DataSheet8_Krill Oil Alleviated Methamphetamine-Induced Memory Impairment via the MAPK Signaling Pathway and Dopaminergic Synapse Pathway.XLSX

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 via 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（Methamphetamine, METH）滥用会对多个器官造成严重损害，尤其累及大脑，还可诱发人类出现认知功能障碍与记忆缺损。磷虾油富含多不饱和脂肪酸，但其对甲基苯丙胺诱导的认知损伤与精神障碍的作用及潜在分子机制仍不明确。本研究旨在探究磷虾油对甲基苯丙胺诱导的记忆缺损的保护作用，并通过生物信息学分析与实验验证相结合的策略探索其潜在分子机制。将暴露于甲基苯丙胺的小鼠分为磷虾油处理组与对照组，采用莫里斯水迷宫（Morris water maze）实验评估小鼠的学习与记忆功能；结合网络药理学方法构建药物-成分-靶点网络，并采用蛋白质免疫印迹（Western blot）技术对预测得到的核心基因与通路进行验证。经磷虾油干预后，甲基苯丙胺诱导的记忆损伤得到显著改善。通过网络药理学分析，共获得210个靶点以构建药物-成分-靶点网络；筛选出DRD2、MAPK3、CREB、BDNF及半胱天冬酶-3（caspase-3）等20个核心基因，作为磷虾油改善甲基苯丙胺诱导记忆缺损的潜在作用机制。京都基因与基因组百科全书（KEGG）通路富集分析与基因本体（GO）富集分析结果显示，丝裂原活化蛋白激酶（MAPK）信号通路、环磷酸腺苷（cAMP）信号通路及多巴胺能突触通路参与了磷虾油的神经保护作用。在海马组织中，甲基苯丙胺组的DRD2、裂解型半胱天冬酶-3（cleaved caspase-3）及γ-H2AX的表达水平显著升高，而磷虾油干预组的上述指标表达水平则显著降低；与此同时，磷虾油可上调磷酸化蛋白激酶A（p-PKA）、磷酸化细胞外调节蛋白激酶1/2（p-ERK1/2）及磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）的表达。本研究结果表明，磷虾油可改善甲基苯丙胺诱导的记忆缺损，其作用机制可能与MAPK信号通路及多巴胺能突触通路相关。网络药理学方法与实验验证相结合的策略，可为解析多成分复合物的分子机制提供有效工具。