SMTP-44D Exerts Antioxidant and Anti-Inflammatory Effects through Its Soluble Epoxide Hydrolase Inhibitory Action in Immortalized Mouse Schwann Cells upon High Glucose Treatment.

Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) for 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 explore the mechanism of these effects of SMTP-44D in regard to its inhibition of soluble epoxide hydrolase (sEH) in immortalized mouse Schwann cells (IMS32) following high glucose treatment. IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D for 48 h. After incubation, the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, such as NADPH oxidase-1 and malondialdehyde, inflammatory factors, such as the ratio of nuclear to cytosolic levels of NF-κB and the levels of IL-6, MCP-1, MMP-9, the receptor for the advanced glycation end product (RAGE), and apoptosis, were evaluated. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, RAGE induction, and apoptosis after high glucose treatment. In conclusion, 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.

SMTP-44D improves diabetic neuropathy symptoms in mice through its antioxidant and anti-inflammatory activities.

Diabetic neuropathy (DN) is one of the major complications of diabetes. However, there are few approved effective therapies for painful or insensate DN. Recent studies have implicated oxidative stress and inflammation in the pathogenesis of DN, and suppressing these could be an important therapeutic strategy. We previously reported that Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) exhibits both antioxidant and anti-inflammatory activities. The aim of this study was to evaluate the effects of SMTP-44D in a mouse model of streptozotocin-induced DN. SMTP-44D was administered for 3 weeks after the disease induction, and its effects were evaluated on the basis of mechanical and thermal thresholds, blood flow in the bilateral hind paw, and blood flow and conduction velocity in the sciatic nerve. Furthermore, the levels of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and malondialdehyde (MDA), in the sciatic nerve were assessed. Neurological degeneration was assessed by measuring myelin thickness and g-ratio in the sciatic nerve. SMTP-44D treatment significantly improved allodynia, hyperalgesia, blood flow, and conduction velocity in DN model mice in a dose-dependent manner. Neurological degeneration was also significantly improved, accompanied by decreased levels of inflammatory factors (TNF-α, 57.8%; IL-1ß, 51.4%; IL-6, 62.8%; and MDA, 40.7% reduction rate against the diabetes mellitus + normal saline group). Thus, SMTP-44D can improve allodynia and hyperalgesia in DN without affecting the body weight and blood glucose levels, which may be due to its antioxidant and anti-inflammatory properties. In conclusion, SMTP-44D could be a potential therapeutic agent for the treatment of DN.