In Project, we will test two types of clinically-safe N-methyl-D-aspartate receptor (NMDAR) antagonists for their ability to prevent hypoxic-ischemic damage relevant to mental retardation. In these studies we will attempt to ameliorate NMDAR-mediated neurotoxicity first in vitro and subsequently in vivo in stroke models with therapy initiated greater than or equal to 2 hours after the insult. First, open-challenge NMDA blockers (adamantanes) will be tested; one of these drugs, memantine, is currently in clinical use in Europe for other disorders such as Parkinson's disease and spasticity. Second to be tested is nitroglycerin (NTG), which generates a redox-related form of nitric oxide that NO-related species is transferred to cysteine sulfhydryl groups of the NMDAR, a reaction termed S-nitrosylation. Additionally, a series of novel compounds, nitro-memantines, combining the features of NO+ transfer with open-channel block, are being developed. These combinatorial drugs will target NO+ to the NMDAR via memantine and thus avoid systemic side effects of NO such as hypotension. These combinatorial drugs will target NO+ to the NMDAR via memantine and thus avoid systemic side effects of NO such as hypotension. These studies with novel and potentially safe NMDA antagonists have important implications for the treatment of mental retardation and developmental disabilities due to overstimulation of glutamate receptors. To try to extend the potential window of treatment after a stroke, we will attempt to intervene therapeutically in apoptotic pathways activated with a delay after excessive NMDAR stimulation. The pathways studied here involve the action of caspases in the intracellular signaling cascade leading to neuronal apoptosis. Inhibition of caspase activity pharmacologically and with a caspase dominant-negative transgenic mouse will be use din conjunction with fluorescent indicators for Ca2+, reactive oxygen species, mitochondrial membrane depolarization, and lipid peroxidation in an attempt to decipher where caspases act in these signaling pathways that lead to hypoxic/ischemic neuronal damage. According, the Specific Aims of Project II are-2. To test drugs that we hypothesize nitrosylate the NMDAR to prevent hypoxic-ischemic neurotoxicity, including nitroglycerin (NTG) and novel nitro-memantine drugs that target NO+ to the NMDAR to avoid systemic side effects such as hypotension. 3. To characterize the action of caspases on intracellular signaling in excitotoxin-induced neuronal apoptosis.
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