2. Academic Validation
  3. Agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in parvalbumin-expressing neurons of the hippocampal ventral dentate gyrus

Agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in parvalbumin-expressing neurons of the hippocampal ventral dentate gyrus

  • Neuropharmacology. 2026 Jul 1:292:110945. doi: 10.1016/j.neuropharm.2026.110945.
Suhong Ye 1,  Qiaolu Xu 1,  Ling Bao 1,  Azhar Badry Hussein 2,  Qinglin Lu 3,  Xia Yuan 4,  Nashwa Amin 5,  Marong Fang 6
Affiliations

Affiliations

  • 1 Department of Neurology and Psychiatry, The Second Hospital of Jinhua, Jinhua, 321016, China.
  • 2 Institute of System Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China; Department of Zoology, Faculty of Science, Aswan University, Aswan, 81521, Egypt.
  • 3 Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China.
  • 4 Institute of System Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China.
  • 5 Institute of System Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China; Department of Zoology, Faculty of Science, Aswan University, Aswan, 81521, Egypt; Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial, People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 314408, China.
  • 6 Department of Orthopedics of Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Children and Adolescents' Health and Diseases, Hangzhou, 310052, China. Electronic address: [email protected].
PMID: 41887570 DOI: 10.1016/j.neuropharm.2026.110945
Abstract

Background: Major depressive disorder (MDD) is highly prevalent, but some patients are refractory to conventional treatments. Mitochondrial dysfunction, impaired Mitophagy, and parvalbumin (PV)-expressing hippocampal neuron deficits are linked to MDD pathogenesis, while agomelatine's antidepressant mechanism involving these elements remains unclear.

Aim: This study aimed to clarify whether agomelatine alleviates depressive-like behaviors in mice by promoting Mitophagy in PV neurons of the hippocampal ventral dentate gyrus (vDG).

Methods: Male C57BL/6J and Pvalb-creAi14 mice underwent chronic unpredictable mild stress (CUMS) for depression modeling. Groups included Control, CUMS, CUMS + Fluoxetine (FLX), CUMS + Agomelatine (AGO), CUMS + AGO+3-Methyladenine (Autophagy inhibitor), CUMS + AGO + Rapamycin (an mTORC1 Inhibitor that indirectly promotes Autophagy in a cell-type-dependent manner), and CUMS with vDG-targeted AAV-Beclin1 overexpression (oeBeclin1) ± AGO. Behavioral tests (TST, FST, SPT, OFT, SIT) and molecular/morphological analyses (Western blotting, IF, RT-qPCR, DHE staining, TEM, Golgi staining) were conducted.

Results: CUMS induced depressive-like behaviors and reduced PV neuron density. AGO's performance is no less effective than FLX. Mechanistically, it upregulated autophagy-related proteins (Beclin1, ATG5, LC3II/I) and downregulated p62. oeBeclin1 synergized with agomelatine to improve mitochondrial morphology, reduce ROS, and inhibit neuroinflammation.

Conclusion: In conclusion, agomelatine alleviates CUMS-induced depressive-like behaviors in mice, which is associated with the promotion of Mitophagy in vDG PV neurons of the hippocampus, mitigating mitochondrial damage and neuroinflammation. This uncovers a novel mechanism for its efficacy and highlights targeted Mitophagy activation as a promising MDD therapeutic strategy.

Keywords

Agomelatine; Ai14 mice; Chronic unpredictable mild stress; Mitophagy; PV neuron.

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