2. Academic Validation
  3. Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis

Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis

  • Neurobiol Dis. 2024 Jun 18:199:106573. doi: 10.1016/j.nbd.2024.106573.
Lijia Chang 1,  Yan Wei 2,  Youge Qu 3,  Mingming Zhao 3,  Xiangyu Zhou 4,  Yang Long 5,  Kenji Hashimoto 6
Affiliations

Affiliations

  • 1 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, 646000, China.
  • 2 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan, China.
  • 3 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
  • 4 Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, 646000, China; Department of Thyroid and Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 5 Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, China; Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 6 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan. Electronic address: hashimoto@faculty.chiba-u.jp.
PMID: 38901783 DOI: 10.1016/j.nbd.2024.106573
Abstract

Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the Oxidative Phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-β1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-β1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-β1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.

Keywords

Arketamine; Oxidative phosphorylation; Spleen; Spleen-brain axis; Transforming grow factor β1; Vagus nerve.

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