Translational Stroke Research on Blood-Brain Barrier Damage: Challenges, Perspectives, and Goals.

Over the past few decades, basic and clinical research has identified numerous risk factors for the development of stroke and led to major improvements in health management in the USA. As a result of these efforts, the relative rate of stroke death dropped by 33.7 %, and the actual occurrence of stroke deaths fell by 18.2 % in the decade spanning from 2003 to 2013, according to the American Heart Association. Thus, stroke fell from the fourth to the fifth leading cause of death in 2013, behind heart disease, cancer, chronic lower respiratory diseases, and unintentional injuries. These improvements are largely attributed to superior control of hypertension, diabetes mellitus, high cholesterol, and tobacco use [1]. To date, the treatment of acute ischemic stroke is largely dependent on recanalization using recombinant tissue-type plasminogen activator (tPA) in the appropriate patient population [2, 3]. Encouragingly, recent clinical trials have demonstrated significant benefits for intra-arterial thrombectomy in a subset of acute stroke patients with intracranial large artery occlusion [4]. Despite these improvements in population health and stroke treatment, stroke still remains a leading cause of longterm disability and approximately 795,000 people experience a new or recurrent stroke every year [1]. Thus, basic and clinical investigations of the mechanisms underlying ischemic brain injurymust remain an urgent priority in order to promote the discovery of novel therapeutic targets and improve the safety and efficacy of current tPA and thrombectomy treatments. During and after ischemic stroke, loss of blood-brain barrier (BBB) integrity is a prominent pathological event that contributes to further evolution of the injury. BBB dysfunction is also a hallmark of intracerebral hemorrhage [5, 6]. Despite its obvious clinical relevance, BBB protection has received much less attention than is warranted. An impaired BBB not only facilitates the development of brain edema and neuroinflammation, but also increases the risk of lethal hemorrhagic transformation during thrombolysis, thereby limiting the use of tPA and leading to poor patient outcomes [7, 8]. Recent advances in stroke telemedicine provide an effective and promising method to increase the use of tPA therapy [9], which, together with the growing application of thrombectomy, is likely to improve post-ischemia reperfusion in a larger population of stroke patients in the near future. As this treatment method works better when the BBB remains intact, therapeutic strategies aimed at neurovascular unit protection and prevention of BBB damage after ischemia/reperfusion (I/R) need to be better prioritized in stroke research. In earlier reports, it was widely held that all forms of BBB rupture after I/R were the direct consequence of matrix metalloproteinase (MMP)-mediated degradation of endothelial intercellular junctions and basal lamina [10–14]. However, recent animal models of stroke have revealed a complex, biphasic temporal profile of BBB breakdown, with an immediate phase of early BBB hyperpermeability 4–6 h after stroke, followed by a delayed opening of the BBB 48–72 h after stroke. In recent years, the availability of advanced imaging techniques and novel transgenic animal models have greatly facilitated research on BBB dysfunction after stroke, with * Jun Chen chenj2@upmc.edu