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联合代谢型谷氨酸受体正构刺激和变构调节可减轻帕金森病恒河猴模型中 L-DOPA 诱导的精神病样行为和运动障碍。

Combined mGlu orthosteric stimulation and positive allosteric modulation alleviates L-DOPA-induced psychosis-like behaviours and dyskinesia in the parkinsonian marmoset.

机构信息

Comparative Medicine and Animal Resource Centre, McGill University, Montreal, QC, Canada.

Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, QC, H3A 2B4, Canada.

出版信息

J Neural Transm (Vienna). 2020 Jul;127(7):1023-1029. doi: 10.1007/s00702-020-02185-z. Epub 2020 Apr 3.

Abstract

In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu) receptor with the orthosteric agonist (OA) LY-354,740 and the positive allosteric modulator (PAM) LY-487,379 is effective at alleviating both dyskinesia and psychosis-like behaviours (PLBs) triggered by the administration of L-3,4-dihydroxyphenylalanine (L-DOPA). Because mGlu OAs and PAMs bind to different sites on the receptor, we hypothesised that greater reductions of dyskinesia and PLBs would be obtained upon concurrent administration of LY-354,740 and LY-487,379. In experiments performed in six MPTP-lesioned marmosets, we administered LY-354,740 (0.1 mg/kg), LY-487,379 (1 mg/kg), LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg), or vehicle, in combination with L-DOPA and determined the effect of each treatment on dyskinesia, PLBs, and parkinsonism. When compared to vehicle, LY-354,740 and LY-487,379, administered alone or concurrently, significantly reduced dyskinesia. The combination LY-354,740 + LY-487,379 provided mild additional benefit when compared to LY-487,379 alone, but not compared to LY-354,740. For PLBs, when compared to vehicle treatment, LY-354,740, LY-487,379, and combination thereof all alleviated the abnormal behaviours, but the combination LY-354,740 + LY-487,379 did not provide greater relief than either drug alone. The anti-parkinsonian effect of L-DOPA was not altered by any of the treatments. Our results provide further evidence that mGlu activation might be a novel approach to treat L-DOPA-induced dyskinesia and dopaminergic psychosis in PD. However, they do not suggest that greater therapeutic effect would be achieved upon combining an mGlu OA and an mGlu PAM.

摘要

在最近进行的 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)恒河猴模型的研究中,我们已经证明,使用正构激动剂(OA)LY-354,740 和正变构调节剂(PAM)LY-487,379 激活代谢型谷氨酸 2(mGlu)受体可有效缓解 L-3,4-二羟基苯丙氨酸(L-DOPA)给药引发的运动障碍和类精神病行为(PLBs)。因为 mGlu OAs 和 PAMs 结合在受体的不同部位,我们假设同时给予 LY-354,740 和 LY-487,379 会导致运动障碍和 PLBs 得到更大程度的缓解。在六只 MPTP 诱导的恒河猴中进行的实验中,我们给予 LY-354,740(0.1mg/kg)、LY-487,379(1mg/kg)、LY-354,740(0.1mg/kg)+LY-487,379(1mg/kg)或载体,与 L-DOPA 联合使用,并确定每种治疗方法对运动障碍、PLBs 和帕金森病的影响。与载体相比,LY-354,740 和 LY-487,379 单独或联合使用时,均可显著减少运动障碍。与 LY-487,379 相比,LY-354,740+LY-487,379 的联合使用提供了轻度的额外益处,但与 LY-354,740 相比则没有。对于 PLBs,与载体治疗相比,LY-354,740、LY-487,379 和两者的联合均缓解了异常行为,但 LY-354,740+LY-487,379 的联合使用并未提供比单独使用任何一种药物更大的缓解作用。L-DOPA 的抗帕金森病作用不受任何治疗的影响。我们的结果进一步证明,mGlu 激活可能是治疗 PD 中 L-DOPA 诱导的运动障碍和多巴胺能精神病的一种新方法。然而,它们并没有表明,联合使用 mGlu OA 和 mGlu PAM 会获得更大的治疗效果。

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