West Anhui Health Vocational College, Luan, 237000, China.
Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
J Mol Neurosci. 2022 Aug;72(8):1656-1669. doi: 10.1007/s12031-022-02020-y. Epub 2022 May 20.
Our previous research found that activation of GPR55 can alleviate cognitive impairment induced by amyloid-beta 1-42 (Aβ) and streptozotocin in mice, but the role of GPR55 in the pathogenesis of cognitive impairment remains unknown. Here, we used a lipopolysaccharide (LPS) mouse model to further investigate the role and mechanism of O-1602, a GPR55 agonist, on cognitive dysfunction. ICR mice were treated with an intracerebroventricular (i.c.v.) injection of LPS, followed by cognitive function tests. The expression of GPR55, NF-κB p65, caspase-3, Bax, and Bcl-2 in the hippocampus was examined by Western blotting. Inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The levels of MDA, GSH, SOD, and CAT were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis. Our results showed that i.c.v. injection of LPS in mice exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment (2.0 or 4.0 μg/mouse, i.c.v.). Importantly, we found that O-1602 treatment reversed GPR55 downregulation, decreased the expression of NF-κB p65, suppressed the accumulation of proinflammatory cytokines and microglia activation, increased the anti-inflammatory cytokines, and reduced the levels of MDA, increased the levels of GSH, SOD, and CAT in the hippocampus. In addition, O-1602 treatment also significantly reduced Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus. These observations indicate that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress, and apoptosis mediated by the NF-κB pathway in mice.
我们之前的研究发现，GPR55 的激活可以减轻淀粉样蛋白-β 1-42（Aβ）和链脲佐菌素诱导的小鼠认知障碍，但 GPR55 在认知障碍发病机制中的作用尚不清楚。在这里，我们使用脂多糖（LPS）小鼠模型进一步研究 GPR55 激动剂 O-1602 对认知功能障碍的作用和机制。我们用脑室内（i.c.v.）注射 LPS 处理 ICR 小鼠，然后进行认知功能测试。通过 Western blot 检测海马中 GPR55、NF-κB p65、caspase-3、Bax 和 Bcl-2 的表达。通过 ELISA 试剂盒和免疫组织化学分析检测炎症细胞因子和小胶质细胞。通过试剂盒检测 MDA、GSH、SOD 和 CAT 的水平。此外，用 TUNEL 染色检测神经元凋亡。我们的结果表明，LPS 脑室内注射可使小鼠在行为测试中表现出受损的表现，而 O-1602 治疗（2.0 或 4.0 μg/只，脑室内）可改善这种表现。重要的是，我们发现 O-1602 治疗可逆转 GPR55 的下调，降低 NF-κB p65 的表达，抑制促炎细胞因子的积累和小胶质细胞的激活，增加抗炎细胞因子，并降低海马中 MDA 的水平，增加 GSH、SOD 和 CAT 的水平。此外，O-1602 治疗还可显著降低 Bax 表达，增加 Bcl-2 表达，并降低海马中 caspase-3 活性和 TUNEL 阳性细胞。这些观察结果表明，O-1602 可能通过抑制 NF-κB 通路介导的神经炎症、氧化应激和细胞凋亡来改善 LPS 诱导的认知缺陷。
