Mackovski Nikolce, Liao Jinchi, Weng Ruihui, Wei Xiaobo, Wang Rui, Chen Zhaoyu, Liu Xu, Yu Yinghua, Meyer Barbara J, Xia Ying, Deng Chao, Huang Xu-Feng, Wang Qing
Department of Neurology, The Third Affiliated Hospital of Sun-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, People's Republic of China; Centre of Translational Neurosciences, School of Medicine, University of Wollongong, NSW, 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia.
Department of Neurology, The Third Affiliated Hospital of Sun-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, People's Republic of China.
Life Sci. 2016 Jun 15;155:123-32. doi: 10.1016/j.lfs.2016.05.005. Epub 2016 May 4.
Cannabinoid 1(CB1) receptors are closely correlated to the dopaminergic system and involved in cognitive function. Since statins have been used to regulate the progression of Parkinson's disease (PD) via its anti-inflammation and neuroprotective effects, we asked if statins affect the CB1 receptors in the 6-hydroxydopamine (6-OHDA) lesioned rat.
The PD rat model was established by injecting 6-OHDA into the unilateral medial forebrain bundle; while rats were orally pre-treated with simvastatin (1 or 10mg/kg/day), or saline for 5days before surgery, and the same treatments for each group were continued for 3weeks post-surgery. [(3)H] SR141716A binding autoradiography was adopted to investigate the alterations in CB1 receptor density in the brains.
The 6-OHDA induced a remarkable downregulation of CB1 receptor density in the prefrontal cortex, caudate putamen, nucleus accumbens, cingulate cortex, hippocampus, and substantia nigra; while simvastatin (10mg/kg/day) significantly ameliorated this downregulation in those regions. Furthermore, simvastatin (1mg/kg/day) reversed the 6-OHDA-induced downregulation of CB1 receptors in the substantia nigra and hippocampus. Simvastatin showed minimal changes in [(3)H] SR141716A binding in the examined regions in sham rats, but did reveal a significant down-regulation of binding density within the striatum, prefrontal cortex and substantia nigra.
Alterations in the [(3)H] SR141716A binding in the examined brain areas may represent the specific regions that mediate motor and cognitive dysfunctions in PD via the endocannabinoid system. Our data suggest a critical role of CB1 receptors in treating PD with simvastatin, and implicate CB1 receptors as a potential therapeutic target in the treatment of PD.
大麻素1（CB1）受体与多巴胺能系统密切相关，并参与认知功能。由于他汀类药物已通过其抗炎和神经保护作用用于调节帕金森病（PD）的进展，我们研究他汀类药物是否会影响6-羟基多巴胺（6-OHDA）损伤大鼠的CB1受体。
通过向单侧内侧前脑束注射6-OHDA建立PD大鼠模型；大鼠在手术前5天口服给予辛伐他汀（1或10mg/kg/天）或生理盐水，每组在手术后继续相同治疗3周。采用[³H]SR141716A结合放射自显影术研究脑内CB1受体密度的变化。
6-OHDA导致前额叶皮质、尾状壳核、伏隔核、扣带回皮质、海马和黑质中CB1受体密度显著下调；而辛伐他汀（10mg/kg/天）显著改善了这些区域的下调。此外，辛伐他汀（1mg/kg/天）逆转了6-OHDA诱导的黑质和海马中CB1受体的下调。辛伐他汀在假手术大鼠的检测区域中[³H]SR141716A结合变化最小，但确实显示纹状体、前额叶皮质和黑质内结合密度显著下调。
所检测脑区中[³H]SR141716A结合的变化可能代表通过内源性大麻素系统介导PD运动和认知功能障碍的特定区域。我们的数据表明CB1受体在辛伐他汀治疗PD中起关键作用，并暗示CB1受体是PD治疗的潜在靶点。
