Sigma Receptor Signaling in Focal Ischemia

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During the past five years we have demonstrated that pharmacologic activation of sigma1 receptors greatly ameliorates the natural process of brain injury following transient focal ischemia. In addition, it is known that neurologic deterioration of aging, may be at least partially result from the natural reducation in endogenous hormones (e.g. DHEA) that are known to be agonists of the sigma1 receptor. Our previous work demonstrates that systemic administration of sigma1-receptor agonists improve outcome from experimental stroke, even when these agents are administered after the onset of reperfusion. In addition, we demonstrated that sigma1receptor agonists interfere with a primary mechanism of ischemic brain injury (NMDA receptor mediated NO toxicity). The overall goal of the current proposal is to test the hypothesis that sigma1receptor agonists cause neuroprotection by acting at sigma1receptors and interfering with specific parallel mechanisms of brain injury. Aim 1 will use cell culture techniques to determine the mechanism by which sigma1 receptors agonists interfere with NMDA induced NO production. The hypothesis to be tested is that the prototypic sigma1 receptor agonist PPBP indirectly impairs binding of NMDA to its receptor and does not have a direct effect on subsequent steps in the signal transduction pathway. Regardless of the exact site of action, since some sigma1 receptor agonists have been demonstrated to work through G-protein mechanisms, aim 2 will characterize the role of G-protein in basal and post-ischemic sigma1 receptor signaling mechanisms. The hypothesis is that PPBP impairs NMDA-stimulated NOS activity via a mechanism that involves a G-protein. As a parallel pathway we will also evaluate whether systemic administration of PPBP will impact the occurance of apoptosis. To this end aim 3 will test the hypothesis that PPBP administration is associated with increased bcl-2 and bcl-x-1 and decreased expression of bax in ischemic borderzones. Aim 4 will assess the therapeutic efficacy of endogenous hormones that are known to be agonists of the sigma1 receptor. We will test the hypothesis that the therapeutic efficacy of DHEA following transient focal ischemia is linked to decreased production of NO and can be blocked by specific sigma1 receptor antagonists. Aim 5 is designed to determine the mechanism for protection when the sigma1 receptor agonist is administered at the time of reperfusion. We will test the hypothesis that that delayed administration of PPBP during reperfusion from focal ischemia is associated with decreased expression of iNOS via a mechanism that is blocked by administration of a sigma1 receptor antagonist.