2. Academic Validation
  3. Intrathecal STAT3 inhibitor Bt354 ameliorates chronic constriction injury-induced nociceptive sensitization by modulating neuroinflammation

Intrathecal STAT3 inhibitor Bt354 ameliorates chronic constriction injury-induced nociceptive sensitization by modulating neuroinflammation

  • Neurotherapeutics. 2025 Oct;22(6):e00763. doi: 10.1016/j.neurot.2025.e00763.
Hao-Jung Cheng 1,  Nan-Fu Chen 2,  Yueh-Chiao Tang 3,  Po-Chang Shih 4,  Wu-Fu Chen 5,  Ya-Jen Chiu 6,  Chun-Sung Sung 7,  Zhi-Hong Wen 8
Affiliations

Affiliations

  • 1 Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan.
  • 2 Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan.
  • 3 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan.
  • 4 Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
  • 5 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan; Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833401, Taiwan.
  • 6 National Museum of Marine Biology and Aquarium, Pingtung, 94450, Taiwan.
  • 7 Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan; School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan. Electronic address: cssung@vghtpe.gov.tw.
  • 8 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan; National Museum of Marine Biology and Aquarium, Pingtung, 94450, Taiwan. Electronic address: wzh@mail.nsysu.edu.tw.
PMID: 41067955 DOI: 10.1016/j.neurot.2025.e00763
Abstract

Neuropathic pain poses a significant societal and clinical burden and is closely linked to neuroinflammation of the central nervous system. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of inflammatory processes and has been implicated in the development of nociceptive hypersensitivity. In this study, we aimed to elucidate the therapeutic potential and underlying mechanisms of STAT3 inhibition in a rodent model of neuropathic pain. Using behavioral assessments of nociceptive sensitivity and immunofluorescence analysis, we investigated the analgesic mechanisms of the intrathecal STAT3 Inhibitor, Bt354, in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. Cellular and molecular markers of glial activation and inflammation were examined to assess the effects of Bt354 on neuroinflammatory pathways. Intrathecal administration of Bt354 significantly reduced CCI-induced mechanical allodynia and thermal hyperalgesia, accompanied by a marked decrease in phosphorylated STAT3 (pSTAT3) expression in spinal neurons. Bt354 treatment attenuated the polarization of M1-type microglia and A1-type astrocytes, suppressed inflammasome-related signaling, and mitigated neuroinflammatory responses. Importantly, Bt354 inhibited the nuclear translocation of neuronal pSTAT3, which is a critical step in regulating pro-inflammatory gene transcription. Moreover, CCI-induced angiogenesis and microglial phosphorylation of CREB and P38 were mitigated by pSTAT3 inhibition. These findings suggest that STAT3 plays a central role in the pathogenesis of neuropathic pain by regulating glial cell polarization and neuroinflammation. Targeting STAT3 with Bt354 may represent a promising therapeutic strategy for treating neuropathic pain.

Keywords

Glial cell polarization; NLRP3; Neuroinflammation; Neuropathic pain; STAT3.

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