Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset modelof Parkinson's disease

Dopamine-replacement strategies form the basis of most symptomatic treatmen ts for Parkinson's disease. However, since long-term dopamine-replacement t herapies are characterized by many side effects, most notably dyskinesia, t he concept of a nondopaminergic therapy for Parkinson's disease has attract ed great interest. To date, it has proved difficult to devise a nondopamine rgic therapy with efficacy comparable to that of dopamine replacement. In a nimal models of Parkinson's disease, loss of striatal dopamine leads to enh anced excitation of striatal NR2B-containing NMDA receptors. This is respon sible, in part at least, for generating parkinsonian symptoms. Here we demo nstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-sele ctive NMDA receptor antagonist, ifenprodil, administered de novo, has antip arkinsonian effects equivalent to those of L-DOPA (administered as its meth yl ester form). In MPTP-lesioned marmosets, median mobility scores, followi ng vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-1 21) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) t reatment in MPTP-lesioned marmosets, the median mobility score was 66/h (ra nge 34-93), and following L-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-9 2). The data support the proposal that NR2B-selective NMDA receptor antagon ists have potential as a nondopaminergic monotherapy for the treatment of p arkinsonian symptoms when given de novo. (C) 2000 Academic Press.