Parthenolide inhibits methamphetamine-induced depressive-like behavior by targeting ADORA2A.

BACKGROUND: Methamphetamine (METH) abuse often results in persistent depressive-like behaviors, while current treatments show limited efficacy. Parthenolide, a natural compound with neuroprotective and anti-inflammatory properties, has shown benefits in several CNS disorders, but its role in METH-induced depression remains unknown. PURPOSE: This study aimed to evaluate whether parthenolide alleviates METH-induced depressive-like behaviors and to identify key brain regions and molecular targets involved. METHODS: Mice were administered METH using a 15-day escalating regimen and treated with parthenolide. Behavioral tests, histopathology, Nissl staining, and c-Fos mapping were conducted to assess neural alterations. Metabolomics and network pharmacology were used to predict targets, followed by molecular docking, dynamics simulations, cellular thermal shift assay, and pharmacological modulation for validation. RESULTS: Parthenolide significantly improved METH-induced depressive-like behaviors. The medial prefrontal cortex (mPFC) emerged as the most affected region, where parthenolide reduced neuronal damage. Integrative analyses identified ADORA2A as a key target, further supported by pharmacological inhibition and activation experiments. CONCLUSION: Parthenolide mitigates METH-induced depressive-like behaviors by modulating ADORA2A signaling in the mPFC, providing mechanistic insight into its antidepressant-like effects and supporting its potential as a therapeutic candidate for substance-induced mood disorders.