GPR55: A therapeutic target for Parkinson's disease?
GPR55: A therapeutic target for Parkinson's disease?
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DOI：
10.1016/j.neuropharm.2017.08.017
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发表时间：
2017-10-01
影响因子：
4.7
通讯作者：
Aymerich, Maria S.
中科院分区：
文献类型：
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作者：
Celorrio, Marta;Rojo-Bustamante, Estefania;Aymerich, Maria S.
GPR55受体在大脑中大量表达，尤其是在纹状体中，这表明它可能在运动功能中发挥作用。事实上，缺乏GPR55的小鼠的运动行为受损，也表现出抑制的炎症反应。异常大麻二酚（Abn-CBD）是一种合成大麻二酚（CBD）异构体，是一种GPR55激动剂，可作为治疗炎症性疾病的治疗剂。在这项研究中，我们探讨了调节GPR55是否也可以作为治疗帕金森病（PD）的一种治疗方法。首先通过原位杂交分析GPR55 mRNA的分布，将GPR55转录本定位于与运动控制相关的脑核、纹状体、苍白球、丘脑下核、黑质和皮层的神经元。帕金森病患者纹状体中GPR55的表达下调。给1-甲基-4-苯基-1,2,3,6四氢吡啶和丙苯酸（MPTPp）治疗5周以上的小鼠长期给予Abn-CBD和CBD (5 mg/kg)， Abn-CBD而非CBD可预防MPTPp诱导的运动障碍。Abn-CBD虽然能保护多巴胺能细胞体，但不能防止终末变性或维持纹状体中的多巴胺水平。这两种化合物诱导小胶质细胞的形态变化，这些变化与抗炎表型相容，而与神经保护活性无关。在氟哌啶醇致猝睡小鼠模型中进一步研究Abn-CBD的症状缓解作用。Abn-CBD具有被CBD和新合成的GPR55拮抗剂PSB1216逆转的抗催化作用，另外两种GPR55拮抗剂CID1792197和CID2440433也具有抗催化作用。这些结果首次表明，激活GPR55可能有助于对抗PD。(C) 2017 Elsevier Ltd.版权所有。
The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD. (C) 2017 Elsevier Ltd. All rights reserved.