Shinouchi_2025_J.Diabetes.Complications_39_109061

BACKGROUND: Diabetic neuropathy (DN) is a debilitating complication of diabetes, driven by oxidative stress, inflammation, and advanced glycation end products (AGE) signaling through its receptor (RAGE). Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into pro-inflammatory dihydroxyeicosatrienoic acids (DHETs), exacerbating DN pathology. SMTP-44D, an sEH inhibitor, has demonstrated antioxidant and anti-inflammatory effects in vitro; however, its in vivo efficacy remains unclear. AIM: To investigate the antioxidant and anti-inflammatory activities of SMTP-44D in relation to sEH inhibition and AGE/RAGE signaling in a streptozotocin (STZ)-induced DN mouse model. METHODOLOGY: STZ-induced diabetic mice were treated with SMTP-44D (30 mg/kg) from days 8 to 28 post STZ injection (200 mg/kg). Oxidative stress markers, inflammatory factors, AGE in the sciatic nerve, and RAGE in serum were assessed via ELISA. DHET levels in serum were measured using LC-MS/MS, and apoptosis in the sciatic nerve was assessed via TUNEL staining and fluorescent immunohistochemistry for cleaved caspase-3. RESULTS: Our findings indicated that SMTP-44D inhibited sEH, reducing DHET levels and sustaining anti-inflammatory effects. It attenuated the migration of nuclear factor-kappa B, decreased AGE and RAGE levels, and suppressed oxidative stress and inflammatory markers in the sciatic nerve. Moreover, SMTP-44D inhibited apoptosis, potentially mitigating the axonal damage associated with DN. CONCLUSION: Our findings suggest that SMTP-44D is a promising therapeutic agent for DN, acting through sEH inhibition and reducing AGE/RAGE levels.