Evidence from cultured rat cortical neurons of differences in the mechanism of ischemic preconditioning of brain and heart.
Ca2+ influx and activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) during nonlethal ischemic preconditioning have been implicated in the protection of the heart against subsequent lethal ischemic injury. Thus, we determined if Ca2+ influx, PKC and MAPK also mediate ischemic preconditioning-induced protection in neurons. Preconditioning by exposure of E18 rat cortical cultures to 90 min of nonlethal oxygen-glucose deprivation (OGD) 24 h prior to 180-240 min of lethal OGD was neuroprotective. Exposure to nominally free Ca2+, or blockade of the alpha-amino-hydroxy-5-methyl-isoxazolepropionate (AMPA) receptor with CNQX did not eliminate protection. MAPK activity did not change and PKC activity decreased by 50% relative to normal baseline levels at 0 and 24 h following preconditioning. The sustained decrease in PKC activity was not due to a loss of enzyme as determined from immunoblots using pan and epsilon-, beta- and zeta-specific PKC antibodies. Neuroprotection was maintained with pharmacological inhibition of PKC activity by staurosporine, chelerythrine and calphostin C and MAPK activity by PD 98059 during preconditioning, indicating that activation of these enzymes during preconditioning was not necessary for protection. Therefore, in contrast to cardiac tissue, ischemic preconditioning of neurons does not require activation of PKC and MAP kinase, and protection is maintained with substantial removal of extracellular Ca2+ or blockade of the AMPA receptor.
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D019194:Ischemic Preconditioning; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010100:Oxygen / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats