Ameliorative effect of cannabinoid 2 receptor agonist JWH-015 on cognitive impairment of Alzheimer′s disease model mice and its possible mechan ism
10.13220/j.cnki.jipr.2017.06.014
- VernacularTitle:大麻素2型受体激动剂JWH-015对阿尔茨海默病样小鼠认知功能的改善作用及其可能机制
- Author:
Chao LI
;
Jingpu SHI
;
Likuan WANG
;
Huiqun JIA
;
Bo WANG
;
Jin LI
- Keywords:
Alzheimer's disease;
cannabinoid receptor 2;
microglial phenotype;
cognitive ability
- From:
Journal of International Pharmaceutical Research
2017;44(6):537-543
- CountryChina
- Language:Chinese
-
Abstract:
Objectives To investigate the ameliorative effect of cannabinoid 2 receptor(CB2R)agonist JWH-015 on the cog-nitive impairment of Alzheimer' s disease(AD)model mice and to assess the correlation with microglial phenotype transformation. Methods Twenty adult male C57BL/6J mice were randomly divided into four groups:C57BL/6J solvent group,JWH-015 control group,AD model group,and AD model treated with JWH-015 group. Amyloidβ1-42 oligomers of 4μg and the same volume of saline were intraventricularly administered to construct the AD mouse model and the solvent groups. CB2R agonist JWH-015 or the corre-sponding vehicle at a dose of 0.5 mg/(kg·d)was administered by intraperitoneal injection for 3 weeks. Non-spatial learning and memo-ry was measured using novel object recognition task. Furthermore,the mRNA expression levels of M1 microglia marker inducible ni-tric oxide synthase(iNOS)and M2 microglia marker chitinase-3 like protein(Ym1/2)in brain samples of cortex and hippocampus were evaluated using real-time quantitative PCR(qPCR). In the meantime,fifteen CB2R knockout(CB2RKO)mice and five CB2R wild-type(CB2RWT)littermates were assigned to identify the specificity of CB2R in the research. Based on the genotype and different treatment,the animals were divided into four groups:CB2RKO solvent group,CB2RKO AD model group,CB2RKO AD model treat-ed with JWH-015 group and CB2RWT solvent group. Results Compared with solvent group,there was a significant decrease in nov-el object recognition index in C57BL/6J AD model group(P<0.01). The mRNA expression levels of M1 phenotype microglia marker iNOS in cortex and hippocampus were significantly up-regulated(both P<0.05)and the mRNA expression levels of M2 phenotype mi-croglia marker Ym1/2 were significantly down-regulated(both P<0.01). Interestingly,administration of JWH-015 could reverse the impairment of novel object recognition index(P<0.05);compared with C57BL/6J AD model group,administration of JWH-015 also decreased the iNOS mRNA expression levels(both P<0.05)and increased the Ym1/2 mRNA expression levels(both P<0.05)in cortex and hippocampus;compared with CB2RKO solvent group,the novel object recognition index of CB2RKO AD model group was decreased(P<0.05);the mRNA expression levels of iNOS in cortex and hippocampus were significantly up-regulated(both P<0.05),the mRNA expression level of Ym1/2 in cortex was significantly down-regulated in cortex(P<0.05);compared with CB2RKO AD model group,administration of JWH-015 had no effect on novel object recognition index and the mRNA expression level of M1/M2 in cortex and hippocampus,respectively. Conclusion JWH-015 improves the cognitive impairment of Aβ-induced AD mice by the specific activation of CB2R,the mechanism of which is related to the direct regulation of CB2R on the M1/M2 microglial phenotype transformation and microglia-mediated neuroinflammation in brain.
