Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid.
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 gamma1 (RXRgamma1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRgamma1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRgamma1 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.
Mahmoudi
Souha
S
Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada.
Samadi
Pershia
P
Gilbert
François
F
Ouattara
Bazoumana
B
Morissette
Marc
M
Grégoire
Laurent
L
Rouillard
Claude
C
Di Paolo
Thérèse
T
Lévesque
Daniel
D
D000110:Acetylcholinesterase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D005260:Female; D007456:Iodine Isotopes / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000473:pathology; D008252:Macaca fascicularis; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D013223:Statistics as Topic
D000978:Antiparkinson Agents; D007456:Iodine Isotopes; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; C079213:RTI 121; D004281:Docosahexaenoic Acids; D007980:Levodopa; D000110:Acetylcholinesterase; D003042:Cocaine