Reversal effect of simvastatin on the decrease in cannabinoid receptor 1 density in 6-hydroxydopamine lesioned rat brains

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• 作者：Nikolce Mackovski^a ; ^b ; ^c ; ¹ ; Jinchi Liao^a ; ¹ ; Ruihui Weng^a ; ¹ ; Xiaobo Wei^a ; Rui Wang^a ; Zhaoyu Chen^a ; Xu Liu^a ; Yinghua Yu^b ; ^c ; Barbara J. Meyer^b ; ^c ; Ying Xia^d ; Chao Deng^b ; ^c ; Xu-Feng Huang^b ; ^c ; ^{xhuang@uowmail.edu.au" class="auth_mail" title="E-mail the corresponding author} ; Qing Wang^a ; ^b ; ^{denniswq@yahoo.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：6-OHDA ; 6-hydroxydopamine ; 2-AG ; 2-arachidonoylglycerol ; BDNF ; brain derived neurotrophic factor ; CB1 ; cannabinoid receptor type 1 ; Cg ; cingulate cortex ; CNS ; central nervous system ; CO2 ; carbon dioxide ; Cpudl ; caudate putamen dorsolateral ; Cpum ; caudate putamen medial ; Cpuvl ; caudate putamen ventrolateral ; Cpuvm ; caudate putamen ventromedial ; DOPAC ; 3 ; 4-dihydroxyphenylacetic acid ; eNOS ; endothelial nitric oxide synthase ; FPP ; farnesyl pyrophosphate ; GABA ; gamma-aminobutyric acid ; GGP ; geranylge
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：155
• 期：Complete
• 页码：123-132
• 全文大小：1478 K

文摘

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.

Methods

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 10 mg/kg/day), or saline for 5 days before surgery, and the same treatments for each group were continued for 3 weeks post-surgery. [³H] SR141716A binding autoradiography was adopted to investigate the alterations in CB1 receptor density in the brains.

Findings

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 (10 mg/kg/day) significantly ameliorated this downregulation in those regions. Furthermore, simvastatin (1 mg/kg/day) reversed the 6-OHDA-induced downregulation of CB1 receptors in the substantia nigra and hippocampus. Simvastatin showed minimal changes in [³H] 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.

Significance

Alterations in the [³H] 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.