Esculin alleviates early brain injury by inhibiting neuronal ferroptosis via activating the Nrf2/FSP1 pathway after subarachnoid hemorrhage

Abstract

Early brain injury (EBI) is defined as the acute pathological process that occurs within 72 h after subarachnoid hemorrhage (SAH), directly affecting the prognosis of the patients. Esculin is an effective anti-inflammatory and antioxidant herbal extract; however, whether esculin is effective in improving the prognosis of SAH and its mechanisms remain to be elucidated. This study aims to investigate the neuroprotective effects and possible mechanisms of esculin in alleviating EBI after SAH. Our present study found that esculin mitigated neurological deficit, brain edema, blood−brain barrier (BBB) permeability, lipid peroxidation levels, the morphological changes in mitochondria and neuronal cell death in SAH rats. Moreover, esculin alleviated SAH-induced long-term spatial learning and memory impairment. In vitro, esculin effectively increased cell viability and mitigated the degree of mitochondrial impairment induced by oxy-Hb stimulation in HT22 cells. Mechanistic investigations revealed that esculin alleviated lipid peroxidation and neuronal ferroptosis by upregulating FSP1 expression through the Nrf2 pathway. All these findings indicate that esculin inhibits neuronal ferroptosis to improve the prognosis of SAH via Nrf2/FSP1 pathway, which provides new insights into the clinical treatment of SAH.

Keywords

subarachnoid hemorrhage / early brain injury / ferroptosis / esculin / Nrf2 / FSP1

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Higher Education Press 2026

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