Intranasal administration of β-1, 3-galactosyltransferase 2 confers neuroprotection against ischemic stroke by likely inhibiting oxidative stress and NLRP3 inflammasome activation.
Xun GuoYang ZhangChang LiuLili RenShuang GaoJing BiJia LiangPeng WangPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2022)
Ischemic stroke is one of the major causes of morbidity and mortality. The β-1, 3-galactosyltransferase 2 (B3galt2), a member of β-1, 3-galactosyltransferase family, is playing a vital role in the pathological process of cerebral ischemic injury, but its underlying mechanisms remain unclear. In the present study, we examined the involvement of oxidative stress and NLRP3 inflammasome activation in the neuroprotective effect of B3galt2. Cerebral ischemia/reperfusion (I/R) injury was simulated in a mouse middle cerebral artery occlusion (MCAO) model. Recombinant human B3galt2 (rh-B3galt2) was administered intranasally 1 h post MCAO, and TGF-β1-siRNA was administered intracerebroventricularly 24 h before MCAO. Outcome measures included brain infarct volume, neurological function, blood-brain barrier (BBB) permeability, neuronal apoptosis, oxidative stress, and the inflammatory response. First, we found that rh-B3galt2 significantly alleviated brain infarct volume and BBB permeability, improved neurological function, and attenuated I/R-induced neuron apoptosis and oxidative stress. Furthermore, rh-B3galt2 attenuated pro-inflammatory cytokines, NF-κB, IL-6, TNF-α, and IL-1β, and inhibited NLRP3 inflammasome activation. Finally, inhibition of TGF-β1 by TGF-β1-siRNA abolished the anti-oxidative and anti-inflammatory effects of rh-B3galt2 in mice after I/R. Collectively, our study demonstrated that rh-B3galt2 exerts neuroprotective effects by regulating cerebral ischemia-induced oxidative stress and NLRP3 inflammasome, which is mainly dependent on the heightening of the TGF-β1 pathway. Thus, B3galt2 might be considered a new therapeutic target for ischemic stroke treatment.
Keyphrases
- cerebral ischemia
- nlrp inflammasome
- blood brain barrier
- oxidative stress
- subarachnoid hemorrhage
- diabetic rats
- brain injury
- transforming growth factor
- inflammatory response
- middle cerebral artery
- dna damage
- induced apoptosis
- ischemia reperfusion injury
- anti inflammatory
- atrial fibrillation
- signaling pathway
- endothelial cells
- recombinant human
- rheumatoid arthritis
- endoplasmic reticulum stress
- metabolic syndrome
- multiple sclerosis
- lps induced
- high glucose
- adipose tissue
- cell death
- white matter
- coronary artery disease
- drug delivery
- cancer therapy
- insulin resistance
- heat stress