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

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

The authors received no extramural funding for the study.

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

YBY: Conception or design of the work, literature search, data analysis and interpretation, manuscript preparation, critical revision of the article, and final approval of the version to be published. MZQ: Conception of the work, data collection, manuscript editing and revision, critical revision of the article, and final approval of the version to be published. DYZ: Literature search, data analysis and interpretation, manuscript editing, and revision, critical revision of the article, and final approval of the version to be published.

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