Acute ischemic brain injury associated with Subarachnoid hemorrhage (SAH) is the most important determinant of outcome after SAH, but its mechanisms are poorly understood and effective treatments do not exist. The goal of this study is to characterize alterations in cerebral Nitric oxide (NO) levels and NO synthase (NOS) pathways after SAH and to determine their contribution to SAH-induced acute cerebral ischemic injury. Three primary hypotheses will be tested: 1) SAH is accompanied by acute triphasic alterations in the NO/NOS pathway that cause ischemic neuronal injury. 2) CBF changes and neuronal apoptosis can be used to study participation of NO in ischemic injury after SAH 3) Participation of NO in ischemic neuronal injury after SAH can be pharmacologically manipulated to decrease ischemic damage. In this proposal cerebral NO levels will be determined and activity and protein levels of NOS isozymes, endothelial (eNOS), neuronal (nNOS) and inducible (iNOS), will be studied after experimental SAH. The influence of NO levels on CBF and apoptosis in each putative phase of SAH will be examined. NO donors and NOS inhibitors will be administered to study the phase-dependent modulation of NO and NOS activity and expression on markers of cerebral ischemia. The experimental design will focus on three major questions: 1) What are the time dependent alterations in cerebral NO levels and their relation to NOS expression and activity during the first 72 hours after SAH? 2) Can changes in CBF and neuronal apoptosis be used as pathophysiological end points to study involvement of NO in ischemic injury after SAH? and 3) Can pharmacological modulation of cerebral NO levels and NOS expression and activity be used to decrease the intensity of ischemic neuronal injury after SAH? This study will increase our understanding of acute SAH induced cerebral ischemia and aid in the development of pharmacological treatments designed to prevent this ischemic injury. ? ?
|Sehba, Fatima A; Mostafa, Gulam; Friedrich Jr, Victor et al. (2005) Acute microvascular platelet aggregation after subarachnoid hemorrhage. J Neurosurg 102:1094-100|
|Sehba, Fatima A; Chereshnev, Igor; Maayani, Saul et al. (2004) Nitric oxide synthase in acute alteration of nitric oxide levels after subarachnoid hemorrhage. Neurosurgery 55:671-7; discussion 677-8|
|Sehba, Fatima A; Mostafa, Gulam; Knopman, Jared et al. (2004) Acute alterations in microvascular basal lamina after subarachnoid hemorrhage. J Neurosurg 101:633-40|