Mechanisms of the Antioxidant and Anti-inflammatory of SMTP-44D through Its Soluble Epoxide Hydrolase Inhibitory Action

Abstract

We have previously reported the efficacy of SMTP-44D for diabetic neuropathy (DN) through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain unclear. The present study aimed to reveal the mechanism of these effects of soluble epoxide hydrolase (sEH) inhibition by SMTP-44D. In the in vivo assay, SMTP-44D (30 mg/kg) was administered to 200 mg/kg streptozotocin (STZ)-induced diabetic mice from the 8 to the 28 days after the injection of STZ. In the in vitro assay, IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D (30 μM) for 48 h. The effects of the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, and inflammatory factors by administration of SMTP-44D were assessed by LC-MS/MS, TBARS, and ELISA assay, respectively. Furthermore, apoptosis was evaluated by TUNEL assay. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, and apoptosis. These results suggested that SMTP-44D can suppress the induction of apoptosis by exerting antioxidant and anti-inflammatory effects, possibly through sEH inhibition. SMTP-44D can be a potential therapeutic agent against DN.