Stimulation of protein tyrosine phophorylation participates in delayd neuronal death in ischemic hippocampus

谷氨酸引发脑缺血/再灌注后的神经元变性。然而，导致细胞死亡的细胞内信号转导的细节尚不清楚。本研究探讨了蛋白酪氨酸磷酸化是否介导缺血性脑的神经元死亡。蒙古沙鼠短暂性前脑缺血5-10 min或Sprague-dawley大鼠谷氨酸类似物（kainic acid, 12 mg/kg）中毒分别在2-4天和1天后导致海马神经元选择性死亡。在这些条件下，缺血后3-12小时或kainic酸诱导癫痫发作后4-8小时，海马160,115,105,92,85 kDa蛋白酪氨酸残基磷酸化选择性显著增加。酪氨酸激酶，包括pp60c-src，在酪氨酸磷酸化酶没有改变的情况下被激活。给予选择性酪氨酸激酶抑制剂radicicol，可减轻缺血后酪氨酸磷酸化和海马变性的刺激或kainic酸注射。结果表明，酪氨酸蛋白磷酸化可能通过谷氨酸过载在缺血/再灌注后的成熟海马中传播延迟神经元死亡。

Glutamate triggers neuronal degeneration following ischemia/reperfusion in the brain. However, the details of intracellular signal transduction that propagate cell death remain unknown. The present work investigated whether protein tyrosine phophorylation mediates neuronal death in the ischemic brain. Transient forebrain ischemia for 5-10 min in Mobgolian gerbils or intoxication of 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, 160,115,105,92,85 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 kinase, including pp60c-src, were activated without a change of tyrosine phophatases. Administration of radicicol, a selective inhibitor of tyrosine kinases, attenuated stimulation of tyrosine phophorylation and hippocampal degeneration after ischemia or kainic acid injection. the results suggest that protein tyrosine phosphorylation might propagate delayd neuronal death in the amture hippocampus through glutamate overload after ischemia/reperfusion.