Current neurovascular research
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As a member of the secreted extracellular matrix associated proteins of the CCN family, Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) is garnering increased attention not only as a potent proliferative entity, but also as a robust cytoprotective agent during toxic insults. Here we demonstrate that WISP1 prevents forkhead transcription factor FoxO3a mediated caspase 1 and caspase 3 apoptotic cell death in primary neurons during oxidant stress. ⋯ Through an autoregulatory loop, WISP1 also minimizes deacytelation of FoxO3a, prevents caspase 1 and 3 activation, and promotes an effective neuroprotective level of SIRT1 activity through SIRT1 nuclear trafficking and prevention of SIRT1 caspase degradation. Elucidation of the critical pathways of WISP1 that determine neuronal cell survival during oxidative stress may offer novel therapeutic avenues for neurodegenerative disorders.
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Non-traumatic subarachnoid hemorrhage (SAH) represents about 5 to 6% of the overall incidence of stroke and is associated with high morbidity and mortality. Despite the substantial research and clinical efforts, delayed cerebral ischemia (DCI) is still the major complication after SAH and represents an important factor for severe neurological deficits. ⋯ Understanding the plethora of different pathophysiological derangements after SAH is very important for the development of new therapies, in order to abolish secondary ischemic brain injuries early-on and improve patients' outcome. In this review, we strive to summarise the mechanisms and therapeutic developments of DCI.
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Studies investigating cognitive impairment in stroke-free patients with carotid artery stenosis have led to inconsistent results. Furthermore, the pathophysiological mechanism leading to cognitive impairment remains unclear. Cerebral hypoperfusion and arterio-arterial microembolization are discussed. ⋯ In our selected group of patients, a higher grade of carotid artery stenosis is associated with cognitive decline. This process is independent of white matter lesion load. Possible pathophysiological implications are discussed.
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Nimodipine improved outcome in patients with subarachnoid hemorrhage (SAH) although hypotension limited the dose that could be administered systemically. Subarachnoid delivery of nicardipine or nimodipine may be more efficacious. We tested the efficacy of cisternal application of sustained release nicardipine and nimodipine in SAH in monkeys and dogs, respectively. ⋯ There was no reduction in microthrombi in animals treated with nimodipine PLGA compared to placebo PLGA. Site-specific, sustained release formulations of dihydropyridines can deliver high concentrations to the cerebrospinal fluid without causing systemic side effects, and may reduce angiographic vasospasm after SAH. Since nimodipine improves outcome in patients with SAH without necessarily preventing vasospasm, further studies are warranted.
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Ischemic stroke is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. ⋯ Data from animal models and clinical studies of ischemic stroke have demonstrated an increase in expression and processing of amyloid precursor protein (APP) to a neurotoxic form of oligomeric β-amyloid peptide (Aβ) and hyperphosphorylation of tau protein. The authors of this review are using advances in methods and technologies to study cerebrovascular diseases and this review examines the hypothesis that pathological mechanisms common to both brain ischemia and Alzheimer's dementia are contributing to cognitive impairment and brain ischemia-related dementia.