Role of protein kinase C in thedevelopment of ischemic brain edema

为了阐明PKC在缺血性脑水肿发生中的作用，我们检测了局灶性脑缺血大鼠的蛋白激酶C活性、Na^+/K^+- atp酶活性和脑含水量。右脑中动脉闭塞引起局灶性脑出血。虽然在MCA闭塞后2小时，缺血区域的PKC活性与缺血前水平相比没有显著变化，但在MCA闭塞后4小时，细胞底和膜部分的缺血区域PKC活性与缺血前水平相比均显著降低（p<0.001）。在MCA闭塞后4小时，缺血性脑半球的Na^+/K^+- atp酶活性比非缺血性脑半球下降。PKC激活剂phorbol 12-肉豆蔻酸酯13-乙酸酯（PMA）诱导缺血脑半球Na^+/K^+- atp酶活性水平升高至非缺血脑半球水平。MCA闭塞后4小时，缺血性脑半球脑含水量较缺血前显著增加。预处理PMA可防止中动脉闭塞后4小时缺血性脑半球含水量的增加。另一方面，PKC抑制剂H-7和阿托孢素预处理并不能阻止MCA闭塞后4小时缺血半球脑含水量的增加。提示蛋白激酶C调节Na^+/K^+-ATPasa活性，脑缺血时PKC活性降低导致Na^+/K^+-ATPase活性降低，导致缺血性脑水肿的发生。

To clarify the oile of protein kinase C (PKC) in the development of ischemic brain edema, we examined protein kinase C activity, Na^+/K^+-ATPase activity and brain water content in focal cerebral ischemia in the rat.Focal carebral ishemia was induced by the occlusion of the right middle cerebral artery (MCA occlusion).While PKC activity in the ischemic areas did mot sihnificantly change compared to preischemic levels at 2 hours after MCA occlusion, PKC activity in the ischemic areas significantly decreased in both cytosole and membrane fraction compared to preischemic levels at 4 hours after MCA occlusion(p<0.001).Na^+/K^+-ATPase activity in the ischemic cerebral hemispheres decreased in comparison to the non-ischemic cerebral hemisphere at 4 hours after MCA occlusion. PKC activator, phorbol 12-myristate 13-acetate (PMA), elicited an increase of the level of Na^+/K^+-ATPase activity in the ischemic cerebral hemisphere to the level present in the non-ischemic cerebral hemisphere. Four hours after MCA occlusion, brain water content in the ischemic cerebral himisphere significantly increased compared to the preischemic level. pretreatment with PMA prevented an increase in water content in the ischemic hemishere at 4 hours after MCA occlusion. On the other hand, pretreatment with PKC inhibitor, H-7 and ataurosporine, did not prevent an increase in brain water content in the ischemic hemispere at 4 hours after MCA occlusion.These results suggest that protein kinase C regulates Na^+/K^+-ATPasa activity and that decreased activity of PKC in cerebral ischemia induces the reduction if Na^+/K^+-ATPase activity, leading to the development of ischemic brain edema.