Prevention of apoptosis by p21 gene tranfer in central nervous system

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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.