Fo-Shou-San Ameliorates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment in Mice by Regulating NRF2/HO-1 Pathway Against Ferroptosis

Abstract

Fo-Shou-San (FSS) is a traditional Chinese medicine (TCM) decoction that can effectively treat vascular dementia (VD). In the face of unclear pharmacological mechanisms, we set out to validate that FSS treats chronic cerebral hypoperfusion (CCH)-induced cognitive impairment in mice. CCH animal model caused by permanent right unilateral common carotid arteries occlusion (rUCCAO) was established to verify that FSS could treat subcortical ischemic vascular dementia (SIVD). We performed novel object recognition test and Morris water maze test, observed morphological changes via HE and Nissl staining, and detected hippocampus apoptosis by TUNEL staining and oxidative stress by biochemical assays. Ferroptosis-related markers and NRF2/HO-1 signaling-related expressions were examined via qPCR and immunofluorescence staining. We found that FSS ameliorated cognitive disorders, and lessened oxidative stress by decreasing MDA and GSH-PX while increasing the reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG) ratio, which are associated with ferroptosis. Additionally, FSS reduced expression of SLC7A11, GPX4, ROX and 4HNE, as vital markers of ferroptosis. Further, FSS regulated NRF2/HO-1 signaling by downregulating NRF2 and HO-1. Our study suggests that FSS may ameliorate chronic cerebral hypoperfusion-induced cognitive deficits through regulation of the NRF2/HO-1 pathway against ferroptosis. Taken together, our study highlights the neuroprotective efficacy of FSS.