Abstract
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.
Highlights
As one of the most commonly abused psychostimulants in the world (Siefried et al, 2020), methamphetamine (METH) abuse results in various severe complications systemically affecting multiple organs, especially the brain (Casaletto et al, 2015; Huang et al, 2019)
Compared with the METH group, 10 mg/kg krill oil treatment greatly reduced the increase of learning latency in mice induced by METH on day 5 (p < 0.01), and mice pretreated with 100 mg/kg of krill oil performed significantly better than those that received METH alone on day 4 and day 5 (p < 0.01), suggesting that learning deficits were improved following krill oil treatment
We found that krill oil enhanced the neurocognitive functions of METH-treated mice, and targets like DRD2, MAP kinases (MAPK), cAMP-response element-binding protein (CREB), CASP3, and brain-derived neurotrophic factor (BDNF), and some signaling pathways such as the MAPK signaling pathway, PI3K-Akt signaling pathway, AMPK signaling pathway, neurotrophin signaling pathway, and cAMP signaling pathway were filtered out as the underlying mechanisms of krill on improving memory deficits induced by METH
Summary
As one of the most commonly abused psychostimulants in the world (Siefried et al, 2020), methamphetamine (METH) abuse results in various severe complications systemically affecting multiple organs, especially the brain (Casaletto et al, 2015; Huang et al, 2019). It is important to note that neurocognitive deficits did not just occur in people who are currently abusing METH but has been found in those who have stopped taking METH for an extended period of time (Cherner et al, 2010; Silva et al, 2014) In line with these clinical investigations, several studies in animal models have documented that repeated METH administration could essentially affect different brain areas including the frontal cortex and hippocampus, which are all associated with cognitive and memory function (Fan et al, 2020; Golsorkhdan et al, 2020; Lwin et al, 2020; Veschsanit et al, 2021). A deep understanding of its mechanism may provide more valuable ideas for the treatment of METH addiction and its induced mental disorders
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