Evaluation of the Antioxidant and Anti‐inflammatory Effects of SMTP‐44D against Streptozotocin‐Induced Diabetic Neuropathy in Mice

Abstract

ObjectiveDiabetic neuropathy (DN), a major complication of diabetic mellitus, is present in more than 50% of diabetic patients. During the early stages of pathologic progression, patients with DN may experience sensory defects such as allodynia and hyperalgesia. Patients in advanced stages may present with sensory paralysis, such as nerve injury and the degeneration of axons, which are frequently accompanied by foot ulcerations, amputations, and poor prognoses. The pathogenesis of DN primarily involves oxidative stress and inflammation; thus, oxidative stress and inflammation are considered important therapeutic targets. However, few effective therapies are approved for the treatment of painful or insensate DN. The study aimed to evaluate the antioxidant and anti‐inflammatory effects of Stachybotrys microspora triprenyl phenol‐44D (SMTP‐44D) in a mouse model of DN.MethodsWe induced diabetes in C57BL/6J male mice by administering a single intraperitoneal injection of streptozotocin (200 mg/kg). SMTP‐44D (0.3, 3, and 30 mg/kg) was subsequently administered daily from 1 to 4 weeks after the injection of streptozotocin. The effects of SMTP‐44D were evaluated by mechanical and thermal thresholds to assess allodynia and hyperalgesia, and conduction velocity and blood flow in sciatic nerves. In addition, the levels of oxidative stress and inflammatory cytokines in sciatic nerves were determined via a thiobarbituric acid reactive substances assay and enzyme‐linked immunosorbent assay, respectively. To evaluate for neurological degeneration, G‐ratios (ratio of axon diameter to myelinated fiber diameter) and myelin thickness in the Schwann cells of sciatic nerves were measured.ResultsMechanical and thermal thresholds, conduction velocity, blood flow, and myelin thickness were significantly lower in the diabetic group than in the nondiabetic group. Moreover, the levels of oxidative stress (e.g., malondialdehyde), inflammatory cytokines (e.g., tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6), and G‐ratios were significantly higher in the diabetic group than in the nondiabetic group. Such results demonstrated that the DN model was successfully established. In mice with DN, treatment with SMTP‐44D significantly and dose‐dependently improved allodynia, hyperalgesia, conduction velocity of sciatic nerves, and blood flow in sciatic nerves. Furthermore, G‐ratios and myelin thickness in the Schwann cells of sciatic nerves were also significantly improved by the suppression of oxidative stress and inflammatory cytokines.ConclusionIt is believed that oxidative stress and inflammation are involved in the pathological progression of DN and that they are important therapeutic targets. Our results showed that SMTP‐44D improved DN by exerting antioxidant and anti‐inflammatory effects, which suggests that SMTP‐44D is a potential novel therapeutic agent for the treatment of DN.Support or Funding InformationThis study was supported in part by the Japan Society for the Promotion of Science KAKENHI (Grant Number 26460346, awarded to KN; Grant Number 18K14958, awarded to KS). SMTP‐44D was generously donated by TMS Co., Ltd. (Tokyo, Japan).