Ameliorative effect of cannabinoid 2 receptor agonist JWH-015 on cognitive impairment of Alzheimer′s disease model mice and its possible mechan ism / 国际药学研究杂志

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 groupsC57BL/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 groupsCB2RKO 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.