Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway

•DMF improved learning and memory decline in rats subjected to CCH.•Ferroptosis was involved in hippocampal neurons damage and loss in rats subjected to CCH.•DMF reduced hippocampal neurons injury and loss in rats subjected to CCH through alleviating oxidative stress, neuroinflammation and inhibition of ferroptosis.•DMF mitigated hippocampal neuronal oxidative stress, neuroinflammation and inhibition of ferroptosis via NRF2/ARE/NF-κB signal pathway. Cerebrovascular disease and its risk factors cause persistent decrease of cerebral blood flow, chronic cerebral hypoperfusion (CCH) is the major foundation of vascular cognitive impairment (VCI). The hippocampus is extremely vulnerable to cerebral ischemia and hypoxia. Oxidative stress and neuroinflammation injury are important pathophysiological mechanisms of this process, which is closely related to hippocampal neurons damage and loss. Dimethyl fumarate (DMF), an FDA-approved therapeutic for multiple sclerosis (MS), plays a protective role in multiple neurological disorders. Studies have shown that DMF exerts anti-inflammatory and antioxidant effects via the NRF2/ARE/NF-κB signaling pathway. Thus, this study aimed to evaluate the neuroprotective effect of DMF in the CCH rat model. Ferroptosis, a novel defined iron-dependent cell death form, were found to be strongly associated with the pathophysiology of CCH. Emerging evidences have shown that inhibition of ferroptosis by targeting NRF2 exerted neuroprotective effect in neurodegeneration diseases. We also investigated whether DMF can alleviate cognitive deficits through inhibition of ferroptosis by the NRF2 signaling pathway in this study. DMF was intragastric for consecutive five weeks (100 mg/kg/day). Then behavior test and histological, molecular, and biochemical analysis were performed. We found that DMF treatment significantly improved cognitive deficits and partially reversed hippocampus neuronal damage and loss caused by CCH. And DMF treatment decreased hippocampus IL-1β, TNF-α, and IL-6 pro-inflammatory cytokines concentration, and mediated the NF-κB signaling pathway. And DMF also alleviated hippocampus oxidative stress through reducing MDA, and increasing GSH and SOD levels, which are also closely associated with ferroptosis. Besides, DMF treatment reduced the expression of PTGS2, and increased the expression of FTH1 and xCT, and the iron content is also reduced, which were the important features related to ferroptosis. Furthermore, DMF activated th