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<p>Neuropathic pain (NP) and depression frequently co-occur, creating a complex clinical challenge with limited therapeutic options due to poorly understood shared mechanisms. Our preliminary screening identified the mitochondrial deacetylase SIRT3 as a potential key regulator of this comorbidity. Building on this finding, we hypothesized that Gastrodin, a natural compound with documented neuroprotective properties, exerts its therapeutic effects by targeting SIRT3. This study was therefore designed to investigate whether Gastrodin alleviates NP-depression comorbidity through a SIRT3-dependent mechanism. A rat model of NP-depression comorbidity was established by combining spared sciatic nerve injury (SNI) with chronic unpredictable mild stress (CUMS). Behavioral tests were conducted to assess mechanical allodynia, thermal hyperalgesia, and depression-like behaviors. Molecular mechanisms were evaluated using Western blot, ELISA, qPCR, and transmission electron microscopy. The specific role of SIRT3 was confirmed using the inhibitor 3-TYP in vivo and siRNA in vitro. Gastrodin administration (200/300&#xa0;mg/kg) significantly ameliorated both pain hypersensitivity and depression-like behaviors in the comorbidity model. Mechanistically, Gastrodin upregulated SIRT3 expression and enhanced its deacetylase activity in the hippocampus, as evidenced by reduced acetylation of SOD2. This led to attenuated neuroinflammation (TNF-α, IL-1β, IL-6) and oxidative stress (MDA, ROS). Furthermore, Gastrodin improved mitochondrial ultrastructure and promoted mitochondrial biogenesis via the PGC-1α/TFAM pathway in astrocytes. Critically, all therapeutic benefits of Gastrodin were abolished upon SIRT3 inhibition. Gastrodin exerts dual therapeutic effects on NP-depression comorbidity by activating the SIRT3 pathway, thereby rescuing mitochondrial function in hippocampal astrocytes. These findings identify Gastrodin as a promising candidate for treating pain-depression comorbidity and underscore SIRT3 as a critical therapeutic target.</p>

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Gastrodin Ameliorates Pain-Depression Comorbidity through SIRT3-Dependent Alleviation of Oxidative Stress and Promotion of Mitochondrial Biogenesis

  • 期刊论文

  • 发表日期：

    2026年1月28日

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  • Feiran Zhou,
  • Yijian Luo,
  • Yan Liu,
  • Lin Luo,
  • Ping Jiang,
  • Qing Liu,
  • Ying Zhang

摘要

Neuropathic pain (NP) and depression frequently co-occur, creating a complex clinical challenge with limited therapeutic options due to poorly understood shared mechanisms. Our preliminary screening identified the mitochondrial deacetylase SIRT3 as a potential key regulator of this comorbidity. Building on this finding, we hypothesized that Gastrodin, a natural compound with documented neuroprotective properties, exerts its therapeutic effects by targeting SIRT3. This study was therefore designed to investigate whether Gastrodin alleviates NP-depression comorbidity through a SIRT3-dependent mechanism. A rat model of NP-depression comorbidity was established by combining spared sciatic nerve injury (SNI) with chronic unpredictable mild stress (CUMS). Behavioral tests were conducted to assess mechanical allodynia, thermal hyperalgesia, and depression-like behaviors. Molecular mechanisms were evaluated using Western blot, ELISA, qPCR, and transmission electron microscopy. The specific role of SIRT3 was confirmed using the inhibitor 3-TYP in vivo and siRNA in vitro. Gastrodin administration (200/300 mg/kg) significantly ameliorated both pain hypersensitivity and depression-like behaviors in the comorbidity model. Mechanistically, Gastrodin upregulated SIRT3 expression and enhanced its deacetylase activity in the hippocampus, as evidenced by reduced acetylation of SOD2. This led to attenuated neuroinflammation (TNF-α, IL-1β, IL-6) and oxidative stress (MDA, ROS). Furthermore, Gastrodin improved mitochondrial ultrastructure and promoted mitochondrial biogenesis via the PGC-1α/TFAM pathway in astrocytes. Critically, all therapeutic benefits of Gastrodin were abolished upon SIRT3 inhibition. Gastrodin exerts dual therapeutic effects on NP-depression comorbidity by activating the SIRT3 pathway, thereby rescuing mitochondrial function in hippocampal astrocytes. These findings identify Gastrodin as a promising candidate for treating pain-depression comorbidity and underscore SIRT3 as a critical therapeutic target.