Inhibition Of P38Mitogen Activated Protein Kinase Pathway Attenuates Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage

PART Ⅰ:Potential role of p38MAPK pathway in cerebral vasospasm after experimental subarachnoid hemorrhage in rabbitsObjective:Previous studies have demonstrated signal transduction pathways play a critical role in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage and p38MAPK pathway has been shown to be involved in numerous physiological processes, such as cell proliferation,cell survival, apoptosis, inflammation, and embryonic development. This work was conducted to investigate the role of p38MAPK on cerebral vasospasm in a rabbit model of SAH.Methods:In experiment1,24rabbits were assigned randomly to four groups:control, SAH day3, SAH day5, and SAH day7groups,and were killed on days3,5, and7. The time course of the total p38MAPK,p-p38MAPK,total ATF2and p-ATF2activation in the basilar artery after SAH was analyzed by Wester blot.In experiment2,24rabbits were assigned randomly to four groups:control, SAH, SAH+DMSO,SAH+SB203580,and were killed on day7. The blood vessel cross-sectional area was measured by hematoxylin-eosin staining.Results:As a result, the elevated expression of activated p-p38MAPK and p-ATF2was detected in the basilar artery after SAH from day3,peaked on day5. After SB203580intracisternal administration, the level of p-p38MAPK and p-ATF2were decreased and the vasospasm was markedly attenuated in the basilar arteries.Conclusion:p38MAPK pathway was activated in the arterial wall after SAH and contribute to vasospasm development. Administration of p38MAPK inhibitor may attenuate cerebral vasospasm in a rabbit model of SAH.PART Ⅱ:Potential role of p38MAPK pathway in the inflammatory reaction after experimental subarachnoid hemorrhageObjective:Inflammatory recaction is involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to examine whether SB203580,a p38MAPK inhibitor,would suppress inflammatory recaction after experimental SAH.Methods:48rabbits were assigned randomly to four groups:control, SAH, SAH+DMSO,SAH+SB203580,and were killed on day7. The gene expression levels of cytokines and adhesion molecules in the basilar artery were measured by RT-PCR. Immunohistochemical study was performed to assess the expression and localization of CD4、CD68and myeloperoxidase (MPO).Results:SAH could induce increases of the gene expression levels of IL-1β、TNF-α、ICAM-1and VCAM-1, which were reduced in the SAH+SB203580 group.Immunohistochemical study demonstrated that the expression levels of CD4、 CD68and and MPO were all increased in the SAH group, but these increases were attenuated in the SAH+SB203580group.Conclusion:Inflammatory recaction was evoked by SAH,maybe due to the activation of p38MAPK pathway,and could be suppressed by p38MAPK inhibitor SB203580.PART HI:Potential role of p38MAPK pathway in the endothelial apoptosis after experimental subarachnoid hemorrhageObjective:Previous study have demonstrated that p38mitogen-activated protein kinase(MAPK) plays an important role in apoptosis, which is involved in the development of cerebral vasospasm after SAH. This study was conducted to examine whether SB203580,a selective p38MAPK inhibitor could reduce cerebral vasospasm through the suppression of apoptosis.Methods:48rabbits were assigned randomly to four groups:control, SAH, SAH+DMSO,SAH+SB203580,and were killed on day7. The the endothelial apoptosis was examined by was examined by Western blot analysis of caspase-3activity and TUNEL staining.Results:Elevated expression of cleaved caspase-3was detected in the basilar artery after SAH and suppresed after SB203580administration. Apoptosis was not detected in the control group. Strong positive cells were visualized in the SAH and SAH+DMSO groups. Weak positive cells were observed in the SAH+SB203580group. Conclusion:Endothelial apoptosis was evoked by SAH,maybe due to the activation of p38MAPK pathway,and could be suppressed by p38MAPK inhibitor SB203580.