Direct Thrombin Inhibitors’ Potential Efficacy in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with no available disease-modifying drugs. However, it has been postulated that neurovascular damage is a primary occurrence in this disease. Neurovascular damage is the result of the presence of cardiovascular risk factor generating hypoxia, oxidative stress, and metabolic changes that activate the endothelial cells of the brain microvasculature in order to respond to the stress by the development of angiogenesis. This endothelial activation could lead to a secretion of many proinflammatory cytokines and growth factors, such as thrombin. Heparin and related oligosaccharides have been shown to be efficient in the improvement of symptoms of AD. Their efficacy may be limited by their nonselective inhibitory effect of thrombin’s activity. Direct thrombin inhibitors, such as dabigatran, might be efficient in the treatment of patients with AD because of their high selectivity for thrombin’s activity inhibition while having a safer side effects profile than heparin.

Introduction

Alzheimer’s disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Despite intense research efforts, effective disease-modifying therapies are still unavailable. Diagnostic criteria differentiate dementias between vascular dementia and AD despite the fact that mixed features are prevalent. ¹ Increasing literature supports a vascular–neuronal axis in AD because of the presence of common risk factors for both AD and cardiovascular diseases. ² Endothelial dysfunction is increasingly implicated in the development of neurodegenerative diseases with thrombin being an example of a vascular-derived factor possibly being at the basis of the physiopathology cascade resulting in AD. ³

Neurovascular Dysfunction and Inflammation in AD

In addition to a number of cerebrovascular abnormalities described in brains of patients with AD, there is increasing evidence that vascular risk factors are more commonly found in patients with AD possibly contributing to its pathogenesis. ⁴ These risk factors may lead to cerebrovascular dysfunction. The clearance from brain to blood due to blood–brain barrier dysfunction contributes to enhanced β-amyloid levels in the brain. ⁵ Inflammation may result from cerebrovascular injury which may explain why, according to one meta-analysis, nonsteroidal anti-inflammatory drugs have been shown to reduce AD incidence by an average of 58%. ⁶ This inflammation leads to endothelial cell activation and secretion of many cytokines and growth factors that may by themselves perpetuate cerebrovascular injury, inflammation, and neuronal death. ^2,3

Role of Thrombin in Endothelial Activation of Patients With AD

Brain endothelial cells in culture have been shown to synthesize thrombin under stressful conditions, such as oxidative stress with an overexpression of thrombin messenger RNA in brain endothelial cells and microvessels of patients with AD. ^7,8 A possible role for thrombin in proteolysis of tau under physiological and/or pathological conditions in human brains has been suggested along with the hypothesis that phosphorylation of tau inhibits proteolysis by thrombin, leading to its aggregation into insoluble fibrils. ⁹ Furthermore, prothrombin and thrombin have been demonstrated to be expressed ubiquitously in brain cells and especially in neurofibrillary tangles and senile plaques, which suggests that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases. ^10,11 The hyperexpression of thrombin may lead to further endothelial activation and vascular inflammation. Exposure of neurons to thrombin results, experimentally, in significant apoptosis. ¹² Administration of thrombin directly into the rat brain results in neuronal cell death and cognitive deficits. ¹³ Moreover, it has been demonstrated that thrombin exerts direct neurotoxicity. ¹⁴ Furthermore, the proinflammatory effects of thrombin released from endothelial cells are also important because of the ability of thrombin to activate other central nervous system cells, such as microglia. ¹⁵

Role of Indirect Thrombin Inhibitors in AD

Thrombin plays a central role in the generation of a thrombus. Its principal function is to convert soluble fibrinogen into insoluble fibrin, while also stimulating platelet activation. It can be inhibited directly or indirectly by the binding of thrombin-inhibiting drugs to 1 or 2 of its 3 domains, the active site and exosites 1 and 2 (which is a heparin-binding domain). ¹⁶ Traditional anticoagulants such as unfractionated heparin and low-molecular-weight heparin (LMWH) inhibit free thrombin in an indirect manner by forming a heparin–thrombin–antithrombin complex. ¹⁷ The introduction of heparins in the treatment of AD was based on the hypothesis that heparins might improve the cerebral microcirculation through its antithrombotic effects. ¹⁸ However, the hemorrhage potential and adverse effects of heparin held up momentarily its neurological applications despite the available data demonstrating its efficacy. For example, aged rats showed a significant partial reversal of age-related behavioral deficits following a high-molecular-weight glycosaminoglycans polysulfate administration. ¹⁹ The neuroprotective effects of a LMWH-certoparin as demonstrated by significant decrease in the phosphorylated protein tau toxicity in an animal model mimicking the pathology of AD have been evaluated. ²⁰ Using the same animal model, the protective effects of a heparin oligosaccharide mixture on the brain after the injection of amyloid peptide into the amygdale have been demonstrated. ²¹ The underlying mechanisms behind the effects of heparins on AD are not clear, but it is very likely that the anti-inflammatory effects in the central nervous system contribute to the overall mechanism explaining the efficacy heparins in AD. One of the components of this anti-inflammatory effect is generated by its antithrombin and anticoagulant activity. ²²

Disadvantages of Indirect Thrombin Inhibitors

Heparins can simultaneously bind to both fibrin and thrombin and act as a bridge between them. This fibrin–heparin–thrombin complex occupies both thrombin exosites but leaves the active site enzymatically protected from inactivation which may result in further thrombus growth. ²³ In addition to its inability to neutralize fibrin-bound thrombin, heparin has other limitations such as binding to various plasma proteins, creating an unpredictable dose-dependent anticoagulant response, the need for routine dose-adjustments and anticoagulant monitoring, and finally heparin-induced thrombocytopenia (HIT). ²⁴

Known Role of the Oral Direct Thrombin Inhibitor Dabigatran

Direct thrombin inhibitors bind directly to thrombin and do not require a cofactor such as antithrombin to exert their effect. They can inhibit both soluble thrombin and fibrin-bound thrombin. Other key advantages include a more predictable anticoagulant effect compared to heparins because of their lack of binding to other plasma proteins, an antiplatelet effect, and the absence of immune-mediated thrombocytopenia. Dabigatran etexilate is an orally active prodrug that is rapidly converted into dabigatran, a potent, reversible and specific direct thrombin inhibitor. ¹⁷ In 2008, the European Medicines Agency granted marketing authorization for dabigatran etexilate for the prevention of thromboembolic disease following hip or knee replacement surgery; and in 2011, it was approved for use in patients with nonvalvular atrial fibrillation (AF) in the European Union while the US Food and Drug Administration approved dabigatran etexilate in 2010, for prevention of stroke in patients with nonvalvular AF. ^17,25,26 Dabigatran etexilate has undergone phase III, randomized controlled clinical trials for both venous thromboembolism (VTE) and stroke prevention in AF. ²⁶ According to the RE-COVER study, treatment with dabigatran at the dose of 150 mg twice a day (bid) has been shown to be noninferior for efficacy and at least as safe as warfarin at the usual international normalized ratio (INR) level in patients with acute VTE after an initial few days of parenteral anticoagulation. ²⁷ According to the RE-MEDY and RE-SONATE studies regarding the use of dabigatran in secondary VTE prevention, it has been found to be more effective than placebo and as effective as vitamin K antagonists, with a reduced risk of major bleeding but an increased incidence of acute coronary events. ²⁸ In the RE-LY study, 110 mg bid of dabigatran has been proven to be as effective as vitamin K antagonists in the prevention of strokes in patients with nonvalvular AF, with lower rates of major bleeding, while 150 mg bid associated with similar rates of major hemorrhage complications except for intracerebral hemorrhage. ^29,30 However, there has been some concerns about the potential increase in major bleeding events with the administration of dabigatran etexilate in patients receiving it for stroke prevention because of AF. ³¹ Reasons behind these adverse events were considered to be related to prescriber error (including the failure to allow the INR to fall below 2.0), impaired renal function, patient’s age, and complications arising from the lack of a reversal agent. ³¹ Other direct thrombin inhibitors such as lepirudin, desirudin, bivalirudin, and agratroban are administered via parenteral routes for the treatment or prophylaxis of thrombosis complicating HIT, for the prevention of deep vein thrombosis following total hip replacement, for patients with unstable angina undergoing percutaneous transluminal angioplasty, for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI), and finally for patients undergoing PCI with a provisional usage of glycoprotein inhibitors. ¹⁷

Conclusion

Although heparin and related oligosaccharides are known to exhibit anti-inflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents, their major effect in AD could be more pertinently conveyed by their anti-inflammatory action. This anti-inflammatory action is considered to emanate from the endothelial cell activation in the brain microvasculature of patients with AD because of hypoxia, oxidative stress, and metabolic changes due to many cardiovascular risk factors. The inhibition of thrombin resulting from this endothelial cell activation may be one of the most important mechanisms explaining the efficacy of heparin in ameliorating AD symptoms. In this perspective, dabigatran may be more efficient and safer when administered to patients with AD.