Dihydroquercetin Ameliorates Neuronal Ferroptosis in Rats After Subarachnoid Hemorrhage via the PI3K/AKT/Nrf2/HO-1 Pathway

Abstract

Subarachnoid hemorrhage (SAH) is a specific type of stroke. Dihydroquercetin (DHQ), a flavonoid, is known for its various pharmacological properties. This study aimed to explore the roles and mechanisms of DHQ in influencing the progression of SAH. A rat SAH model was established using the endovascular perforation technique. Following SAH induction, DHQ was administered orally 1 h later. Assessments included SAH scores, neurological function, brain swelling, blood-brain barrier (BBB) integrity, neuronal damage, apoptosis levels, inflammation, and indicators of ferroptosis using various treatments. The HT22 cells were exposed to hemin to simulate SAH-like conditions under in vitro settings. Cell counting kit-8 assays, flow cytometry, enzyme?linked immunosorbent assay, BODIPY 581/591 C11 staining, western blot analysis, and biochemical kits were employed to evaluate the potential effects of DHQ. Moreover, the mechanisms responsible for the protective effect of DHQ were examined by western blot analysis. The in vivo findings revealed that DHQ mitigated neurological impairments, brain swelling, BBB disruption, and neuronal injury at 24 h post-SAH. DHQ also reduced neuronal degeneration, inflammation, and ferroptosis following SAH. The in vitro findings revealed that DHQ enhanced cell survival and reduced ferroptosis at 24 h following hemin exposure. Mechanistically, DHQ activated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in SAH rats and hemin-treated HT22 cells to exert neuroprotective effects. In conclusion, this study reveals that DHQ can effectively decrease BBB permeability, brain edema, neurological dysfunctions, and ferroptosis post-SAH by activating the PI3K/AKT/Nrf2/HO-1 pathway.