Oltipraz attenuated cerebral ischemia–reperfusion injury through inhibiting the oxidative stress and ferroptosis in mice

Aug 3, 2024International immunopharmacology

Oltipraz reduced brain damage after blood flow loss and return by lowering oxidative stress and cell death in mice

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Abstract

Oltipraz (OPZ) reduced infarct volume and brain water content in a mouse model of cerebral ischemia/reperfusion injury.

OPZ administration improved neurological deficits in mice subjected to middle cerebral artery occlusion/reperfusion.
Oxidative stress indicators, such as 4-HNE and MDA, were decreased following OPZ treatment, while antioxidant activities of SOD and GSH were increased.
OPZ enhanced the expression of protective proteins SLC7A11 and GPX4 and decreased the expression of the pro-ferroptotic protein ACSL4.
In vitro results indicated that OPZ also mitigated oxidative stress and ferroptosis in PC12 cells exposed to oxygen and glucose deprivation.
The protective effects of OPZ were associated with significant upregulation of Nrf2, and knockout of Nrf2 eliminated these benefits.

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Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.

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