Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A(2) inhibitors.
In kainate-induced neurotoxicity, the stimulation of kainate receptors results in the activation of phospholipase A(2) and a rapid release of arachidonic acid from neural membrane glycerophospholipids. This process raises arachidonic acid levels and produces alterations in membrane fluidity and permeability. These result in calcium influx and stimulation of lipolysis and proteolysis, production of lipid peroxides, depletion of ATP, and loss of reduced glutathione. As well as the above neurochemical changes, stimulation of ornithine decarboxylase, altered activities of protein kinase C isozymes, and expression of immediate early genes, cytokines, growth factors, and heat shock proteins have also been reported. Kainate-induced stimulation of arachidonic acid release, calcium influx, accumulation of lipid peroxides and products of their decomposition, especially 4-hydroxynonenal (4-HNE), along with alterations in cellular redox state and ATP depletion may play important roles in kainate-induced cell death. Thus the consequences of altered glycerophospholipid metabolism in kainate-induced neurotoxicity can lead to cell death. Kainate-induced neurotoxicity initiates apoptotic as well as necrotic cell death depending upon the intensity of oxidative stress and abnormality in mitochondrial function. Other neurochemical changes may be related to synaptic reorganization following kainate-induced seizures and may be involved in recapitulation of hippocampal development and synaptogenesis.
Farooqui
A A
AA
Department of Molecular and Cellular Biochemistry, 1645 Neil Avenue, 465 Hamilton Hall, The Ohio State University, Columbus, OH 43210-1218, USA.
Yi Ong
W
W
Lu
X R
XR
Halliwell
B
B
Horrocks
L A
LA
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020404:Glycerophospholipids / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000378:metabolism
D016718:Arachidonic Acid; D004791:Enzyme Inhibitors; D020404:Glycerophospholipids; D007608:Kainic Acid; D010741:Phospholipases A; D018092:Kainic Acid Receptors