2. Academic Validation
  3. A novel angiotensin II type 2 receptor antagonist TDI05 alleviates the peripheral neuropathic pain

A novel angiotensin II type 2 receptor antagonist TDI05 alleviates the peripheral neuropathic pain

  • Neurosci Lett. 2025 Aug 28:138369. doi: 10.1016/j.neulet.2025.138369.
Qilong Mao 1,  Yu Zeng 2,  Huining Liang 3,  Siyu Hou 3,  Qi Wang 4,  Jiaxin Zhang 1,  Zhou Lan 3,  Hongjun Wang 5,  Jing Wang 6,  Hongmei Zhao 7
Affiliations

Affiliations

  • 1 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China; State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • 2 State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China; State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • 3 Beijing Tide Pharmaceutical Co., Ltd, Beijing Econnomi Technological Development Area (BDA), No.8 East Rongjing Street, Beijing 100176, China.
  • 4 Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, China.
  • 5 Beijing Tide Pharmaceutical Co., Ltd, Beijing Econnomi Technological Development Area (BDA), No.8 East Rongjing Street, Beijing 100176, China. Electronic address: hongmeizhao@ibms.pumc.edu.cn.
  • 6 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China; State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China. Electronic address: wangjing@ibms.pumc.edu.cn.
  • 7 State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China. Electronic address: wanghj3@tidepharm.com.
PMID: 40885515 DOI: 10.1016/j.neulet.2025.138369
Abstract

Neuropathic pain is a debilitating chronic pain condition often associated with heightened inflammatory responses and increased angiotensin II type 2 receptor (AT2R) expression. This study systematically evaluated the therapeutic efficacy of TDI05, a novel AT2R antagonist, for treating neuropathic pain management. In vitro experiments using RAW 264.7 macrophages showed that TDI05 treatment significantly reduced AT2R expression at both the protein and mRNA levels, as determined by Western blotting and qPCR analysis, while CCK-8 assays confirmed its non-cytotoxicity. ELISA showed TDI05 reduced the production of inflammatory mediators (TNF-α, IL-1β, IL-8) by RAW 264.7 cells. Remarkably, in co-cultured systems with HT22 neuronal cells, these anti-inflammatory effects corresponded to significant down-regulation of pain-related ion channels transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1). In vivo validation utilizing three well-established rodent neuropathic pain models, TDI05 administration produced dose-dependent analgesic effects, significantly increasing mechanical withdrawal thresholds. Furthermore, immunofluorescence staining showed TDI05 reduced AT2R expression in sciatic nerve macrophages, while immunohistochemistry analysis confirmed suppression of TRPA1/TRPV1 expression in sensory neurons in the mouse spared nerve injury (SNI) model. Collectively, these findings establish TDI05 as a compelling therapeutic candidate for neuropathic pain treatment through AT2R-mediated inflammatory pathway inhibition and subsequent nociceptive TRP Channel inhibition.

Keywords

Angiotensin II; Inflammation; Neuropathic pain; angiotensin II Type 2 receptor.

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