Abstract
Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.
Highlights
Stroke is the world’s second leading cause of mortality, resulting around 6,000,000 deaths annually [1]
We have shown that central nervous system (CNS) neurons expressed several Toll Like Receptors (TLRs), and that TLR-activated pro-apoptotic signaling cascade involving jun N-terminal kinase (JNK) and the transcription factor AP-1 occurs during ischemic stroke, and is TLR 2- and 4-mediated [61,62]
The molecular biology of stroke injury is a rapidly growing field of research, that may lead to the identification of novel stroke targets and directed therapies
Summary
Stroke is the world’s second leading cause of mortality, resulting around 6,000,000 deaths annually [1]. Two-vessel occlusion (2-VO) This model is carried out under a general anesthetic and requires the administration of a muscle relaxant It has been well-documented that a bilateral occlusion of the common carotid arteries alone is insufficient either to bring the cerebral blood flow down below the ischemic threshold, or to upset the energy state of the brain tissue to an extent sufficient to produce detectable cell death [10,75]. Photothrombotic distal middle cerebral artery (MCA) occlusion The use of a photochemical reaction to produce focal cortical ischemia in the rat brain was first described in 1985 [90] In this model, vascular thrombosis is induced by transcranial illumination with a filtered light source in combination with intravenous injection of a photosensitive dye [91,92]. The promising pleiotropic action of statins could be extended to the field of neurorepair after ischemic stroke
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