DELAYED NEURONAL DEATH IN ISCHEMIC HIPPOCAMPUS INVOLVES STIMULATION OF PROTEIN-TYROSINE PHOSPHORYLATION

Glutamate triggers neuronal degeneration after ischemia-reperfusion in the brain. However, the details of intracellular signal transduction that propagates cell death remain unknown. The present work investigat ed whether protein tyrosine phosphorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mong olian gerbils or intoxication with the glutamate analogue kainic acid (12 mg/kg) in Sprague-Dawley rats caused neuronal death selectively in the hippocampus 2-4 days or 1 day later, respectively. Under these co nditions, 160-, 115-, 105-, 92-, and 85-kDa proteins showed a signific ant increase in tyrosyl residue phosphorylation selectively in the hip pocampus 3-12 h after ischemia or 4-8 h after kainic acid-induced seiz ures. Tyrosine kinases, including pp60(c-src), were activated without a change of tyrosine phosphatases. Administration of radicicol, a sele ctive inhibitor of tyrosine kinases, attenuated stimulation of tyrosin e phosphorylation and hippocampal degeneration after ischemia or kaini c acid injection. The results suggest that protein tyrosine phosphoryl ation might propagate delayed neuronal death in the mature hippocampus through glutamate overload after ischemia-reperfusion.