ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1642167
Artemisinin Exerts Antidepressant-like Effects via Activation of AKT and ERK Signaling Pathways
Provisionally accepted
- 1University of Macau, Taipa, China
- 2Southern Medical University, Guangzhou, China
- 3Universidade de Sao Paulo, São Paulo, Brazil
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Aims: Depression is a leading cause of disability worldwide, with current treatments often limited by efficacy and side effects. Artemisinin (ART), a natural compound with known anti-inflammatory and neuroprotective properties, has not been extensively studied for its potential antidepressant effects. This study aimed to elucidate the neuroprotective mechanisms of artemisinin against corticosterone (CORT)-induced toxicity in PC12 cells model, and to assess its antidepressant-like behavioral effects in a chronic unpredictable mild stress (CUMS) mouse model. Methods: in vitro, PC12 cells and primary hippocampal neurons were treated with CORT and artemisinin to assess cell viability, oxidative stress, mitochondrial function, and apoptosis. Pharmacological inhibition and CRISPR/Cas9 gene editing were used to explore the roles of AKT and ERK signaling pathways. In vivo, CUMS-induced depression-like behaviors in mice were evaluated using sucrose preference, tail suspension, and forced swim tests. Western blotting and immunohistochemistry studies were performed to analyze molecular mechanisms. Results: Artemisinin attenuated CORT-induced cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis in PC12 cells and hippocampal neurons. These effects were mediated through the activation of AKT and ERK pathways. In CUMS mice, artemisinin improved depression-like behaviors, upregulated the AKT/GSK/NRF2/HO1 and BDNF/TrkB/ERK/CREB pathways, modulated astrocyte activity, and promoted neurogenesis in the hippocampus. Conclusion: Artemisinin exerts significant neuroprotective and antidepressant-like effects through multiple molecular and cellular mechanisms, highlighting its potential as a novel therapeutic agent for depression.
Keywords: Artemisinin, Depression, Corticosterone, Chronic unpredictable mild stress, Oxidative Stress, Akt/Erk signaling
Received: 06 Jun 2025; Accepted: 16 Sep 2025.
Copyright: © 2025 Lin, Zhou, Jiang, Liu, Xie, Wang, Ulrich and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wenhua Zheng, wenhuazheng@umac.mo
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.