Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada.
Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada.
J Chem Neuroanat. 2024 Jul;138:102422. doi: 10.1016/j.jchemneu.2024.102422. Epub 2024 Apr 23.
L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson's disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu activation, we performed autoradiographic binding with [H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals. In the ipsilateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats showed a decrease in [H]-LY-341,495 binding in the entopeduncular nucleus (EPN, 30 % vs sham-lesioned rats, P<0.05), globus pallidus (GP, 28 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (49 % vs sham-lesioned rats, P<0.05; 45 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001). Severely dyskinetic 6-OHDA-lesioned rats exhibited an increase in binding in the primary motor cortex (43 % vs mildly dyskinetic 6-OHDA-lesioned rats, P<0.05). In the contralateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats harboured a decrease in binding in the EPN (30 % vs sham-lesioned rats; 24 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05), GP (34 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (50 % vs sham-lesioned rats; 44 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Severely dyskinetic 6-OHDA-lesioned rats presented a decrease in binding in the GP (30 % vs sham-lesioned rats; 19 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Abnormal involuntary movements scores of 6-OHDA-lesioned animals were positively correlated with [H]-LY-341,495 binding in the ipsilateral striatum, ipsilateral EPN, ipsilateral primary motor cortex and contralateral primary motor cortex (all P<0.05). These results suggest that alterations in mGlu receptor levels may be part of an endogenous compensatory mechanism to alleviate dyskinesia.
L-3,4-二羟基苯丙氨酸（L-DOPA）是治疗帕金森病（PD）运动症状的首选药物，但由于运动障碍等并发症，其长期使用受到阻碍。临床前研究发现，代谢型谷氨酸受体 2 和 3（mGlu）的激活可减轻 L-DOPA 诱导的运动障碍。为了深入了解 mGlu 激活的抗运动障碍作用的机制，我们使用 [H]-LY-341,495 在接受 L-DOPA 治疗的 6-羟基多巴胺（6-OHDA）损伤大鼠的脑切片中进行放射性配体结合研究，这些大鼠出现了轻度或重度运动障碍，以及未经 L-DOPA 治疗的 6-OHDA 损伤和假损伤动物。在同侧半脑，轻度运动障碍的 6-OHDA 损伤大鼠的纹状体外侧部（EPN，与假损伤大鼠相比下降 30%，P<0.05）、苍白球（GP，与假损伤大鼠相比下降 28%，P<0.05；与未经 L-DOPA 治疗的 6-OHDA 损伤大鼠相比下降 23%，P<0.001）和初级运动皮层（与假损伤大鼠相比下降 49%，P<0.05；与未经 L-DOPA 治疗的 6-OHDA 损伤大鼠相比下降 45%，P<0.001）的 [H]-LY-341,495 结合减少。严重运动障碍的 6-OHDA 损伤大鼠的初级运动皮层结合增加（与轻度运动障碍的 6-OHDA 损伤大鼠相比增加 43%，P<0.05）。在对侧半脑，轻度运动障碍的 6-OHDA 损伤大鼠的 EPN（与假损伤大鼠相比下降 30%，P<0.05；与未经 L-DOPA 治疗的 6-OHDA 损伤大鼠相比下降 24%，P<0.05）、GP（与假损伤大鼠相比下降 34%，P<0.05；与未经 L-DOPA 治疗的 6-OHDA 损伤大鼠相比下降 23%，P<0.001）和初级运动皮层（与假损伤大鼠相比下降 50%，P<0.05；与未经 L-DOPA 治疗的 6-OHDA 损伤大鼠相比下降 44%，P<0.05）的 [H]-LY-341,495 结合减少。严重运动障碍的 6-OHDA 损伤大鼠的 GP（与假损伤大鼠相比下降 30%，P<0.05；与未经 L-DOPA 治疗的 6-OHDA 损伤大鼠相比下降 19%，P<0.05）结合减少。6-OHDA 损伤动物的异常不自主运动评分与同侧纹状体、同侧 EPN、同侧初级运动皮层和对侧初级运动皮层的 [H]-LY-341,495 结合呈正相关（均 P<0.05）。这些结果表明，mGlu 受体水平的改变可能是缓解运动障碍的内源性代偿机制的一部分。
