Gastrodia elata fermentation alleviates methamphetamine-induced neuroinflammation and anxiety- and depression-like behaviors by regulating the PI3K-AKT signaling pathway

Background: Intractable depression- and anxiety-like behaviors significantly contribute to methamphetamine (METH) abuse and relapse, which are linked to METH-induced neuroinflammation and impaired neural function. Fermented Gastrodia elata (FGE) is produced through a specific fermentation process. Previous studies have shown that its primary active components, including gamma-aminobutyric acid (GABA) and 4-hydroxybenzyl alcohol (4-HBA), exhibit notable anti-inflammatory and neuroprotective properties. However, the protective effects of FGE against METH-induced neuroinflammation in the brain and the underlying mechanisms remain incompletely understood. Objective: This study aims to investigate the potential protective effects of FGE against METH-induced neuroinflammation in hippocampus neurons and its impact on anxiety- and depression-like behaviors in mice. Additionally, we seek to elucidate the underlying molecular mechanisms. Methods: A mouse model of anxiety- and depression-like behaviors was established using METH induction. Pathological changes in hippocampus neurons were examined via H&E staining. The effects of FGE on these neurons were evaluated through pathological analysis. A series of behavioral tests were conducted to assess the impact of FGE on METH-induced depressive- and anxiety-like behaviors. To further investigate the molecular pathways underlying the neuroprotective effects of FGE, network pharmacology, ELISA, and RT-PCR were employed. Results: The results demonstrated that METH effectively induced anxiety- and depression-like behaviors, which were associated with hippocampus neuroinflammation and neuropathology, along with significant activation of astrocytes and microglia. Intervention with FGE notably improved hippocampus pathology, reduced glial cell activation, and alleviated the associated anxiety- and depression-like behaviors. Furthermore, network pharmacology analysis suggested that the PI3K-AKT signaling pathway may contribute to the protective effects of FGE against METH-induced neuronal injury. Conclusion: This study demonstrates that FGE, a potential natural agent, alleviates anxiety- and depression-like behaviors induced by METH through the reduction of neuroinflammation in the hippocampus. The protective effects of FGE against METH-induced neuronal damage and behavioral deficits are likely mediated by the PI3K-AKT signaling pathway. These findings suggest FGE as a promising therapeutic strategy for METH-related neurological disorders.