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

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.