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|Title:||MODULATION OF NUR77 MRNA LEVELS IN A NON-HUMAN PRIMATE MODEL OF PARKINSON'S DISEASE TREATED WITH L-DOPA AND DOCOSAHEXAENOIC ACIDQ|
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|Authors/Affiliations:||4 Souha Mahmoudi*; 3 Laurent Grégoire; 1 Marc Morissette; 2 Claude Rouillard; 1 Thérèse Di Paolo; 4 Daniel Lévesque; |
1 Laval University, CRCHUL, Molecular Endocrinology and Oncology Unit; 2 Laval University, CRCHUL, Neuroscience Unit; 3 Lavaolecl University, CRCHUL, Mular Endocrinology and Oncology Unit; 4 University of Montreal, Faculty of Pharmacy, QC, Canada
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|Content:||Introduction: L-dopa is the most effective drug for treating Parkinson’s disease (PD). However, long-term use of L-dopa is often associated with the emergence of disabling abnormal involuntary movements known as L-dopa induced dyskinesia (LIDs). We have previously shown that the orphan nuclear receptor and transcription factor Nur77 (NGFI-B) mRNA levels are modulated upon dopamine denervation following a treatment with the neurotoxin 6-hydroxydopamine in rodent models of PD. We have also shown that docosahexaenoic acid (DHA), a polyunsaturated fatty acid suggested to be an endogenous activator of retinoid receptors that are heterodimer partners of Nur77, reduced the severity of LIDs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, a non-human primate model of PD (Samadi et al., Ann. Neurol. 59:282-288, 2006).|
Objective: To further explore putative relationships between Nur77 and parkinsonian state, Dopa-treatment and generation of LIDs, we measured Nur77 mRNA levels in Dopa- and Dopa/DHA-treated MPTP monkeys.
Methods: Twelve cynomolgus female monkeys were ovariectomized and intoxicated with MPTP until they developed a stable parkinsonian state and four animals served as untreated control. MPTP-treated monkeys were assigned to three different groups (n=4 /group): 1) L-DOPA alone for 1 month; 2) L-DOPA + DHA for 1 month; and 3) untreated. L-Dopa- and L-Dopa+DHA-treated animals displayed similar reduction in their parkinsonian state. L-Dopa-treated animals progressively developed LIDs, whereas L-Dopa+DHA-treated monkeys showed a significant LID reduction (Samadi et al., Ann. Neurol. 59:282-288, 2006). Nur77 mRNA levels were evaluated by in situ hybridization using a specific radiolabeled complementary RNA probe.
Results: In naïve animals, Nur77 is expressed in the lateral and caudal portions of the caudate-putamen. Nur77 mRNA levels are slightly reduced by MPTP whereas one month L-Dopa treatment strongly induced Nur77 expression in patch-like territories in the caudate and lateral putamen. Nur77 mRNA levels are also elevated in different parts of the striatal complex in L-Dopa+DHA-treated MPTP monkeys. Interestingly, in the contrast to rodents, Nur77 expression is not modulated in the nucleus accumbens.
Conclusion: These results strongly suggest that Nur77 is involved in the long-term effects induced by L-Dopa. This is in accordance with our hypothesis that Nur77 is involved in the development of LIDs. However, significant differences were noted in the primate model in comparison to rodent models of PD. This work was supported by the Canadian Institutes for Health Research (CIHR) and Parkinson Disease Foundation (PDF) of United States.
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