Lou Zhi-Yin, Yu Wen-Bo, Chen Jie, Li Lin, Jiang Li-Sheng, Xiao Bao-Guo, Liu Zhen-Guo
Department of Neurology, Xinhua Hospital, Medical College, Shanghai Jiaotong University, Shanghai, China.
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
J Mol Neurosci. 2016 Feb;58(2):193-200. doi: 10.1007/s12031-015-0656-9. Epub 2015 Sep 28.
During immuno-mediated demyelinating lesions, endocannabinoid system participates in both inflammatory and neurodegenerative damage through several mechanisms that involve neuronal and immune cells. Here, we constructed lentiviral vector to upregulate CB1 receptor (CB1R) in the lumbar spinal cord 5-6 region and observe the effect of clinical score and possible mechanism on the occurrence and development of experimental autoimmune encephalomyelitis (EAE). The results show that overexpression of CB1R delayed the onset of clinical signs and ameliorated the severity of disease. Overexpression of CB1R significantly inhibited the expression of NF-kB/p65 and TLR-4 as well as levels of IL-1β, IL-6, and TNF-α, followed by a decrease of IL-17 and an increase of IL-10 in the spinal cord of mice. The percentage of M1 marker CD11b(+)CD16/32(+) cells was decreased, while the percentage of M2 marker CD11b(+)CD206(+) and CD11b(+)IL-10(+) cells was elevated in splenic mononuclear cells (MNCs) of mice with overexpression of CB1R. Interestingly, overexpression of CB1R dramatically enhanced the expression of neurotrophic NT-3, BDNF, and GDNF in the spinal cord. These results indicate that local overexpression of CB1R in the spinal cord exhibited neuroprotective effects in EAE, mainly suppressing inflammatory microenvironment and elevating neurotrophic factors, slightly declining IL-1β and IL-17 in the spleen, and increased IL-10 in the brain. Its complexity remains to be carefully considered and further studied in further investigation.
在免疫介导的脱髓鞘病变过程中，内源性大麻素系统通过涉及神经元和免疫细胞的多种机制参与炎症和神经退行性损伤。在此，我们构建慢病毒载体以上调腰脊髓5-6区域的CB1受体（CB1R），并观察其对实验性自身免疫性脑脊髓炎（EAE）发生发展的临床评分影响及可能机制。结果显示，CB1R的过表达延迟了临床症状的出现并改善了疾病严重程度。CB1R的过表达显著抑制了NF-kB/p65和TLR-4的表达以及IL-1β、IL-6和TNF-α的水平，随后小鼠脊髓中IL-17减少而IL-10增加。在CB1R过表达小鼠的脾单个核细胞（MNCs）中，M1标志物CD11b(+)CD16/32(+)细胞的百分比降低，而M2标志物CD11b(+)CD206(+)和CD11b(+)IL-10(+)细胞的百分比升高。有趣的是，CB1R的过表达显著增强了脊髓中神经营养因子NT-3、BDNF和GDNF的表达。这些结果表明，脊髓中CB1R的局部过表达在EAE中表现出神经保护作用，主要是抑制炎症微环境并提高神经营养因子水平，脾脏中IL-1β和IL-17略有下降，大脑中IL-10增加。其复杂性仍有待在进一步研究中仔细考量和深入探究。
