Shinouchi Ryosuke, Shibata Keita, Nagatsuka Taiju, Hasumi Keiji, Nobe Koji
Department of Pharmacology, Showa Medical University Graduate School of Pharmacy (R.S.; K.S.; K.N.), 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; Pharmacological Research Center, Showa Medical University (R.S.; K.S.; K.N.), 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Department of Pharmacology, Showa Medical University Graduate School of Pharmacy (R.S.; K.S.; K.N.), 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; Pharmacological Research Center, Showa Medical University (R.S.; K.S.; K.N.), 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
J Diabetes Complications. 2025 Jul;39(7):109061. doi: 10.1016/j.jdiacomp.2025.109061. Epub 2025 Apr 29.
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.
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.
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.
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.
Our findings suggest that SMTP-44D is a promising therapeutic agent for DN, acting through sEH inhibition and reducing AGE/RAGE levels.
糖尿病性神经病变（DN）是糖尿病的一种使人衰弱的并发症，由氧化应激、炎症以及晚期糖基化终产物（AGE）通过其受体（RAGE）发出的信号所驱动。可溶性环氧化物水解酶（sEH）将具有抗炎作用的环氧二十碳三烯酸（EETs）代谢为具有促炎作用的二羟基二十碳三烯酸（DHETs），从而加剧DN的病理过程。sEH抑制剂SMTP-44D在体外已显示出抗氧化和抗炎作用；然而，其体内疗效仍不明确。
在链脲佐菌素（STZ）诱导的DN小鼠模型中，研究SMTP-44D与sEH抑制及AGE/RAGE信号传导相关的抗氧化和抗炎活性。
在STZ注射（200mg/kg）后第8天至第28天，用SMTP-44D（30mg/kg）治疗STZ诱导的糖尿病小鼠。通过酶联免疫吸附测定法评估坐骨神经中的氧化应激标志物、炎症因子、AGE以及血清中的RAGE。使用液相色谱-串联质谱法测量血清中的DHET水平，并通过TUNEL染色和针对裂解的半胱天冬酶-3的荧光免疫组织化学评估坐骨神经中的细胞凋亡。
我们的研究结果表明，SMTP-44D抑制sEH，降低DHET水平并维持抗炎作用。它减弱了核因子-κB的迁移，降低了AGE和RAGE水平，并抑制了坐骨神经中的氧化应激和炎症标志物。此外，SMTP-44D抑制细胞凋亡，可能减轻与DN相关的轴突损伤。
我们的研究结果表明，SMTP-44D是一种有前景的DN治疗药物，其作用机制是抑制sEH并降低AGE/RAGE水平。
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