Prevention of levodopa-induced dyskinesias by a selective NR1A/2B N-methyl-D-aspartate receptor antagonist in parkinsonian monkeys: implication of preproenkephalin.
Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) -induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N-methyl-D-aspartate (NMDA) receptor antagonist, CI-1041, on the expression of preproenkephalin-A (PPE-A) in brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated monkeys in relation to the development of LD-induced dyskinesias. Four MPTP-monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP-monkeys received LD/benserazide plus CI-1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline-treated MPTP monkeys were also included. MPTP-treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE-A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline-treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE-A mRNA levels remained elevated in LD-treated MPTP monkeys, whereas cotreatment with CI-1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI-1041 normalizes PPE-A mRNA expression and prevents the development of LD-induced dyskinesias in an animal model of Parkinson disease.
Morissette
Marc
M
Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada.
Dridi
Mehdi
M
Calon
Frédéric
F
Hadj Tahar
Abdallah
A
Meltzer
Leonard T
LT
Bédard
Paul J
PJ
Di Paolo
Thérèse
T
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001545:Benserazide / Q000633:toxicity; D001583:Benzoxazoles / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000473:pathology / Q000503:physiopathology*; D004745:Enkephalins / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007980:Levodopa / Q000633:toxicity*; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000978:Antiparkinson Agents; D001583:Benzoxazoles; D004745:Enkephalins; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; C481484:besonprodil; D001545:Benserazide; C033660:preproenkephalin; D004298:Dopamine