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 investigated whether protein tyrosine phosphorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mongolian 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 conditions, 160-, 115-, 105-, 92-, and 85-kDa proteins showed a significant increase in tyrosyl residue phosphorylation selectively in the hippocampus 3-12 h after ischemia or 4-8 h after kainic acid-induced seizures. Tyrosine kinases, including pp60c-src, were activated without a change of tyrosine phosphatases. Administration of radicicol, a selective inhibitor of tyrosine kinases, attenuated stimulation of tyrosine phosphorylation and hippocampal degeneration after ischemia or kainic acid injection. The results suggest that protein tyrosine phosphorylation might propagate delayed neuronal death in the mature hippocampus through glutamate overload after ischemia-reperfusion.
First Department of Medicine, Osaka University Medical School, Japan.
T
T
Ohtsuki
M
M
Matsumoto
K
K
Kitagawa
T
T
Mabuchi
K
K
Mandai
K
K
Matsushita
K
K
Kuwabara
M
M
Tagaya
S
S
Ogawa
H
H
Ueda
T
T
Kamada
T
T
Yanagihara
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D007608:Kainic Acid / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008297:Male; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control; D013997:Time Factors
D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017027:Protein Tyrosine Phosphatases; C035359:monorden; D007608:Kainic Acid