Selenium Alleviates Cerebral Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Fusion and Ferroptosis

Abstract

To clarify the potential role of selenium (Se) on cerebral ischemia/reperfusion (I/R) injury, we utilized mouse middle cerebral artery occlusion (MCAO) followed by reperfusion as an animal model and oxygen–glucose deprivation and reoxygenation (OGD/R) to treat N2a cells as a cell model, respectively. MCAO model was established in mice and then divided into different groups with or without Se treatment. TTC staining was used to observe whether the cerebral I/R modeling was successful, and the apoptosis level was determined by TUNEL staining. The expression of GPx-4 and p22phox was assessed by western blot. In vitro experiments, the OGD/R induced oxidative stress in N2a cells was assessed by levels of GSH/GSSG, malondialdehyde, superoxide dismutase and iron content, respectively. QRT-PCR was used to detect the mRNA levels of Cox-2, Fth1, Mfn1 and mtDNA in N2a cells. JC-1 staining and flow cytometry was performed to detect the mitochondrial membrane potential. Se treatment alleviated cerebral I/R injury and improved the survival rate of mice. Additionally, Se treatment apparently attenuated oxidative stress and inhibited iron accumulation in MCAO model mice and OGD/R model of N2a cells. In terms of its mechanism, Se could up-regulate Mfn1 expression to alleviate oxidative stress and ferroptosis by promoting mitochondrial fusion in vivo and vitro. These findings suggest that Se may have great potential in alleviating cerebral I/R injury.

Association of habitually low intake of dietary selenium with new-onset stroke: A retrospective cohort study (2004–2015 China Health and Nutrition Survey)

“…Although the underlying mechanism for the negative association of selenium with stroke is not known, the relationship is biologically plausible. An important physiopathological mechanism in the development of stroke is oxidative stress, and selenium attenuates cerebral ischaemia/reperfusion injury by regulating oxidative stress, mitochondrial fusion and iron death ( 5 , 59 , 60 ). Secondly, elevated levels of inflammatory markers such as neutrophil/lymphocyte ratio, serum CRP levels and copper/zinc ratio in selenium-deficient patients, in addition to enhanced gene expression of some cytokines and chemokines found in PBMCs of selenium-deficient CVD patients, suggest that reduced selenium levels may favor the progression of inflammation and promote the development of CVD ( 61 ).…”

“…As an essential element for human body, selenium is mainly involved in a variety of metabolic processes, including regulating thyroid hormone ( 4 ), oxidative stress response ( 5 ), antioxidant mechanism ( 6 ) and immune response ( 7 – 9 ) through 25 selenocysteine, as the active center of selenium protein ( 10 ). As a trace element, the health effects of selenium exposure levels are controversial.…”

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

“…Pharmacological selenium administration augmented GPX4 via coordinated activation of transcription factor AP-2 gamma (TFAP2c) and special protein 1 (Sp1) to inhibit ferroptosis and exert neuroprotective effects, providing a new strategy for stroke management. Recently, the anti-ferroptotic effects of several selenium compounds were characterized in murine models of MCAO [ 49 , 50 ], further supporting the strategy of using pharmacological selenium to prevent cerebral I/R injury. Some agents with antioxidant or neuroprotective effects have also been reported to inhibit ferroptosis and reduce cerebral I/R injury.…”

Neuroprotective effect of Dl-3-n-butylphthalide against ischemia–reperfusion injury is mediated by ferroptosis regulation via the SLC7A11/GSH/GPX4 pathway and the attenuation of blood–brain barrier disruption

“…GSS-defective mice cannot survive the embryonic stage, suggesting that GSH is essential for embryogenesis (Aoyama, 2021). In addition, GSH depletion in the brain is a common finding in patients with (Aoyama, 2021;Shi et al, 2022). The SLC7A11/GSH/GPX4 signal pathway is the fundamental element of intracellular antioxidant function, which regulates the production and balance of antioxidants in the intracellular space (Cao and Dixon, 2016).…”