Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset model of Parkinson's disease.
Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.
Nash
J E
JE
Manchester Movement Disorder Laboratory, Room 1.124, Division of Neuroscience, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
Fox
S H
SH
Henry
B
B
Hill
M P
MP
Peggs
D
D
McGuire
S
S
Maneuf
Y
Y
Hille
C
C
Brotchie
J M
JM
Crossman
A R
AR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002144:Callithrix; D015259:Dopamine Agents / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D007980:Levodopa / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D010880:Piperidines / Q000627:therapeutic use*
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C010739:ifenprodil