Review articleBlood-brain barrier dysfunction and recovery after ischemic stroke
Introduction
The blood-brain barrier (BBB) was first identified in the beginning of the 20th century by Lewandowsky and other workers, based on the absence of CNS pharmacological effects of intravenously administered bile acids and ferrocyanide. The concept that this was due to a barrier between blood and brain was fortified by experiments of Goldmann demonstrating the penetration of dyes into brain from cerebrospinal fluid (CSF) but not from blood (Goldmann, 1909, Goldmann, 1913, Zlokovic, 2008). Since those initial studies, our understanding of the BBB has evolved from a physical barrier separating the CNS from periphery, into a dynamic and metabolic interface that bi-directionally regulates the trafficking of fluid, solutes and cells. The concept of neurovascular unit (NVU) has further extended BBB research to include not only endothelial cells (ECs) but also astrocytes, pericytes, neurons and other components. As a site of crosstalk among multiple CNS cell types and blood-borne peripheral cells, the BBB plays a fundamental role in the maintenance of CNS homeostasis and normal neuronal function. BBB dysfunction, referring to its loss of structural integrity and normal functions, is also a prominent pathological feature of many neurological disorders, including stroke (Zlokovic, 2008).
Stroke is the 5th leading cause of death and the leading cause of adult disability in the United States. Ischemia accounts for ∼87% of US strokes (Mozaffarian et al., 2016). Intensive basic and clinical research has revealed multiple stroke risk factors and elucidated many mechanisms underlying ischemic brain injury. However, current therapy for acute ischemic stroke remains largely dependent on tissue plasminogen activator (tPA)-mediated thrombolysis in appropriate patients. During and after ischemic stroke, BBB disruption facilitates injury progression and increases the risk of hemorrhage, predicting poor patient outcome and limiting the use of tPA (Keep et al., 2014, Liu et al., 2016b). The existence of stroke comorbid conditions, such as hypertension and hyperglycemia, induces anatomical and functional changes to the CNS vasculature and often exacerbates BBB breakdown after stroke. Having received much less attention than is warranted, BBB research should be better prioritized, with an emphasis on BBB-related mechanisms of neurovascular injury and developing therapeutic strategies to improve BBB integrity after ischemic stroke.
This review describes our current understanding of BBB dysfunction after ischemic stroke, with an emphasis on recent advances elucidating underlying mechanisms. Common and unique mechanisms that contribute to BBB dysfunction in the presence of stroke risk factors and comorbid conditions are summarized, which have been neglected in a large proportion of BBB studies. The concept of BBB restoration is also examined, where approaches enhancing BBB repair may facilitate long-term functional recovery after ischemic stroke and reduce stroke recurrence.
Section snippets
Structure and functions of the BBB under physiological conditions
A significant structural difference between the cerebral and peripheral vasculatures is the BBB, which strictly regulates the movement of molecules between blood and brain, contributing to CNS homeostasis (Abbott et al., 2010). That regulation includes (a) very limited paracellular diffusion between ECs, (b) low levels of EC transcytosis, (c) an array of endothelial transporters moving substrates from blood to brain or brain to blood, and (d) the presence of cerebrovascular enzymes that
Mechanisms of blood-brain barrier dysfunction after ischemic stroke
BBB dysfunction, characterized by structural disruption of TJs and increased permeability, is a prominent pathological characteristic of both ischemic and hemorrhagic stroke, and is usually associated with poor prognosis (Keep et al., 2008, Prakash and Carmichael, 2015). With an ischemic stroke, blood-borne cells, chemicals and fluid extravasate into brain parenchyma across the impaired BBB as a result of increased paracellular and transcellular permeability and gross lesioning of the
Modulation of blood-brain barrier permeability by different cell types and chemical mediators
The NVU, consisting of neurons, astrocytes, pericytes, ECM, ECs, and circulating blood elements, illustrates a framework where cell–cell and cell-matrix interactions dictate the brain response to ischemic injury (Lo et al., 2003). As the interface where these interactions occur, the BBB is constantly regulated by different cell types in the NVU (Fig. 3). Various chemical mediators present within the NVU also influence BBB permeability, both under physiological and ischemic conditions.
Influence of stroke risk factors and comorbidities on the blood-brain barrier
Comorbidities occur in most stroke patients and have major impacts on stroke outcome. Some comorbid conditions and risk factors are modifiable, e.g. hypertension and hyperlipidemia, and represent areas of interest to reduce stroke occurrence or improve the efficacy of stroke therapies. Despite an urgent need to understand BBB dysfunction in stroke patients with certain comorbid conditions, the majority of basic and preclinical stroke studies have hitherto focused on healthy young adult male
Time course of recovery
Multiple studies have examined the time course of BBB permeability after ischemic stroke in rodents (e.g. (Lin et al., 2008, Moisan et al., 2014, Strbian et al., 2008)). These have shown a peak in permeability in the acute/subacute phase of stroke (∼1-7 days) followed by a gradual reduction. However, it should be noted that studies have still found BBB hyperpermeability 3–4 weeks after ischemia (Lin et al., 2008, Moisan et al., 2014, Strbian et al., 2008) indicating there can be long-term
Novel tools for blood-brain barrier research
The pathogenesis of BBB dysfunction and therapeutic strategies targeting the BBB have received increasing attention in stroke research, and emerging novel research tools may greatly facilitate such investigations. Current advanced imaging techniques enable non-invasive, real-time quantitative and functional assessments of the BBB with improved spatial resolution. More accurate spatial and temporal gene manipulation can be achieved in vivo using various genetic mouse models, while in vitro model
Future perspectives and translation
Over the past decade, there has been marked increase in our understanding of normal BBB and NVU functions and how those are impacted by stroke. There remain, however, substantial facets of BBB endothelial biology that are poorly understood. For example, the dynamic behavior of TJ proteins has been intensively investigated in epithelial and endothelial cells of peripheral organs (Stamatovic et al., 2017). The internalization of TJ proteins from the cell membrane, and subsequent trafficking,
Conflict of interest
None.
Acknowledgements
This work was supported by the U.S. National Institutes of Health grants NS089534, NS045048, NS056118 (to J.C.), NS036736, NS095029 (to M.V.L.B. and J.C.), NS098066 (to A.V.A.), NS093399 (to R.F.K.), the U.S. Department of Veterans Affairs (VA) Merit Review award BX002495 (to J.C.), and the Chinese Natural Science Foundation grant 81529002 (to J.C.). J.C. is a recipient of the VA Senior Research Career Scientist Award, the Richard King Mellon Endowed Professorship, and the University of
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