Nrf2 attenuates oxidative stress to mediate the protective effect of ciprofol against cerebral ischemia–reperfusion injury

Nov 23, 2023Functional & integrative genomics

Nrf2 reduces oxidative stress to help ciprofol protect the brain from blood flow injury

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Abstract

Ciprofol improved neurological scores and reduced infarct volume in a mouse model of cerebral ischemia-reperfusion injury.

Neuroinflammation and oxidative stress may play a role in cerebral ischemia-reperfusion injury (CIRI).
Ferroptosis is associated with lipid peroxidation processes in the context of CIRI.
Ciprofol treatment alleviated reactive oxygen species output and neuronal death linked to ferroptosis.
The neuroprotective effects of ciprofol were diminished in mice lacking the Nrf2 protein.
Ciprofol enhanced the transcription of protective proteins such as GPX4 and xCT in response to oxidative stress.

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Neuroinflammation and oxidative stress damage are involved in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Ferroptosis emerged as a new player in the regulation of lipid peroxidation processes. This study aimed at exploring the potential involvement of ciprofol on ferroptosis-associated CIRI and subsequent neurological deficits in the mouse model of transient cerebral ischemia and reperfusion. Cerebral ischemia was built in male C57BL/6 J wild-type (WT) and Nrf2-knockout (Nrf2 KO) mice in the manner of middle cerebral artery occlusion (MCAO) followed by reperfusion. Ciprofol improved autonomic behavior, alleviated reactive oxygen species output and ferroptosis-induced neuronal death by nucleus transportation of NFE2 like BZIP transcription factor 2 (Nrf2) and the promotion of heme oxygenase 1 (Ho-1), solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4). Additionally, ciprofol improved neurological scores and reduced infarct volume, brain water content, and necrotic neurons. Cerebral blood flow in MCAO-treated mice was also improved. Furthermore, absence of Nrf2 abrogated the neuroprotective actions of ciprofol on antioxidant capacity and sensitized neurons to oxidative stress damage. In vitro, the primary-cultured cortical neurons from mice were pre-treated with oxygen-glucose deprivation/reperfusion (OGD/R), followed by ciprofol administration. Ciprofol effectively reversed OGD/R-induced ferroptosis and accelerated transcription of GPX4 and xCT. In conclusion, we investigated the ciprofol-induced inhibition effect of ferroptosis-sheltered neurons from lipid preoxidation in the pathogenesis of CIRI via Nrf2-xCT-GPX4 signaling pathway.

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