Not open and shut: Complex and prolonged blood-brain barrier responses after stroke

Abstract

Blood-brain barrier dysfunction (BBB) occurs rapidly after stroke and contributes to edema, inflammation, and secondary brain injury including haemorrhage. Two recent studies shed light on the temporal extent of post-stroke BBB dysfunction as well as its consequences for drug delivery. Zhang et al. found increases in BBB permeability that persist up to one-year post-ischemia. Despite increased paracellular leakage, Stanton et al. showed that transcellular transporter systems are required to deliver therapeutics into brain parenchyma. Both studies remind us of the complexity of BBB responses after stroke and provide novel entry points for future research into the underlying mechanisms.

Brain microvessels are lined by a continuous endothelial cell layer sheathed by mural cells and astrocytic end-feet that together provide a multicellular interface between the blood and the brain, traditionally termed the blood-brain barrier (BBB). To provide optimal conditions for neuronal functioning, the BBB regulates molecular flux tighter than systemic capillaries: brain microvessels exhibit a particularly low rate of transcytosis and are sealed by tight junctions between endothelial cells. While oxygen, carbon dioxide, and small lipid-soluble molecules freely diffuse over the BBB, the transport of all other molecules depends on specialized carriers or receptors. ¹ Evolutionary designed to protect the brain from neurotoxic blood-derived molecules and rapid milieu changes, the complexity of the BBB, however, confounds simple strategies for the delivery of drugs to the CNS. ² Most CNS pathologies, including ischemic stroke, are characterized by BBB dysfunction,^3,4 which affects both gatekeeping properties for blood-derived endogenous molecules and exogenous drug delivery. During acute cerebral ischemia, the “opening” of the BBB is believed to develop over several stages with increases in both transcellular and paracellular trafficking, although the exact sequence of changes is still debated.^5,6 How long BBB dysfunction prevails and how BBB dysfunction modifies drug delivery after stroke are the focus of extensive ongoing research with two recent studies now shedding light on these areas.

Following up on previous studies evidencing BBB dysfunction up to three months post-stroke, ⁷ Zhang et al. investigated BBB permeability in adult rhesus monkeys one year after transient middle cerebral artery occlusion. ⁸ Using the CT perfusion-derived permeability surface area product, i.e. the rate of contrast extravasation from intra- to extravascular compartments multiplied with the total surface area of perfused capillary endothelium within a unit mass of tissue (mL min⁻¹ 100 g⁻¹), they found increased BBB permeability in the ipsilateral caudate nucleus as the primary infarct site compared to age-matched controls. Of note, increased BBB permeability was generally not lateralized, with highly significant increases in ipsilateral and contralateral caudate nucleus, hippocampus, and white matter, plus less pronounced BBB dysfunction in bilateral thalamus and contralateral frontal cortex. The increased BBB permeability in contralateral hemisphere might represent a consequence of diaschisis during acute and subacute phases of stroke. These data accord with and extend previous reports on chronic BBB dysfunction after stroke by providing information on the temporal and spatial resolution of BBB dysfunction.

Whether increased BBB permeability after an ischemic insult provides a direct therapeutic window for drug delivery has long been controversially discussed and is confounded by timing after stroke as well as drug properties among others. A recent study by Stanton et al. now provides important insights into how drugs cross the BBB after stroke: ⁹ focusing on memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist with preclinical evidence for neuroprotective efficacy, the group investigated whether the BBB crossing and neuroprotective effects of memantine after stroke require the BBB organic cation transporters (Oct1, Oct2) previously identified as memantine BBB transporters. ¹⁰ Using in situ brain perfusion, they found increased whole-brain and ipsilateral uptake of [³H]memantine after two hours of reperfusion compared to sham-operated rats, which was attenuated by cimetidine, a competitive Oct1/Oct2 inhibitor. Importantly, cimetidine almost completely blocked the effects of memantine on both lowering infarct volumes and improving motor outcomes, indicating for the first time that the Oct1/Oct2-mediated transport of memantine across the BBB is functionally required to exert the full neuroprotective efficacy during cerebral ischemia. These findings emphasize the translational importance of drug delivery strategies for stroke, even in the presence of BBB leakage within ischemic brain tissue.

These two studies continue a research line indicating that the BBB does not simply fully open and then shut again after stroke but rather shows a complex multi-stage response in dependence of time and place, one that affects drug delivery. While the findings of Zhang et al. are of high interest and suggest BBB dysfunction both as a chronic consequence of stroke and as a potentially causative process of post-stroke cognitive impairment, future studies will need to further clarify and validate the consequences of early versus late BBB changes. During the early phase, these issues may pertain to drug delivery. During later stages, preventing the continuation of low-level BBB leakage may help ameliorate vascular mechanisms of cognitive dysfunction. In light of the findings from Stanton et al., in-depth studies are needed to investigate i) the relative post-stroke changes of paracellular and transcellular routes including of all receptor and carrier systems in dependence of time, place, and molecular properties, and ii) the cellular and molecular mechanisms that 1) prevent full BBB recovery, 2) promote spread to cerebral areas originally not affected by the insult, and 3) cause potentially different BBB dysfunction along the vascular tree. Such studies might not only identify molecular treatment targets and inform optimal timing and delivery systems for neuroprotective agents but also will help to improve the understanding of the functional consequences of post-stroke BBB dysfunction with regards to ongoing pharmacological treatment, systemic electrolyte imbalances and other homeostatic disturbances that affect stroke patients more than others.