Despite advances in diagnosis and therapy, cerebral vasospasm remains the greatest treatable cause of morbidity and mortality in patients who survive the ictus of subarachnoid hemorrhage (SAH). In the past decade, up to 30 percent of such patients suffer stroke or death from cerebral vasospasm, despite maximal therapy. The failure of clinical management indicates the poor understanding of cerebral vasospasm in the past and at the present. One of the most important but un-addressed issues is the impact of endothelial death in the initiating, maintaining, and enhancing of cerebral vasospasm. Our published results on oxyhemoglobin-induced endothelial apoptosis and our preliminary data from an established dog double-hemorrhage model demonstrated that endothelial apoptosis occurred before vasospasm and prevention of apoptosis relieved symptoms of vasospasm. However, we need to expand these initial findings to specify the precise apoptotic pathways in vasospasm, to examine the consequences of apoptosis on vasospasm, and to investigate whether inhibition of apoptosis prevents or reverses vasospasm. Our overall hypothesis is that autoTogues blood produces apoptosis in endothelial cells in cerebral arteries by activation of distinct death pathways: prevention of apoptosis in cerebral endothelial cells reduces the degree of vasospasm and shortens the time course of cerebral vasospasm. We will address three specific aims.
In Specific Aim 1, we will examine the hypothesis that subarachnoid blood induces endothelial apoptosis which leads to vasospasm. We will identify apoptotic changes in the endothelial cells in the major and penetrating cerebral arteries and evaluate the time courses of apoptosis in vasospasm.
In Specific Aim 2, we will examine the hypothesis that initiative caspase8, caspase-9, and executive caspase-3, and caspase-7 are involved in apoptosis, and the related caspase inhibitors prevent apoptosis and vasospasm.
In Specific Aim 3, we will examine the hypothesis that poly (ADP-ribose) polymerase (PARP) pathways are involved in apoptosis in endothelial cells, and PARP inhibitors prevent apoptosis and vasospasm. An established dog double-hemorrhage model will be used in all these studies. We expect that our results will ultimately identify potential therapeutic targets of the apoptosis pathway that can be directed towards the treatment of cerebral vasospasm after SAH.
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