In Project II, two types of clinically-safe (N-methyl-D-aspartate) NMDA antagonists will be tested for their ability to prevent hypoxic-ischemic damage relevant to mental retardation. In these studies we will attempt to ameliorate NMDA receptor-mediated neurotoxicity first in vitro and subsequently in vivo in a developmental fashion, including rat pups and adult rats. The first type of NMDA antagonists to be tested are open- channel blockers derived from a chemical class of drugs known as adamantanes; these drugs are currently in clinical use for other disorders such as Parkinson's disease. The second type of NMDA antagonists are mild oxidizing agents that oxidize the redox modulatory site of the NMDA receptor-channel complex to turn off excessive NMDA- evoked current responsible for neuronal injury; some of these drugs act by generating a redox-related form of nitric oxide (NO.); we have shown previously shown that alternative redox states of the NO group down- regulate NMDA receptor activity. NO group donating drugs, such as nitroglycerin (NTG), are also in clinical use for other reasons and can be used safely in this manner. We are developing and investigating these NMDA antagonists in vitro and in vivo in animal models so that they can potentially be used clinically in children to combat hypoxic-ischemic brain injury, trauma, seizures, and various neurodegenerative diseases. In addition, a novel compound, combining the features of an NO group transfer drug with the NMDA channel blocking drug, is being developed. 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. From the preliminary data, open-channel blockers such as memantine will be useful for acute NMDA receptor-mediated neurotoxicity while agents working to down-regulate the redox modulatory site should prove effective in combating chronic NMDA-induced neuronal damage, although their acute administration in conjunction with pressor agent to maintain the blood pressure is also possible.
The Specific Aims of Project II are as follows: 1. To test adamantanes, such as memantine and its derivatives, which we have shown are NMDA open-channel blockers, for their ability to prevent acute NMDA receptor-mediated neurotoxicity in vitro and in vivo in rat models of hypoxic-ischemic damage. 2. To characterize and test redox reagents, including redox-related forms of nitric oxide (NO.), that oxidize the redox modulatory site of the NMDA receptor-channel complex in order to prevent NMDA receptor- mediated neurotoxicity. These drugs donate the NO group in the form of NO+ or NO-, and have one less and one more electron than true nitric oxide, respectively. These redox reagents will be used to ameliorate NMDA receptor-mediated neurotoxicity in vitro and in vivo in animal models of hypoxic-ischemic damage.
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