Nascimento Glauce Crivelaro, Bálico Gabriela Gonçalves, de Mattos Bianca Andretto, Dos-Santos-Pereira Mauricio, Oliveira Igor Gustavo Carvalho, Queiroz Maria Eugênia Costa, do Carmo Heck Lilian, Navegantes Luiz Carlos, Guimarães Francisco Silveira, Del-Bel Elaine
University of São Paulo (USP), School of Dentistry of Ribeirão Preto, Department of Basic and Oral Biology, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil.
USP, Medical School of Ribeirão Preto, Department of Physiology, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jul 18;141:111456. doi: 10.1016/j.pnpbp.2025.111456.
Despite the widespread use of L-3,4-dihydroxyphenylalanine (L-DOPA) as the gold standard for dopamine (DA) replacement in Parkinson's Disease (PD), its prolonged administration frequently leads to L-DOPA-induced dyskinesia (LID), a significant therapeutic challenge. Modulating the endocannabinoid system has emerged as a promising approach for managing LID. This study explored whether cannabidiol (CBD), a non-psychoactive compound of Cannabis sativa, and PECS-101, a fluorinated derivative of CBD, could mitigate the onset and progression of LID. We used unilateral 6-hydroxydopamine-lesioned rats, treated with L-DOPA (10 mg kg - 1) for three weeks to induce severe abnormal involuntary movements (AIMs). Treatments were administered during the final two weeks. CBD (30 mg kg - 1) and PECS-101 (3 and 30 mg kg - 1) significantly reduced AIMs without impairing the motor benefits of L-DOPA. The antidyskinetic effects of CBD were associated with decreased striatal Fos-B and phospho-ERK expression and were independent of lesion severity. CBD effects were prevented by antagonists of CB1 (1 mg kg - 1) and PPARγ (4 mg kg - 1) receptors. Co-administration of TRPV-1 antagonist capsazepine (5 mg kg - 1) enhanced the antidyskinetic effects of CBD. Combining the capsazepine with the neuronal nitric oxide synthase inhibitor, 7-nitroimidazole (10 mg kg - 1) enhanced these effects. CBD did not alter striatal DA levels but significantly increased the concentrations of anandamide and 2-arachidonoylglycerol in dyskinetic animals. The antidyskinetic effects of CBD were associated with a reduction of the enhanced striatal glia and peripheral inflammation markers. These findings suggest that CBD alleviates LID by interacting with the nitrergic neurotransmission and TRPV-1, CB1, and PPARγ receptors.
尽管左旋3,4-二羟基苯丙氨酸（L-DOPA）作为帕金森病（PD）中多巴胺（DA）替代的金标准被广泛使用，但其长期给药经常导致L-DOPA诱导的运动障碍（LID），这是一个重大的治疗挑战。调节内源性大麻素系统已成为管理LID的一种有前景的方法。本研究探讨了大麻二酚（CBD），一种大麻的非精神活性化合物，以及PECS-101，一种CBD的氟化衍生物，是否可以减轻LID的发作和进展。我们使用单侧6-羟基多巴胺损伤的大鼠，用L-DOPA（10mg/kg-1）治疗三周以诱导严重的异常不自主运动（AIMs）。在最后两周进行治疗。CBD（30mg/kg-1）和PECS-101（3和30mg/kg-1）显著降低了AIMs，而不损害L-DOPA的运动益处。CBD的抗运动障碍作用与纹状体Fos-B和磷酸化ERK表达的降低有关，并且与损伤严重程度无关。CB1（1mg/kg-1）和PPARγ（4mg/kg-1）受体拮抗剂可阻止CBD的作用。共给予TRPV-1拮抗剂辣椒素（5mg/kg-1）可增强CBD的抗运动障碍作用。将辣椒素与神经元型一氧化氮合酶抑制剂7-硝基咪唑（10mg/kg-1）联合使用可增强这些作用。CBD没有改变纹状体DA水平，但显著增加了运动障碍动物中花生四烯酸乙醇胺和2-花生四烯酸甘油的浓度。CBD的抗运动障碍作用与纹状体胶质细胞增强和外周炎症标志物的减少有关。这些发现表明，CBD通过与氮能神经传递以及TRPV-1、CB1和PPARγ受体相互作用来减轻LID。
