[Cerebral ischemia-hypoxia and biophysical mechanisms of neurodegeneration and neuroprotection effects].
Neuronal responses to hypoxia-ischemia can be acute or chronic. In the early stages neuronal responses to ischemia-hypoxia are dependent on the modulation of ion channels. Acute responses relay mainly on O2-regulated ion channels which mediate adaptive changes in neuron excitability. Energy failure, an early consequence of hypoxia-ischemia, causes disruption of ionic homeostasis and accumulation of extracellular neurotransmitters. NMDA and AMPA/kainate receptors and Ca2+ channels contribute to excitotoxic neuronal degeneration. Excitotoxicity leads to increased Ca2+ influx, which can activate cytotoxic intracellular pathways. Reactive oxygen species (oxygen free radicals) generated during ischemia-reperfusion contribute to the injury. Oxygen free-radicals serve as important signalling molecules that trigger inflammation and apoptosis. Excitatory amino acid-receptor antagonists and Ca2+ channels blockers can provide neuroprotection in experimental models of hypoxia-ischemia but disrupt normal brain function. Because of their relative lack of behavioral side-effects, voltage-dependent Na+ channels blockers may have advantage over other neuroprotective mechanisms. The blockade of voltage-gated Na+ channels reduces the excitability of neurons, Na+ influx and the accumulation of intracellular Na+. These improve the ionic homeostasis and cellular energy levels and prevent ischemia-hypoxia induced neuronal injury and neuronal damage mediated by Ca2+ overload.
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A.A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kiev.
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism / Q000473:pathology*; D007473:Ion Channels / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D007473:Ion Channels; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017470:Receptors, Glutamate; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012964:Sodium; D010100:Oxygen; D007608:Kainic Acid; D002118:Calcium