The Mechanisms Of Effect And Regulation Of Mitogen Activated Protein Kinases(MAPKs)Signal Transduction Following Traumatic Brain Injury

Background: The brain tissue damage results from both direct mechanical injury and secondary brain impairment involved in a cascade of biochemical changes after traumatic brain injury (TBJ). Increasing evidences show that TBI may induce apoptosis, and that neuronal apoptosis plays an important role in neurodegeneration and neuron loss, therefore, the further studies on the molecular mechanisms of the neuronal apoptosis might give a new insight on the treatment of TBI. Although many signal molecules, such as protein kinase C (PKC), nitric oxide (NO), mitogen-activated protein kinases (MAPK5), caspase, and so on, have been proposted to mediate the apoptofc process, the signal transduction mechanisms involved in it remain unclear. MAPKs, a ubiquitous serine/thronine protein kinases, are essential mediators of the signal transduction pathways and occupy a central position in cell growth, differentiation, and apoptosis. Several MAPKs have been identified, including extracellulal signal-regulated protein kinase(ERK), p38 kinase, c- Jun N-terminal protein kinase(JNK), and ERR5. It was demonstrated that the withdrawal of the nerve growth factor(NGF) from rat PC12 cells might induce the sustained activation of p38 and JNK enzymes but the inhibition of ERK, which resulted in the cells apoptosis. It implied that the activation of p38 and INK and the concurrent inhibition of ERK are critical for induction 9 of apotosis in PC12 cells. Recently, it was reported that p38 and JNK were activated following ischemic brain injury, and SB203580, a specific inhibitor of p38, migt~t inhibit the neuronal apoptosis. In both neuron and PC12 cells, expression of c-Jun mutants with dominant negative charater inhibited the apoptosis. These evidences implied that the signaling pathway of p38 and JNI( might be related to the neuronal apoptosis. However, the activity changes of p38 and JNK in injured cerebral cortex of rats have not been systematically reported yet. Although TBI can cause neuronal apotosis, the mechanism of apoptosis has not been fully elucidated. Experimants showed that the interaction between the Fas molecule and its ligand (Fas ligand, FasL) might induce a apoptotic cell death in various systems. However, few study about neuronal apoptosis involved Fas/FasL after TBI. The expression of genes is generally regulated by transcription fator. The nuclear targets of MAPKs signaling pathways are some related transcription factor, but it has not been checked whether the signaling pathway of p38 and JNK modulate the expressior of FasL gene in injured brain after TBI or not. In the central nervous system, PKC activation initiate and regulate various signal transduction processes by phosphorylating many different intracellular proteins. Evidences showed that PKC inhibition might be neuroprotedtive in cerebral ischemia. Therefore, it was suggested that PKC activation might play an important role in neuronal apoptosis. NO, as a signaling molecule, possesses plentiful biologic activities with either neuroprotective or neurotoxic. The action of NO has been recently found to be relation to induction of apoptosis, in various cells including neuronal cells. These reports demonstrated that the activation of PKC and the excessive release of NO might mediate the process of neuronal apotosis. It has been suggested that the activation of caspase-3, following by cleavage of specific substrats, may contribu?to the process o...