2. Academic Validation
  3. Parthenolide inhibits methamphetamine-induced depressive-like behavior by targeting ADORA2A

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

  • Phytomedicine. 2026 May:154:158030. doi: 10.1016/j.phymed.2026.158030.
Rongji Hui 1,  Tao Feng 2,  Congcong Hou 3,  Jiabao Xu 2,  Rongjie Zhang 2,  Menghan Ji 2,  Meiqi Zhou 4,  Bing Xie 2,  Suozhong Ma 5,  Bin Cong 2,  Chunling Ma 6,  Haitao Shen 7,  Di Wen 8
Affiliations

Affiliations

  • 1 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Province, Shijiazhuang 050017, China; Hebei Medical University Basic Medicine Postdoctoral Research Station, Hebei Province, Shijiazhuang 050017, China.
  • 2 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Province, Shijiazhuang 050017, China.
  • 3 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Province, Shijiazhuang 050017, China; College of Pharmacy, Key Laboratory of Innovative Drug Development and Evaluation, Hebei Medical University, Hebei Province, Shijiazhuang 050017, China.
  • 4 College of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Hebei Province, Shijiazhuang 050017, China.
  • 5 Women's Compulsory Isolation Drug Rehabilitation Center of Hebei Province, Hebei Province, Shijiazhuang 050022, China.
  • 6 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Province, Shijiazhuang 050017, China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Province, Shijiazhuang 050017, China.
  • 7 Center of Metabolic Diseases and Cancer Research (CMCR), Hebei Medical University, Hebei Province, Shijiazhuang 050017, China; Laboratory of Pathology, Hebei Medical University, Hebei Province, Shijiazhuang 050017, China; Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Hebei Province, Baoding 071000, China. Electronic address: [email protected].
  • 8 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Province, Shijiazhuang 050017, China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Province, Shijiazhuang 050017, China. Electronic address: [email protected].
PMID: 41795299 DOI: 10.1016/j.phymed.2026.158030
Abstract

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.

Keywords

ADORA2A; Depression; Metabolomics; Methamphetamine; Network pharmacology.

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