Apigenin ameliorates diabetic neuropathy in rats by modulating the TLR4/MyD88 signaling pathway

Abstract

Objective: To determine the neuroprotective effects of apigenin against streptozotocin (STZ)-induced diabetic neuropathy (DN). Methods: To induce DN, Wistar rats (150-200 g) were administered with STZ (55 mg/kg, i.p.). Then they were randomly assigned to various groups, viz., normal, diabetic control, insulin (10 IU/kg, s.c.), apigenin (5, 10, and 20 mg/kg, p.o.), and insulin (10 IU/kg) plus apigenin (20 mg/kg, p.o.). Various behavioral, biochemical, and molecular markers [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor erythroid 2-related factor 2 (Nrf2)] were assessed. Results: Apigenin (10 and 20 mg/kg, p.o.) substantially reduced plasma glucose levels, lipid profile, aspartate transaminase, alanine transaminase, glycated hemoglobin, and neural advanced glycation end products in STZ-induced DN rats (P<0.05). After apigenin intervention, STZ-induced changes in food and water intake, body weight, urine output, allodynia, hyperalgesia, and insulin levels were markedly improved (P<0.05). Neural antioxidant enzymes (superoxide dismutase and glutathione) and Na+K+ATPase activity were also considerably elevated (P<0.05) while the level of lipid peroxidation was diminished following apigenin therapy (P<0.05). Furthermore, apigenin markedly upregulated the Nrf2 mRNA level while downregulating the mRNA expressions of TNF-α and ILs and the protein expressions of TLR4 and MyD88 (P<0.05). STZ-induced histological abnormalities in the sciatic nerve were also improved by apigenin treatment. Conclusions: Apigenin exerts its neuroprotective effect by modulating the inflammatory and oxidative stress pathways via regulating the TLR4-MyD88 signaling pathway.

Keywords

• apigenin; diabetic neuropathy; myd88; nrf2; proinflammatory cytokines; tlr4