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

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Effect of 40 Hz light flicker on cognitive impairment and transcriptome of hippocampus in right unilateral common carotid artery occlusion mice

“…Our study showed that rUCCAO mice exhibited short-term and spatial working memory impairment. This result is consistent with those of other studies in which CCH induced by rUCCAO was associated with cognitive deficits 8 , 11 . Previous studies have shown that 40 Hz light flicker stimulation can improve cognitive function in mice with CK-p25 and Tau P301S neurodegenerative diseases 25 , transgenic 3×Tg-AD mice 26 and stroke mice 27 .…”

“…Cerebral hypoperfusion is a major cause of degenerative processes that lead to cognitive decline, and is associated with the severity of dementia 5 , 6 . To date, right unilateral common carotid artery occlusion (rUCCAO) is generally used to model chronic cerebral hypoperfusion in mice 7 , 8 . After rUCCAO, cerebral perfusion is reduced by 35% compared to baseline, and hypoperfusion in the ipsilateral hemisphere can last for 4 months 9 , 10 .…”

Nrf2 functions as a pyroptosis-related mediator in traumatic brain injury and is correlated with cytokines and disease severity: a bioinformatics analysis and retrospective clinical study

“…Previous studies showed that Nrf2 is involved in numerous pathophysiological processes, including reducing oxidative stress, promoting mitochondrial biosynthesis, alleviating endoplasmic reticulum stress, and inhibiting ferroptosis. These pathological processes play important roles during secondary brain injury (16,17). After brain trauma, Nrf2 translocates to the nucleus, activates expression of genes with neuroprotective function, and thereby leads to upregulation of expressions of various detoxification and anti-cell death factors, such as Bcl-2 and HSP70s.…”