Treatment with combined NMDA and non-NMDA antagonists to reduce excitotoxic CNS damage

摘要

This invention involves a pharmaceutical mixture for preventing or reducing excitotoxic brain damage caused by hypoxia/ischemia (such as stroke) and various other factors. This mixture comprises an NMDA antagonist and a non-NMDA antagonist, both of which penetrate blood- brain barriers (BBB's) and which, in combination, provide greater protection against excitotoxic damage than can be provided by any quantity of either agent by itself. Suitable NMDA antagonists can be either competitive antagonists which bind directy to the NMDA binding site in the NMDA receptor complex, or non-competitive agents that interact with other binding sites such as the PCP, glycine, or polyamine binding sites. Suitable non-NMDA antagonists include a quinoxalinedione compound referred to as NBQX, and a 2,3-benzodiazepine compound referred to as GYKI 52466. If an NMDA antagonist is used which is stronger than dextromethorphan, the mixture of an NMDA and a non-NMDA antagonist preferably should be administered in combination with a third agent that functions as a "safening agent" to prevent or reduce the neurotoxic side effects caused by strong NMDA antagonists. Two classes of safening agents have been identified: (1) anti-cholinergic agents such as scopolamine and, (2) barbiturates which act as direct agonists of gamma- amino-butyric acid (GABA) receptors, such as secobarbital, pentobarbital, and thiamylal.