There currently exists no effective prophylactic or post-hoc pharmacotherapy for minimizing ischemia-induced neuronal damage. More than one million people in America are believed to suffer neuronal damage and physical and cognitive impairments as a consequence of ischemia associated with chronic cerebrovascular disease or acute cardiac arrest. Nova has discovered two series of compounds that show particular promise in preliminary screens for cerebroprotective activity; lead compounds increase survival in an hypoxic environment and block NMDA and MES - induced seizures. The primary goal of the proposed research is to confirm the cerebroprotective potential of these agents using models of transient global (gerbil carotid artery occlusion) and focal (photochemically- induced thrombosis) ischemia. a second goal will be to complete examination of the two series of compounds in the preliminary cerebroprotection screens. Finally, we propose to evaluate the potency of both series of compounds to displace sigma receptor ligands and to noncompetitively modulate bindings at the [3H] TCP-labeled, NMDA receptor associated """"""""PCP"""""""" site hopes of identifying a binding site/receptor assay predictive of cerebroprotective activity.
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| Clissold, D B; Pontecorvo, M J; Jones, B E et al. (1993) NPC 16377, a potent and selective sigma-ligand. II. Behavioral and neuroprotective profile. J Pharmacol Exp Ther 265:876-86 |
| Pontecorvo, M J; Karbon, E W; Goode, S et al. (1991) Possible cerebroprotective and in vivo NMDA antagonist activities of sigma agents. Brain Res Bull 26:461-5 |
| Clissold, D B; Jones, B E; Pontecorvo, M J (1991) Photochemically induced thrombosis of the precentral cortex impairs operant variable-interval spatial delayed alternation performance by rats. Brain Res Bull 26:647-51 |
