Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

• Published in: Neurobiology of disease 2009-10, Vol.36 (1), p.213-222
• Main Authors: Mahmoudi, Souha, Samadi, Pershia, Gilbert, François, Ouattara, Bazoumana, Morissette, Marc, Grégoire, Laurent, Rouillard, Claude, Di Paolo, Thérèse, Lévesque, Daniel
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Analysis of Variance; Animals; Antiparkinson Agents - adverse effects; Autoradiography - methods; Basal ganglia; Brain - drug effects; Brain - metabolism; Caudate nucleus; Cocaine - analogs & derivatives; Cocaine - metabolism; DHA; Disease Models, Animal; Docosahexaenoic Acids - pharmacology; Drug Interactions; Dyskinesia, Drug-Induced - drug therapy; Female; Iodine Isotopes - metabolism; L-Dopa-induced dyskinesia (LID); Levodopa - adverse effects; Macaca fascicularis; MPTP Poisoning - drug therapy; MPTP Poisoning - pathology; MPTP-treated monkey; Neurology; NGFI-B; NR4A1; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Parkinson's disease; Primates; Protein Binding - drug effects; Putamen; Retinoid X receptor (RXR); RNA, Messenger - metabolism; Statistics as Topic; Striatum; Substance P
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2009.07.017

Abstract We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopa-induced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys (Samadi et al., Ann. Neurol. 59:282–288, 2006). In the present study, we measured for the first time mRNA levels of Nur77 , an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77 , in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was observed following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking place in substance P positive cells and are associated with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudate-putamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a non-human primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.