Biology of ischemic cerebral cell death.
With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+ -dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors.
Small
D L
DL
Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario. Dan.Small@nrc.ca
Morley
P
P
Buchan
A M
AM
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D005343:Fibrinolytic Agents; D005609:Free Radicals; D017470:Receptors, Glutamate; D010959:Tissue Plasminogen Activator