KIU Publications

Background: Post- traumatic stress disorder (PTSD) is a complicated neuropsychiatric disorder that is marked by long- term neuroinflammation, oxidative stress, and poor neuroplasticity in stress- sensitive brain areas. Hesperidin is a citrus- derived flavanone glycoside that has been reported to have multitarget neuroprotective effects with antioxidant, anti- inflammatory, and neurotrophic regulatory activities. However, its integrated effects across convergent pathological pathways in validated PTSD models remain insufficiently defined. Methods: Male Wistar rats were subjected to the single prolonged stress (SPS) para digm and treated with hesperidin (50, 100, and 200 mg/kg), fluoxetine (20 mg/kg), or vehicle for 14 days. Biochemical assessments (malondialdehyde [MDA], catalase [CAT], superoxide dismutase [SOD]) and immunohistochemical measurements of neu ronal and glial integrity (NeuN, glial fibrillary acidic protein [GFAP], brain- derived neu rotrophic factor [BDNF]) in the hippocampus, amygdala, and prefrontal cortex were performed. Results: SPS exposure induced marked oxidative imbalance, evidenced by increased MDA levels and reduced CAT activity, alongside significant upregulation of tumor ne crosis factor α (TNF- α), interleukin 6 (IL- 6), and IL- 1β, increased astrocytic reactivity (GFAP), and reduced BDNF expression. Hesperidin treatment significantly attenuated lipid peroxidation, partially restored CAT activity, and suppressed pro- inflammatory cytokines, with the most pronounced effect observed for IL- 1β. Notably, hesperidin reduced astrocytic activation and preserved neuronal morphology, while enhancing BDNF expression in a dose- dependent manner, with optimal effects at 50–100 mg/kg. Conversely, there was little group variation in the activity of SOD, implying pathway- selective redox regulation. Conclusion: Hesperidin has multipathway, coordinated, modulatory effects on oxida tive stress, neuroinflammation, glial activation, and neurotrophic signaling in the SPS model of PTSD. These findings support its utility as a mechanistic probe for interro gating convergent stress- related neuropathological pathways.