Amantadine as N-methyl-D-aspartic acid receptor antagonist: new possibilities for therapeutic applications?

The N-methyl-D-aspartic acid (NMDA) receptor is an intriguing target for the development of drugs with anti-Parkinsonian activity as well as with protective actions against degenerative processes induced by brain ischemia. Amantadine is used in the treatment of Parkinson's disease without a well established mechanism of action. We show here that amantadine inhibits, in a non-competitive way, the NMDA receptor-mediated stimulation of acetylcholine release from rat neostriatum in vitro in "therapeutic" (i.e., low micromolar) concentrations. This indicates that amantadine might exert its anti-Parkinsonian effect via blockade of NMDA receptors. Sustained stimulation of NMDA receptors induces so-called excitotoxicity. Recently, it was demonstrated that amantadine is able to inhibit NMDA induced cell death in a neuronal culture. On the basis of these findings it seems worth investigating if amantadine is also able to protect against neurodegenerative processes caused by brain ischemia in vivo.