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As a result of ischemia or hemorrhage, blood supply to neurons is disrupted which subsequently promotes a cascade of pathophysiological responses resulting in cell loss. Many mechanisms are involved solely or in combination in this disorder including excitotoxicity, mitochondrial death pathways, and the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy and inflammation. Besides neuronal cell loss, damage to and loss of astrocytes as well as injury to white matter contributes also to cerebral injury. The core problem in stroke is the loss of neuronal cells which makes recovery difficult or even not possible in the late states. Acute treatment options that can be applied for stroke are mainly targeting re-establishment of blood flow and hence, their use is limited due to the effective time window of thrombolytic agents. However, if the acute time window is exceeded, neuronal loss starts due to the activation of cell death pathways. This review will explore the most updated cellular death mechanisms leading to neuronal loss in stroke. Ischemic and hemorrhagic stroke as well as subarachnoid hemorrhage will be debated in the light of cell death mechanisms and possible novel molecular and cellular treatment options will be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Among the central nervous system (CNS) disorders, diseases like ischemic and hemorrhagic stroke which are important health care problems as well as leading causes for emergency admissions, primarily affect neurovascular structure. Despite their high rate of mortality and morbidity, very few efficient treatment targets have been established until now., Objective: Blood-brain barrier (BBB) is the mostly effected structure in stroke as detected in both clinical studies and experimental settings. BBB is composed of endothelia, astrocyte end-foot, pericytes and basal lamina. Neurovascular unit, pericytes and BBB forming endothelia play significant pathophysiological roles in both ischemic and hemorrhagic stroke., Discussion: In this mini-review, the role of microcirculation and cells of blood-brain barrier in stroke pathophysiology will be discussed with a special emphasis based on pericytes. Pericytes are especially important for providing adequate microcirculatory supply according to needs of neuronal tissue and form one of the functionally important part of BBB and take role in neurovascular coupling. Understanding the role and disease producing mechanisms of neurovascular unit elements in different neurological conditions will provide novel targets for future treatments., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Although progress has been made for recanalization therapies after ischemic stroke, post-treatment imaging studies show that tissue reperfusion cannot be attained despite satisfactory recanalization in a significant percentage of patients. Hence, investigation of microcirculatory changes in both surface and deep cortical levels after ischemia reperfusion is important for understanding the post-stroke blood flow dynamics. In this study, we applied optical coherence tomography (OCT) imaging of cerebral blood flow for the quantification of the microcirculatory changes. We obtained OCT microangiogram of the brain cortex in a mouse stroke model and analyzed the data to trace changes in the capillary perfusion level (CPL) before, during, and after the stroke. The CPL changes were estimated in 1 and 2 h ischemia groups as well as in a non-ischemic sham-operated group. For the estimation of CPL, a decorrelation amplitude-based algorithm was implemented and used. As a result, the CPL considerably decreased during ischemia but recovered to the baseline when recanalization was performed 1 h after ischemia; however, the CPL was significantly reduced when recanalization was delayed to 2 h after ischemia. These data demonstrate that ischemia causes microcirculation dysfunction, leading to a decreased capillary reperfusion after recanalization. Microcirculatory no-reflow warrants more rigorous assessment in clinical trials, whereas advanced optical imaging techniques may provide mechanistic insight and solutions in experimental studies.

Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood-brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke.

Currently, the best way of neuroprotection for acute ischemic stroke appears to be restoration of blood flow to the ischemic area by thrombolysis. Unfortunately, a short therapeutic time window as well as thrombolysis-induced bleeding and edema limit the use of recanalization therapies. Here, we review the evidence suggesting that ischemia/reperfusion-induced microvascular injury plays a critical role in determining tissue survival after recanalization in focal cerebral ischemia by disrupting the blood-brain barrier integrity and promoting microcirculatory clogging. Among many complex mechanisms of the ischemia-reperfusion injury, overproduction of oxygen and nitrogen radicals on the microvascular wall appears to significantly contribute to these pathological processes. These developments bring about the exciting possibility that effective suppression of oxidative/nitrative stress during pharmacological or interventional re-opening of the occluded artery may significantly improve the outcome of recanalization therapies in stroke patients by improving microcirculatory reflow as well as by preventing hemorrhagic conversion and vasogenic edema. They also point to the critical (but partly neglected) importance of the microcirculation in neuroprotection., (© 2012 The Authors Journal of Neurochemistry © International Society for Neurochemistry.)

Object: Hydrogen peroxide (H2O2) is used as a hemostatic agent in many neurosurgery centers. The authors used a 3% H2O2 solution for final hemostasis after removal of a left insular tumor. Immediately afterward, air bubbles were observed within the lumen of the polar temporal artery. Postoperative MR imaging revealed punctate areas of infarction in the lenticulostriate artery territory. The authors designed an experimental study to elucidate the mechanism of remote O2 emboli and reactive O2 species-related vasoactive responses and thrombus formation., Methods: In this study, H2O2 irrigation was used in mice with either an intact pial layer or after the pia mater was removed through a corticotomy. Normal saline irrigation was used in the corresponding control groups. Vessels were examined for intravascular O2 emboli under the microscope. Tissue sections were then obtained and stained with H & E and the 3-nitrotyrosine (3-NT) antibody to evaluate intravascular thrombus formation and peroxynitrite reaction, respectively., Results: Multiple bubbles were observed within the lumen of the vessels after exposure to H2O2 regardless of whether the pial layer was destroyed or intact. Immunofluorescent staining for 3-NT showed an abundant positive reaction in the vessel walls of all animals exposed to H2O2 as well as vascular occlusion with acute thrombus formation. Samples taken from the animals that received saline showed no positive staining for 3-NT and no vascular occlusion., Conclusions: Exposure to H2O2 may cause serious ischemic complications. The formation of peroxynitrite may cause vasoactive responses to H2O2 and platelet aggregation/thrombus formation, and the free diffusion of H2O2 through the vessel walls and its conversion to water and O2 leads to O2 bubbles within the closed vessel lumen. If used intradurally, H2O2 may have deleterious ischemic effects, and it can only be used carefully in open extradural spaces.