Mechanisms of ischemic brain damage

Abstract

In the United States stroke is the third leading cause of death and the leading cause of disability. Brain injury following stroke results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, ionic imbalance, peri-infarct depolarization, oxidative and nitrative stress, inflammation and apoptosis. There are very few treatments for stroke and the development of new treatments requires a comprehensive understanding of the diverse mechanisms of ischemic brain damage that are responsible for neuronal death. Here, we discuss the underlying pathophysiology of this devastating disease and reveal the intertwined pathways that are the target of therapeutic intervention.

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

“…Indeed, hyperexcitability is a common feature of many diseases such as epilepsy and ischemia; massive neurotransmitters release occurs during brain ischemia, possibly due to damageinduced depolarization and/or the rising of intracellular Ca 2+ concentrations. 2 Thus, modulation of K + channel activity has been acknowledged as a possible target for neuroprotection. Among the different neurotransmitters, dopamine release has been shown to reach very high levels soon after an ischemic insult in the caudate, and also to contribute to neuronal damage; 5 indeed, depletion of dopaminergic nigro-striatal projections has been shown to reduce ischemic damage.…”

“…In stroke and hypoxia, ATP loss results in failure of membrane transporters and ion channels, with subsequent membrane depolarization and aberrant neurotransmitters efflux, thus amplifying injury. 2 Increased neuronal excitability seems to be a pathogenic mechanism underlying different diseases, such as Alzheimer's disease and epilepsy; moreover, epidemiologic studies as well as experiments on animal models have shown a relationship between ischemia and seizures. 3 Based on these observations, antiepileptic drugs have been also proposed for stroke treatment.…”

Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat

“…the number of life-years lost due to premature death and years lived with disability adjusted for severity, and accounts for 80-85% of all stroke incidents [1].…”

“…An ischemic event triggers a complex molecular cascade including impaired cellular energy metabolism, cell depolarization, excitotoxicity, and disruption of the blood-brain barrier [1]. Depending on the duration of the ischemic event, these pathophysiological changes can lead to extensive neuronal and glial cell injury and/or death, and axonal loss or demyelination, resulting in severe functional deficits [2].…”

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

“…The formation of the mitochondrial permeability transition pore (PTP) triggered by Ca 2+ overload or reactive oxygen is well documented [27][28][29][30]. This might happen by excitotoxicity including excessive glutamate release from depolarized neurons or dead cells, which causes permanent activation of glutamate receptors and persistent increase in the cytosolic Ca 2+ concentration [31][32][33]. Pro-apoptotic proteins like Bak and Bax promote the permeabilization of the outer mitochondrial membrane and release pro-apoptotic factors from the mitochondrial intermembrane space.…”