β‐1,4‐Galactosyltransferase 1 protects against cerebral ischemia injury in mice by suppressing ferroptosis via the TAZ/Nrf2/HO‐1 signaling pathway

Abstract

AbstractBackgroundIschemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of β‐1,4‐galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury.MethodsRecombinant human B4galt1 (rh‐B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh‐B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5‐triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence‐labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels.ResultsWe demonstrated that rh‐B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood–brain barrier (BBB) for preventing damage. These findings further illustrated that rh‐B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh‐B4galt1 could increase the levels of TAZ, Nrf2 and HO‐1 after I/R. And TAZ‐siRNA and ML385 reversed the neuroprotective effects of rh‐B4galt1.ConclusionsThe results indicated that rh‐B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO‐1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy.