Prevention of apoptosis by p21 gene tranfer in central nervous system

我们在包括局灶性脑缺血、神经损伤和蛛网膜下腔出血在内的多种脑损伤模型中检测到了p21 mRNA的表达。将p21 mRNA表达量与热休克蛋白(hsp)-70、c-fos和c-jun等基因表达量进行比较。局灶性缺血时，p21在缺血区和半暗区均有表达，在缺血后12-24小时表达量最大。缺血侧海马锥体细胞也有p21 mRNA表达。与c-fos、c-jun和hsp-70的表达相比，p21 mRNA的表达存在时间延迟，表明细胞内信号通路不同。神经元的p21 mRNA表达高于神经胶质细胞。Western blot证实p21蛋白在缺血半球表达。在神经损伤模型中也得到了类似的结果，表明p21反应是神经元对损伤的普遍反应。我们在蛛网膜下腔出血模型中检测到p21 mRNA的表达，该模型是由于穿孔侧海马轻度缺血引起的细胞凋亡。蛛网膜下腔出血的表达高峰持续24 ~ 120 h。该模型的神经元凋亡发生在48小时内。这些数据表明，p21不会导致细胞凋亡，而是在应激下起到细胞恢复的作用。然后我们在胶质瘤细胞系中检测了p21基因表达的调节物质。在这项研究中，p21 mRNA与前列腺素一起上调，表明可能存在细胞周期调节药物。

We have detected p21 mRNA expression in various types of brain injury models, which includes focal cerebral ischemia, neurotrauma and subarachnoid hemorrhage. The p21 mRNA expression was compared to the other gene expression such as heat shock protein (hsp)-70, c-fos and c-jun. In the focal ischemia, p21 expression was detected in the area of ischemia and penumbra zone with maximal expression at 12-24 hours after ischemi. Hippocampal pyramidal cells of the ischemia side also showed p21 mRNA expression. The p21 mRNA expression has time delay as compared to expression of c-fos, c-jun and hsp-70, indicating different intracellular signalling pathway. Neurons showed more p21 mRNA expression than glia. Western blot study confirmed p21 protein expression in the ischemic hemisphere. Similar results were obtained in the neurotrauma model indicating p21 response as an ubiquitous response of neurons against injury. We detected p21 mRNA expression in the subarachnoid hemorrhage model which caused apoptosis due to mild ischemia in the pefforated side hippocampus. The peak expression in subarachnoid hemorrhage lasted from 24 hours till 120 hours. Neuronal apoptosis in this model occurred within 48 hours. These data suggest that p21 did not cause apoptosis but act as cell recovery from stress. We then detected regurating substance for p21 gene expression in the glioma cell line. In this study, p21 mRNA were upregulated with prostanoids indicating possible cell cycle-regulating drugs.