From the Laboratory of Functional Neurochemistry (SC, GL, GA, EM, GFA, FB, MTA), C. Mondino National Neurological Institute, Pavia, Italy; Cell and Molecular Neuropharmacology (RF), Neurosciences Division (JLL), Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain; Department of Biochemistry and Molecular Biology (RF), University of Barcelona, Barcelona, Spain; CIBERNED (JLL), Spain; Pharma Center Bonn (YB, CEM), University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany; Department of Chemistry (YB), Faculty of Science, Sultan Qaboos University, Muscat, Oman; and National Research Council of Italy (AP), Institute of Neuroscience, Cagliari, Italy.
J Neuropathol Exp Neurol. 2014 May;73(5):414-24. doi: 10.1097/NEN.0000000000000064.
The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation,is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.
开发非多巴胺能治疗策略，可能改善运动和非运动缺陷，同时可能减缓神经退行性过程和相关的神经炎症，是帕金森病（PD）研究的主要目标。我们研究了联合和单一治疗腺苷 A2A 和大麻素 CB1 受体拮抗剂 MSX-3 和利莫那班在 PD 啮齿动物模型中的神经保护和抗炎潜力。在单侧纹状体 6-羟多巴胺损伤的大鼠中，用 MSX-3（0.5 或 1mg/kg/d）和利莫那班（0.1mg/kg/d）进行慢性治疗，分别作为单一疗法或联合治疗。通过免疫组织化学分别检测酪氨酸羟化酶和神经胶质细胞标志物，评估治疗对多巴胺能细胞死亡和神经炎症的影响。当单独给予时，利莫那班和 MSX-3（1mg/kg/d）均促进黑质致密部（SNc）中的多巴胺能神经元存活；当化合物联合使用时，这种作用减弱。MSX-3（1mg/kg/d）对神经胶质细胞激活没有明显影响，而利莫那班似乎增加了 SNc 中的星形胶质细胞密度。我们的研究结果表明单一治疗具有神经保护潜力，并表明神经胶质细胞可能参与这种保护作用。结果还表明，联合治疗的神经保护潜力不一定反映或促进单一药物的作用，并指出在考虑 PD 的多药物治疗时应特别小心。
