Multipathway modulation of neuroinflammation and oxidative stress by hesperidin in a rat single prolonged stress model of post‐traumatic stress disorder
Godson Emeka Anyanwu, Ogan Christopher Akanaku, Augustine Oviosun, Precious E. Ekwueme, Paul Anyiom Odey, Chima Paul Okechukwu Ugwu, Chinyere Nkemjika AnyanwuAbstract
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) paradigm 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 neuronal and glial integrity (NeuN, glial fibrillary acidic protein [GFAP], brain‐derived neurotrophic 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 necrosis 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 oxidative stress, neuroinflammation, glial activation, and neurotrophic signaling in the SPS model of PTSD. These findings support its utility as a mechanistic probe for interrogating convergent stress‐related neuropathological pathways.