Ru Qin, Tian Xiang, Xiong Qi, Xu Congyue, Chen Lin, Wu Yuxiang
Wuhan Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
Department of Health and Physical Education, Jianghan University, Wuhan, China.
Front Pharmacol. 2021 Oct 29;12:756822. doi: 10.3389/fphar.2021.756822. eCollection 2021.
Methamphetamine (METH) abuse exerts severe harmful effects in multiple organs, especially the brain, and can induce cognitive dysfunction and memory deficits in humans. Krill oil is rich in polyunsaturated fatty acids, while its effect on METH-induced cognitive impairment and mental disorders, and the underlying mechanism remain unknown. The aim of the present study was to investigate the protective effect of krill oil on METH-induced memory deficits and to explore the molecular mechanisms by using an integrated strategy of bioinformatics analysis and experimental verification. METH-exposed mice were treated with or without krill oil. Learning and memory functions were evaluated by the Morris water maze. The drug-component-target network was constructed in combination with network pharmacology. The predicted hub genes and pathways were validated by the Western blot technique. With krill oil treatment, memory impairment induced by METH was significantly improved. 210 predicted targets constituted the drug-compound-target network by network pharmacology analysis. 20 hub genes such as DRD2, MAPK3, CREB, BDNF, and caspase-3 were filtered out as the underlying mechanisms of krill oil on improving memory deficits induced by METH. The KEGG pathway and GO enrichment analyses showed that the MAPK signaling pathway, cAMP signaling pathway, and dopaminergic synapse pathway were involved in the neuroprotective effects of krill oil. In the hippocampus, DRD2, cleaved caspase-3, and γ-H2AX expression levels were significantly increased in the METH group but decreased in the krill oil-treated group. Meanwhile, krill oil enhanced the expressions of p-PKA, p-ERK1/2, and p-CREB. Our findings suggested that krill oil improved METH-induced memory deficits, and this effect may occur the MAPK signaling pathway and dopaminergic synapse pathways. The combination of network pharmacology approaches with experimental validation may offer a useful tool to characterize the molecular mechanism of multicomponent complexes.
甲基苯丙胺（METH）滥用会对多个器官，尤其是大脑产生严重的有害影响，并可导致人类认知功能障碍和记忆缺陷。磷虾油富含多不饱和脂肪酸，但其对METH诱导的认知障碍和精神障碍的影响及其潜在机制尚不清楚。本研究的目的是探讨磷虾油对METH诱导的记忆缺陷的保护作用，并通过生物信息学分析和实验验证的综合策略来探索其分子机制。将暴露于METH的小鼠分为磷虾油处理组和未处理组。通过莫里斯水迷宫评估学习和记忆功能。结合网络药理学构建药物-成分-靶点网络。通过蛋白质印迹技术验证预测的枢纽基因和信号通路。经磷虾油治疗后，METH诱导的记忆障碍得到显著改善。通过网络药理学分析，210个预测靶点构成了药物-化合物-靶点网络。筛选出20个枢纽基因，如DRD2、MAPK3、CREB、BDNF和caspase-3，作为磷虾油改善METH诱导的记忆缺陷的潜在机制。KEGG通路和GO富集分析表明，MAPK信号通路、cAMP信号通路和多巴胺能突触通路参与了磷虾油的神经保护作用。在海马体中，METH组的DRD2、裂解的caspase-3和γ-H2AX表达水平显著升高，而磷虾油治疗组则降低。同时，磷虾油增强了p-PKA、p-ERK1/2和p-CREB的表达。我们的研究结果表明，磷虾油改善了METH诱导的记忆缺陷，这种作用可能通过MAPK信号通路和多巴胺能突触通路实现。网络药理学方法与实验验证相结合可能为表征多组分复合物的分子机制提供有用的工具。
