Nikolce Mackovski1, Jinchi Liao2, Ruihui Weng2, Xiaobo Wei2, Rui Wang2, Zhaoyu Chen2, Xu Liu2, Yinghua Yu3, Barbara J Meyer3, Ying Xia4, Chao Deng3, Xu-Feng Huang5, Qing Wang6. 1. 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. 2. Department of Neurology, The Third Affiliated Hospital of Sun-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, People's Republic of China. 3. Centre of Translational Neurosciences, School of Medicine, University of Wollongong, NSW, 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia. 4. Department of Neurosurgery, The University of Texas Medical School at Houston, TX 77030, USA. 5. Centre of Translational Neurosciences, School of Medicine, University of Wollongong, NSW, 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia. Electronic address: xhuang@uowmail.edu.au. 6. 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. Electronic address: denniswq@yahoo.com.
Abstract
AIMS: 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 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. 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 (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. SIGNIFICANCE: 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.
AIMS: 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 PDrat 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. 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 (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. SIGNIFICANCE: 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.
Authors: Le Yang; Lei Tian; Zhi Zhang; Xuan Zhou; Xiaofang Ji; Fuquan Liu; Chengbin Dong; Lei Hou; Xinhao Zhao; Na Chang; Lin Yang; Liying Li Journal: Mol Ther Nucleic Acids Date: 2020-04-28 Impact factor: 8.886