Dexmedetomidine enables copper homeostasis in cerebral ischemia/reperfusion via ferredoxin 1

Abstract

Excessive oxygen free radicals and toxic substances are generated in cerebral ischemia-reperfusion (I/R) process. Dexmedetomidine (DEX), a common anesthetic and sedative drug, can considerably boost glutathione (GSH), which has anti-copper influx effects. Focusing on cuproptosis, the mechanism of DEX in the I/R was revealed. Using the I/R rat model, the effects of DEX and the copper chelator D-penicillamine on cerebral infarct volume, copper levels, mitochondrial respiration and membrane potential, GSH content, and enrichment of cuproptosis functional proteins were examined. The involvement of ferredoxin 1 (FDX1) in the DEX regulatory pathway was verified by overexpressing FDX1 in vitro . DEX could significantly reduce cerebral infarction in rats, reduce copper levels, maintain mitochondrial functions, increase GSH, and reduce the content of key proteins related to cuproptosis. These aspects were replicated in vitro and revealed that FDX1 overexpression partially reversed the impacts of DEX. Together, cuproptosis occurs in the brain I/R process and DEX can enhance cell survival by blocking the primary pathway mediated by FDX1. KEY MESSAGES Dexmedetomidine reduces cerebral infarction in the I/R rat models. Dexmedetomidine reduces cuproptosis in the I/R rat models. FDX1, an upstream of protein fatty acylation, mediates regulation of Dexmedetomidine.

Cellular and molecular mechanisms of cell damage and cell death in ischemia–reperfusion injury in organ transplantation

“…In two rat models of IRI in which isolated rat hearts were subjected to 20 min of warm ischemia followed by 30 min of reperfusion, removal of redox-active copper prior to ischemia prevented post-ischemic cardiac oxidative injury and enhanced recovery of myocardial function, with significantly reduced levels of hydroxyl radicals and efflux of lactic dehydrogenase compared to control hearts that were loaded with copper [ 113 , 114 ]. Recently, Guo and colleagues [ 115 ] also reported that pharmacological inhibition of cuproptosis with dexmedetomidine targeted at ferredoxin-1 markedly reduced copper levels, preserved mitochondrial function, increased antioxidant status and reduced cuproptosis-related proteins in in vitro and in vivo models of cerebral IRI. Although research on the mediatory role of cuproptosis in organ IRI is in its infantile stage, its inhibition is expected to become a potential therapeutic approach for clinical conditions involving IRI, including organ transplantation.…”

Comprehensive bioinformatics analysis reveals the role of cuproptosis-related gene Ube2d3 in myocardial infarction

“…Though existing research on the mechanisms of cuproptosis remains relatively limited, there is compelling evidence to suggest that cuproptosis plays an important role in cancer progression. For instance, cuproptosis affects the activity of immune cells in the tumor microenvironment of kidney renal clear cell carcinoma ( 23 ); Dexmedetomidine mitigates cerebral infarction in I/R rat models by blocking FDX1-mediated cuproptosis ( 24 ); Cuproptosis has been shown to impact both presynaptic and postsynaptic regulatory mechanisms in a mouse model of cognitive dysfunction ( 25 ). Drawing from existing literature, it is believed that continued in-depth investigation of cuproptosis in various diseases and a deeper analysis of its molecular mechanisms will enhance our comprehension of cuproptosis in the field of MI.…”

Dexmedetomidine alleviates blood-brain barrier disruption in rats after cerebral ischemia-reperfusion by suppressing JNK and p38 MAPK signaling

“…Rats were randomly divided into seven groups: sham; MCAO; MCAO + dexmedetomidine (Hengrui Pharmaceutical Co., Ltd.) (injected intravenously with 9 μg/kg dexmedetomidine 30 min after MCAO) [ 38 , 39 ]; MCAO + SB203580 (Shanghai Baililai Biotech) (injected intraperitoneally with 200 μg/kg SB203580 30 min before MCAO) [ 40 , 41 ]; MCAO + dexmedetomidine + anisomycin (Beyotime) (injected intravenously with 9 μg/kg dexmedetomidine plus intraperitoneally with 100 μg/kg anisomycin 30 min after MCAO) [ 42 , 43 ]; MCAO + dexmedetomidine + P79350 (Acmec) (injected intravenously with 9 μg/kg dexmedetomidine plus intraperitoneally with 100 μg/kg P79350 30 min after MCAO) [ 44 ]; MCAO + dexmedetomidine + EGF (Peprotech) (injected intravenously with 9 μg/kg dexmedetomidine plus intraperitoneally with 250 μg/kg EGF 30 min after MCAO) [ 45 ].…”