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.
Stoof
J C
JC
Department of Neurology, Medical Faculty, Free University, Amsterdam, The Netherlands.
Booij
J
J
Drukarch
B
B
D000109:Acetylcholine / Q000378:metabolism*; D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D010300:Parkinson Disease / Q000503:physiopathology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine; D000109:Acetylcholine