Implication du système gabaergique et des peptides neuromodulateurs dans la survenue des dyskinésies induites par la lévodopa

Ce travail explore certains mécanismes moléculaires impliqués dans la genèse des dyskinésies induites par la dopa thérapie. Nos travaux ont été effectués sur des échantillons de cerveaux de singes parkinsoniens ayant développé des complications motrices suite au traitement à la Lévodopa. Nos résultats montrent l'absence de corrélation entre les niveaux striataux de l'ARNm de la préprotachykinine et la survenue des dyskinésies et l'existence d'un lien de causalité entre l'augmentation des niveaux striataux des ARNm de la préproenképhaline et de la préprodynorphine ainsi que l'augmentation de la densité des récepteurs GABA-A au niveau des noyaux gris centraux et la physiopathologie de ces dyskinésies. Les traitements adjuvants avec le Ro 61-8048 , l'acide docosahéxaénoïque et le CI-I041 en association avec la Lévodopa, permettent de corriger certains paramètres biochimiques impliqués , dans la genèse de ces complications motrices et de prévenir ces dyskinésies sur le plan comportemental contrairement au Naltrexone qui les a exacerbées

Effect of non-dopaminergic drug treatment on Levodopa induced dyskinesias in MPTP monkeys : common implication of striatal neuropeptides

Dopamine denervation in Parkinson's disease and repeated Levodopa (L-DOPA) administration that induces dyskinesias are associated with an enhancement of basal ganglia neuropeptide transmission. Various adjunct non-dopaminergic treatments to Levodopa were shown to reduce and/or prevent dyskinesias. The aim of this study was to seek if non-dopaminergic drug treatments to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned monkeys combined with L-DOPA to prevent dyskinesia were associated with changes of striatal neuropeptides. Chronic treatment with Ro 61-8048 a kynurenine hydroxylase inhibitor, docosahexaenoic acid (DHA) a polyunsaturated fatty acid (omega-3), naltrexone an opioidergic antagonist and CI-1041 an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist with L-DOPA prevented dyskinesias to various extents except naltrexone whereas all MPTP monkeys treated with L-DOPA alone developed dyskinesias. Striatal preproenkephalin (PPE), preprodynorphin (PPD) and preprotachykinin A (PPT-A) mRNA levels were measured by in situ hybridization. An increase of PPE and PPD mRNA levels was observed in anterior caudate nucleus of L-DOPA treated MPTP monkeys compared to controls and to Saline-treated MPTP monkeys whereas PPT-A mRNA levels were unchanged. Striatal PPE and PPD mRNA levels remained elevated in L-DOPA plus naltrexone-treated MPTP monkeys, while co-treatment with DHA, CI-1041 or Ro 61-8048 prevented their increase to various extents. Maximal dyskinesias scores of MPTP monkeys correlated significantly with striatal PPE and PPD mRNA levels but not with PPT-A mRNA levels. These results show that drugs displaying a wide range of pharmacological activities can modulate L-DOPA induced dyskinesias and this activity is correlated with striatal PPD and PPE mRNA levels suggesting a convergent mechanism