Neuroprotective potential of Hesperidin in Alcohol withdrawal syndrome: A preclinical study in Swiss albino mice

Background: Hesperidin (Chinese: 橙皮苷, Chéng pí gān) is a bioflavonoid primarily found in citrus fruits such as oranges and tangerines. It has been used for centuries in Traditional Chinese Medicine (TCM) as a key active component of Citri reticulatae Pericarpium (陈皮, Chénpí) and Aurantii fructus immaturus (枳实, Zhǐshí), which are traditionally employed to treat digestive disorders, circulatory problems, and respiratory ailments. These herbs are well-established in classical TCM formulations and have recently been included in Chinese guidelines for epidemic management, highlighting hesperidin’s broad therapeutic potential. Modern studies have demonstrated hesperidin’s strong antioxidant, anti-inflammatory, neuroprotective, and hepatoprotective effects. Owing to these properties, hesperidin has gained interest as a natural therapeutic candidate for neuropsychiatric conditions such as alcohol withdrawal syndrome (AWS). Accordingly, this study aimed to assess the efficacy of hesperidin in alleviating behavioral and biochemical alterations in a murine model of AWS. Thirty male Swiss albino mice ( n = 6 per group) were randomly divided into five groups. Four groups received a modified liquid diet (MLD) containing ethanol for 21 days to induce alcohol dependence, while the control group received an ethanol-free MLD. Upon ethanol withdrawal, mice were treated for 48 h with hesperidin (50 mg/kg or 100 mg/kg, orally) or diazepam (1 mg/kg, intraperitoneally), serving as the reference standard. Behavioral evaluations were conducted at 6 th , 24 th , and 48 th h post-withdrawal using the elevated plus maze, open field test (for anxiety), forced swim and tail suspension tests (for depression), actophotometer (for locomotor activity), and hot plate and tail immersion tests (for nociception). Biochemical analyses included estimation of brain antioxidant enzymes such as, superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and liver enzymes like aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Hesperidin produced statistically significant improvements in anxiety- and depression-like behaviors, locomotor activity, nociceptive responses, brain antioxidant status, and hepatic enzyme levels compared to the ethanol withdrawal group. Hesperidin alleviated behavioral, biochemical, and histopathological alterations associated with AWS in this study. Although the results indicate potential neuroprotective and hepatoprotective effects that may involve antioxidant mechanisms, these findings are preliminary. Comprehensive pharmacological and mechanistic studies are warranted to confirm its therapeutic relevance in AWS management.