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  3. Decoding the mechanism of proanthocyanidins in central analgesia: redox regulation and KCNK3 blockade

Decoding the mechanism of proanthocyanidins in central analgesia: redox regulation and KCNK3 blockade

  • Exp Mol Med. 2025 Mar;57(3):567-583. doi: 10.1038/s12276-025-01412-5.
Junxiang Gu # 1 2,  Jian Wang # 2 3,  Hongwei Fan # 2 4,  Yi Wei 2 5,  Yan Li 6,  Chengwen Ma 1,  Keke Xing 2,  Pan Wang 2,  Zhenyu Wu 2,  Teng Wu 1,  Xiaoyi Li 7,  Luoying Zhang 7,  Yunyun Han 8,  Tao Chen 9,  Jianqiang Qu 10,  Xianxia Yan 11
Affiliations

Affiliations

  • 1 Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Human Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China.
  • 3 Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
  • 4 Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 School of Medicine, Northwest University, Xi'an, China.
  • 6 Shaanxi University of Chinese Medicine, Xianyang, China.
  • 7 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 8 Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Department of Human Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China. chtkkl@fmmu.edu.cn.
  • 10 Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. qujianqiang@xjtu.edu.cn.
  • 11 Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. yanxx07@xjtu.edu.cn.
  • # Contributed equally.
PMID: 40025170 DOI: 10.1038/s12276-025-01412-5
Abstract

Neuropathic pain causes enduring physical discomfort and emotional distress. Conventional pharmacological treatments often provide restricted relief and may result in undesirable side effects, posing a substantial clinical challenge. Peripheral and spinal redox homeostasis plays an important role in pain processing and perception. However, the roles of oxidative stress and Antioxidants in pain and analgesia on the cortical region during chronic pain remains obscure. Here we focus on the ventrolateral orbital cortex (VLO), a brain region associated with pain severity and involved in pain inhibition. Using a spared nerve injury mouse model, we observed the notable Reactive Oxygen Species (ROS)-mediated suppression of the excitability of pyramidal cells (PYRVLO) in the VLO. Nasal application or microinjection of the natural Antioxidants proanthocyanidins (PACs) to the VLO specifically increased the activity of PYRVLO and induced a significant analgesic effect. Mechanistically, PACs activate PYRVLO by inhibiting distinct potassium channels in different ways: (1) by scavenging ROS to reduce ROS-sensitive voltage-gated potassium currents and (2) by acting as a channel blocker through direct binding to the cap structure of KCNK3 to inhibit the leak potassium current (Ileak). These results reveal the role of cortical oxidative stress in central hyperalgesia and elucidate the mechanism and potential translational significance of PACs in central analgesia. These findings suggest that the effects of PACs extend beyond their commonly assumed antioxidant or anti-inflammatory effects.

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