Molecular Endocrinology and Genomic Research Centre, CHUQ, Laval University Medical Centre, Quebec, Canada.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Apr 16;34(3):446-54. doi: 10.1016/j.pnpbp.2009.12.011. Epub 2009 Dec 16.
L-Dopa treatment, the gold standard therapy for Parkinson's disease, is hampered by motor complications such as dyskinesias. Recently, impairment of striatal Akt/GSK3 signaling was proposed to play a role in the mechanisms implicated in development of L-Dopa-induced dyskinesias in a rodent model of Parkinson's disease. The present experiment investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, the effects on Akt/GSK3 of chronic L-Dopa treatment inducing dyskinesias compared to L-Dopa with CI-1041 (NMDA receptor antagonist) or a low dose of cabergoline (dopamine D2 receptor agonist) preventing dyskinesias. The extensive dopamine denervation induced by MPTP was associated with a decrease by about half of phosphorylated Akt(Ser473) levels in posterior caudate nucleus, anterior and posterior putamen; smaller changes were observed for phosphorylated Akt(Thr308) levels that did not reach statistical significance. Dopamine depletion reduced phosphorylated GSK3beta(Ser9) levels, mainly in posterior putamen whereas pGSK3beta(Tyr216) and pGSK3alpha(Ser21) were unchanged. In posterior caudate nucleus, anterior and posterior putamen of dyskinetic L-Dopa-treated MPTP monkeys, pAkt(Ser473) and pGSK3beta(Ser9) were elevated whereas L-Dopa+cabergoline treated MPTP monkeys without dyskinesias had lower values in posterior striatum as vehicle-treated MPTP monkeys. In non-dyskinetic MPTP monkeys treated with L-Dopa+CI-1041, putamen pAkt(Ser473) and pGSK3beta(Ser9) levels remained elevated as in dyskinetic monkeys while in posterior caudate nucleus, these levels were low as vehicle-treated and lower than L-Dopa treated MPTP monkeys. Extent of phosphorylation of Akt and GSK3beta in putamen correlated positively with dyskinesias scores of MPTP monkeys; these correlations were higher with dopaminergic drugs (L-Dopa, cabergoline) suggesting implication of additional mechanisms and/or signaling molecules in the NMDA antagonist antidyskinetic effect. In conclusion, our results showed that in MPTP monkeys, loss of striatal dopamine decreased Akt/GSK3 signaling and that increased phosphorylation of Akt and GSK3beta was associated with L-Dopa-induced dyskinesias.
左旋多巴治疗是帕金森病的金标准疗法，但它会引起运动并发症，如运动障碍。最近有研究提出，纹状体 Akt/GSK3 信号的损伤在帕金森病的啮齿动物模型中，与左旋多巴诱导的运动障碍的发展机制有关。本实验在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）猴中进行，研究了与 CI-1041（NMDA 受体拮抗剂）或卡培他滨（多巴胺 D2 受体激动剂）联合左旋多巴预防运动障碍相比，慢性左旋多巴治疗诱导运动障碍对 Akt/GSK3 的影响。MPTP 引起的广泛多巴胺神经末梢损伤与后尾状核、前和后壳核磷酸化 Akt（Ser473）水平降低约一半有关；磷酸化 Akt（Thr308）水平的变化较小，未达到统计学意义。多巴胺耗竭降低了磷酸化 GSK3beta（Ser9）水平，主要在后壳核，而 pGSK3beta（Tyr216）和 pGSK3alpha（Ser21）没有变化。在运动障碍性左旋多巴治疗的 MPTP 猴的后尾状核、前和后壳核中，pAkt（Ser473）和 pGSK3beta（Ser9）升高，而无运动障碍的 L-Dopa+卡培他滨治疗的 MPTP 猴的后纹状体值较低，与载体处理的 MPTP 猴相同。在接受 L-Dopa+CI-1041 治疗的非运动障碍性 MPTP 猴中，壳核 pAkt（Ser473）和 pGSK3beta（Ser9）水平仍然升高，与运动障碍猴相同，而在后尾状核中，这些水平较低，与载体处理和低于 L-Dopa 治疗的 MPTP 猴。壳核中 Akt 和 GSK3beta 的磷酸化程度与 MPTP 猴的运动障碍评分呈正相关；与多巴胺能药物（左旋多巴、卡培他滨）的相关性更高，表明 NMDA 拮抗剂抗运动障碍作用涉及其他机制和/或信号分子。总之，我们的结果表明，在 MPTP 猴中，纹状体多巴胺的丧失降低了 Akt/GSK3 信号，而 Akt 和 GSK3beta 的磷酸化增加与左旋多巴诱导的运动障碍有关。
