Prevention of levodopa‐induced dyskinesias by a selective NR1A/2B N‐methyl‐D‐aspartate receptor antagonist in parkinsonian monkeys: Implication of preproenkephalin
Prevention of levodopa‐induced dyskinesias by a selective NR1A/2B N‐methyl‐D‐aspartate receptor antagonist in parkinsonian monkeys: Implication of preproenkephalin
复制标题
帕金森猴中选择性 NR1A/2B N-甲基-D-天冬氨酸受体拮抗剂预防左旋多巴引起的运动障碍：前脑啡肽原的意义
作者：
M. Morissette;Mehdi Dridi;F. Calon;A. Hadj Tahar;L. Meltzer;P. Bédard;T. Di Paolo
据报道，脑啡肽在左旋多巴（LD）诱导的运动障碍的病理生理学中发挥重要作用。本研究探讨了选择性NR 1A/2B N-甲基-D-天冬氨酸（NMDA）受体拮抗剂CI-1041长期给药对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）给药猴脑中前脑啡肽原-A（PPE-A）表达的影响，与LD诱导的运动障碍的发生有关。4只MPTP猴单独接受LD/苄丝肼;它们均发生了运动障碍。另外4只MPTP-猴接受LD/苄丝肼加CI-1041;其中只有1只在治疗第4周结束时出现轻度运动障碍。还包括4只正常猴和4只盐水处理的MPTP猴。MPTP处理的猴具有广泛且相似的纹状体多巴胺去神经支配。与对照组相比，通过原位杂交测定，在盐水处理的MPTP猴的外侧壳核（吻侧和尾侧）和尾状核（吻侧）中观察到PPE‐A mRNA水平增加，而在其内侧部分未观察到变化或略有增加。在LD处理的MPTP猴中，纹状体PPE‐A mRNA水平仍然升高，而与CI‐1041共同处理使其恢复到对照值。这些发现表明，在帕金森病动物模型中，用CI-1041长期阻断纹状体NR 1A/2B NMDA受体可使PPE-A mRNA表达正常化，并防止LD诱导的运动障碍的发生。© 2005运动障碍协会
Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) ‐induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N‐methyl‐D‐aspartate (NMDA) receptor antagonist, CI‐1041, on the expression of preproenkephalin‐A (PPE‐A) in brains of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) ‐treated monkeys in relation to the development of LD‐induced dyskinesias. Four MPTP‐monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP‐monkeys received LD/benserazide plus CI‐1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline‐treated MPTP monkeys were also included. MPTP‐treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE‐A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline‐treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE‐A mRNA levels remained elevated in LD‐treated MPTP monkeys, whereas cotreatment with CI‐1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI‐1041 normalizes PPE‐A mRNA expression and prevents the development of LD‐induced dyskinesias in an animal model of Parkinson disease. © 2005 Movement Disorder Society