Abstract
BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe neurological emergency with high morbidity and mortality, primarily due to vasospasm and delayed ischemia. Hesperidin (HSP), a natural flavonoid, possesses strong antioxidant and vasoprotective properties. This experimental animal study examined HSP's neuroprotective role in oxidative stress and vascular remodeling after SAH, focusing on the extracellular regulated kinase 5-Kruppel-like factor 2-endothelial nitric oxide synthase (Erk5-KLF2-eNOS) pathway. METHODS: The study was conducted from 2021 to 2022. Forty female Wistar albino rats were divided into five groups: control (G1, n=8), sham (G2, n=8), SAH + Vehicle (G3, n=8), SAH with low-dose HSP (G4, n=8), and SAH with high-dose HSP (G5, n=8). SAH was induced using a double injection of homologous blood into the cisterna magna. Biochemical markers (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], nitric oxide [NOS]), basilar artery morphometry, and molecular expressions (Erk5, p-Erk5, KLF2, eNOS) were evaluated 48 hours post-SAH. RESULTS: SAH significantly increased oxidative stress and reduced vascular lumen diameter in untreated rats (G3). Both HSP-treated groups (G4 and G5) showed improved antioxidant enzyme levels (SOD, CAT, GPx) and near-normal NOS levels. Morphometric analysis demonstrated significant preservation of basilar artery lumen diameter in treated groups, with no significant changes in wall thickness. Molecular analysis revealed upregulation of the Erk5-KLF2-eNOS pathway, suggesting a role in vasodilation and mitigation of oxidative stress. CONCLUSION: HSP protects against SAH-induced vasospasm and oxidative damage by enhancing antioxidant capacity and modu-lating the Erk5-KLF2-eNOS pathway, suggesting its therapeutic potential.