Investigation of the efficacy of tangeretin treatment on diabetes-induced neuropathic pain in rats

In this thesis study, the potential efficacy of tangeretin, a pentamethoxyflavone abundantly found in citrus peels, was investigated on neuropathic pain induced by experimental diabetes in rats. The effect of tangeretin on hyperglycemia was evaluated by measuring fasting blood glucose and HbA1c levels, while its effect on neuropathic pain parameters was assessed using the Randall–Selitto, dynamic plantar, Hargreave's plantar, and warm plate tests. Fourteen days of tangeretin administration (10 mg/kg and 20 mg/kg) significantly reduced fasting blood glucose and HbA1c levels in diabetic rats. Findings from neuropathic pain tests demonstrated that tangeretin, at both doses, comparably attenuated mechanical and thermal hyperalgesia and allodynia responses, similar to the reference drug gabapentin. No statistically significant difference was observed between the 10 mg/kg and 20 mg/kg doses in terms of anti-allodynic and anti-hyperalgesic efficacy. Mechanistic studies aimed at elucidating tangeretin's mode of action revealed that the pre-administration of yohimbine and ICI 118,551 reversed the anti-hyperalgesic and anti-allodynic effects observed with the 10 mg/kg dose of tangeretin, whereas pre-treatment with WAY 100635, AM251, and AM630 had no effect. These findings demonstrate that the anti-hyperalgesic and anti-allodynic effects of tangeretin are mediated through α2- and β2-adrenergic receptors. This study is the first to indicate the efficacy of tangeretin in diabetes-associated neuropathic pain. The next step toward the development of tangeretin as a potential therapeutic agent will depend on the outcomes of comprehensive efficacy and safety studies in diabetic patients.