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  3. Trans-cinnamaldehyde alleviates IFN-α-induced depressive-like behaviors by restoring astrocytic Cx43 gap junction

Trans-cinnamaldehyde alleviates IFN-α-induced depressive-like behaviors by restoring astrocytic Cx43 gap junction

  • Int Immunopharmacol. 2025 Oct 28:167:115741. doi: 10.1016/j.intimp.2025.115741.
Run Zhou 1,  Ruolan Yuan 2,  Junrui Ye 2,  Shasha Wang 2,  Yuqi Chen 2,  Xiaofen Zhou 1,  Shifeng Chu 3,  Zhao Zhang 4,  Naihong Chen 5
Affiliations

Affiliations

  • 1 College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, China.
  • 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: chushifeng@imm.ac.cn.
  • 4 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: zhangzhao@imm.ac.cn.
  • 5 College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: chennh@imm.ac.cn.
PMID: 41160920 DOI: 10.1016/j.intimp.2025.115741
Abstract

Interferon-alpha (IFN-α)-induced depression lacks effective treatments, and its neuroinflammatory mechanisms remain unresolved. Trans-cinnamaldehyde (TCA), a cinnamon-derived bioactive compound with anti-inflammatory properties, was investigated for its antidepressant potential in an IFN-α-induced murine depression model. Behavioral tests, fMRI, and electrophysiology revealed that TCA dose-dependently alleviated depressive-like behaviors, restored functional connectivity (mPFC-DMN-Hb), and enhanced mPFC neuronal excitability. Mechanistically, TCA downregulated phosphorylated connexin 43 (Cx43) in astrocytes while preserving total Cx43 expression, suppressed COX-2/NF-κB signaling, and reduced proinflammatory cytokines (IL-6, TNF-α) in the mPFC. Crucially, astrocyte-specific Cx43 knockout (Gfap-Cre; Cx43fl/fl) mice exhibited depression-like phenotypes and hyperactivated neuroinflammation, abolishing TCA's therapeutic effects. These results demonstrate that TCA mitigates IFN-α-induced depression by modulating astrocytic Cx43 gap junctions and inhibiting COX-2/NF-κB-driven neuroinflammation, positioning it as a novel immunopharmacological agent for inflammation-associated depression and highlighting Cx43 as a potential therapeutic target.

Keywords

COX-2; Cx43; Depression; Gap junction; Interferon-α; Trans-cinnamaldehyde.

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