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Pathophysiology, treatment, and animal and cellular models of human ischemic stroke.

Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV - Mol Neurodegener (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. t.woodruff@uq.edu.au.

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.

No MeSH data available.


Related in: MedlinePlus

Major cellular patho-physiological mechanisms of ischemic stroke. Ischemia-induced energy failure leads to the depolarization of neurons. Activation of specific glutamate receptors dramatically increases intracellular Ca2+, and Na+, and K+ is released into the extracellular space. Edema results from water shifts to the intracellular space. Increased levels of intracellular messenger Ca2+ activates proteases, lipases and endonucleases. Free radicals are generated which damage membranes, mitochondria and DNA, in turn triggering cell death and inducing the formation of inflammatory mediators, which then induce JNK, p-38, NFκB and AP-1 activation in glial cells, endothelial cells, and infiltrating leukocytes. This culminates in pro-inflammatory cytokine and chemokine secretion and leads to the invasion of leukocytes via up-regulation of endothelial adhesion molecules.
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Figure 1: Major cellular patho-physiological mechanisms of ischemic stroke. Ischemia-induced energy failure leads to the depolarization of neurons. Activation of specific glutamate receptors dramatically increases intracellular Ca2+, and Na+, and K+ is released into the extracellular space. Edema results from water shifts to the intracellular space. Increased levels of intracellular messenger Ca2+ activates proteases, lipases and endonucleases. Free radicals are generated which damage membranes, mitochondria and DNA, in turn triggering cell death and inducing the formation of inflammatory mediators, which then induce JNK, p-38, NFκB and AP-1 activation in glial cells, endothelial cells, and infiltrating leukocytes. This culminates in pro-inflammatory cytokine and chemokine secretion and leads to the invasion of leukocytes via up-regulation of endothelial adhesion molecules.

Mentions: The pathophysiology of stroke is complex and involves numerous processes, including: energy failure, loss of cell ion homeostasis, acidosis, increased intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, generation of arachidonic acid products, cytokine-mediated cytotoxicity, complement activation, disruption of the blood-brain barrier (BBB), activation of glial cells, and infiltration of leukocytes (Figure 1). These are interrelated and co-ordinated events, which can lead to ischemic necrosis, which occurs in the severely affected ischemic-core regions. Within a few minutes of a cerebral ischemia, the core of brain tissue exposed to the most dramatic blood flow reduction, is mortally injured, and subsequently undergoes necrotic cell death. This necrotic core is surrounded by a zone of less severely affected tissue which is rendered functionally silent by reduced blood flow but remains metabolically active [14,15]. Necrosis is morphologically characterized by initial cellular and organelle swelling, subsequent disruption of nuclear, organelle, and plasma membranes, disintegration of nuclear structure and cytoplasmic organelles with extrusion of cell contents into the extracellular space [14,15]. The region bordering the infarct core, known as the ischemic penumbra, comprises as much as half of the total lesion volume during the initial stages of ischemia, and represents the region in which there is opportunity for salvage via post-stroke therapy [16]. Less severe ischemia, as occurs in the penumbra region of a focal ischemic infarct, evolves more slowly, and depends on the activation of specific genes and may ultimately result in apoptosis [17-19]. Recent research has revealed that many neurons in the ischemic penumbra, or peri-infarct zone, may undergo apoptosis only after several hours or days, and thus they are potentially recoverable for some time after the onset of stroke. In contrast to necrosis, apoptosis appears to be a relatively orderly process of energy-dependent programmed cell death to dispose of redundant cells. Cells undergoing apoptosis are dismantled from within in an organized way that minimizes damage and disruption to neighboring cells [15]. There are two general pathways for activation of apoptosis: the intrinsic and extrinsic pathways. Over the last decade, experimental studies have provided considerable new information characterizing apoptotic processes occurring after ischemic stroke.


Pathophysiology, treatment, and animal and cellular models of human ischemic stroke.

Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV - Mol Neurodegener (2011)

Major cellular patho-physiological mechanisms of ischemic stroke. Ischemia-induced energy failure leads to the depolarization of neurons. Activation of specific glutamate receptors dramatically increases intracellular Ca2+, and Na+, and K+ is released into the extracellular space. Edema results from water shifts to the intracellular space. Increased levels of intracellular messenger Ca2+ activates proteases, lipases and endonucleases. Free radicals are generated which damage membranes, mitochondria and DNA, in turn triggering cell death and inducing the formation of inflammatory mediators, which then induce JNK, p-38, NFκB and AP-1 activation in glial cells, endothelial cells, and infiltrating leukocytes. This culminates in pro-inflammatory cytokine and chemokine secretion and leads to the invasion of leukocytes via up-regulation of endothelial adhesion molecules.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037909&req=5

Figure 1: Major cellular patho-physiological mechanisms of ischemic stroke. Ischemia-induced energy failure leads to the depolarization of neurons. Activation of specific glutamate receptors dramatically increases intracellular Ca2+, and Na+, and K+ is released into the extracellular space. Edema results from water shifts to the intracellular space. Increased levels of intracellular messenger Ca2+ activates proteases, lipases and endonucleases. Free radicals are generated which damage membranes, mitochondria and DNA, in turn triggering cell death and inducing the formation of inflammatory mediators, which then induce JNK, p-38, NFκB and AP-1 activation in glial cells, endothelial cells, and infiltrating leukocytes. This culminates in pro-inflammatory cytokine and chemokine secretion and leads to the invasion of leukocytes via up-regulation of endothelial adhesion molecules.
Mentions: The pathophysiology of stroke is complex and involves numerous processes, including: energy failure, loss of cell ion homeostasis, acidosis, increased intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, generation of arachidonic acid products, cytokine-mediated cytotoxicity, complement activation, disruption of the blood-brain barrier (BBB), activation of glial cells, and infiltration of leukocytes (Figure 1). These are interrelated and co-ordinated events, which can lead to ischemic necrosis, which occurs in the severely affected ischemic-core regions. Within a few minutes of a cerebral ischemia, the core of brain tissue exposed to the most dramatic blood flow reduction, is mortally injured, and subsequently undergoes necrotic cell death. This necrotic core is surrounded by a zone of less severely affected tissue which is rendered functionally silent by reduced blood flow but remains metabolically active [14,15]. Necrosis is morphologically characterized by initial cellular and organelle swelling, subsequent disruption of nuclear, organelle, and plasma membranes, disintegration of nuclear structure and cytoplasmic organelles with extrusion of cell contents into the extracellular space [14,15]. The region bordering the infarct core, known as the ischemic penumbra, comprises as much as half of the total lesion volume during the initial stages of ischemia, and represents the region in which there is opportunity for salvage via post-stroke therapy [16]. Less severe ischemia, as occurs in the penumbra region of a focal ischemic infarct, evolves more slowly, and depends on the activation of specific genes and may ultimately result in apoptosis [17-19]. Recent research has revealed that many neurons in the ischemic penumbra, or peri-infarct zone, may undergo apoptosis only after several hours or days, and thus they are potentially recoverable for some time after the onset of stroke. In contrast to necrosis, apoptosis appears to be a relatively orderly process of energy-dependent programmed cell death to dispose of redundant cells. Cells undergoing apoptosis are dismantled from within in an organized way that minimizes damage and disruption to neighboring cells [15]. There are two general pathways for activation of apoptosis: the intrinsic and extrinsic pathways. Over the last decade, experimental studies have provided considerable new information characterizing apoptotic processes occurring after ischemic stroke.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. t.woodruff@uq.edu.au.

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.

No MeSH data available.


Related in: MedlinePlus