. Preliminary results of the NABTT 9809 clinical trial. Neuro-Oncology. 2002; 4: 373.

309.

Rudek

New

Mikkelsen

. Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas. J Neurooncol 2011; 105: 375–381.

310.

Coussens

Werb

. Inflammation and cancer. Nature 2002; 420: 860–867.

311.

Dezube

Krown

Lee

. Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi’s sarcoma: an AIDS Malignancy Consortium Study. J Clin Oncol 2006; 24: 1389–1394.

312.

Drummond

Beckett

Brown

. Preclinical and clinical studies of MMP inhibitors in cancer. Ann N Y Acad Sci 1999; 878: 228–235.

313.

Goffin

Anderson

Supko

. Phase I trial of the matrix metalloproteinase inhibitor marimastat combined with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res 2005; 11: 3417–3424.

314.

Macaulay

O’Byrne

Saunders

. Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. Clin Cancer Res 1999; 5: 513–520.

315.

Miller

Saphner

Waterhouse

. A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer. Clin Cancer Res 2004; 10: 1971–1975.

316.

Rudek

Figg

Dyer

. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin Oncol 2001; 19: 584–592.

317.

Skiles

Gonnella

Jeng

. The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors. Curr Med Chem 2004; 11: 2911–2977.

318.

Sparano

Bernardo

Stephenson

. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol 2004; 22: 4683–4690.

319.

Vandenbroucke

Libert

. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 2014; 13: 904–927.

320.

Zabad

Metz

Todoruk

. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. Mult Scler 2007; 13: 517–526.

321.

Zhang

Metz

Yong

. Pilot study of minocycline in relapsing-remitting multiple sclerosis. Can J Neurol Sci 2008; 35: 185–191.

322.

Chu

Forouzesh

Syed

. A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 2007; 25: 359–367.

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

Abstract

Keywords

Introduction

Matrix metalloproteinases

History

Classification

Function and role

Expression, activation, and regulation

MMPs in brain and blood–brain barrier

Methods and techniques to study MMPs

MMPs in central nervous system disease

Neuroinflammation

Multiple sclerosis

Cerebral aneurysms

Stroke

Epilepsy

Alzheimer’s disease

Parkinson’s disease

Brain cancer

MMP inhibition as a therapeutic strategy

Conclusion and future perspectives

Footnotes

Funding

Acknowledgements

Declaration of conflicting interests

Author’s contributions

References