Z-Guggulsterone alleviated oxidative stress and inflammation through inhibiting the TXNIP/NLRP3 axis in ischemic stroke

Ischemic stroke is a serious and life-threatening cerebrovascular thrombotic disease; however, the therapeutic strategy is limited for the complicated mechanism and narrow therapeutic window. Our previous study suggested that Z-Guggulsterone (Z-GS), an active component derived from myrrh, is a good candidate for cerebral injury. The object of this study is to investigate the exact mechanisms of Z-GS in cerebral ischemic stroke. Rats were used to conduct middle cerebral artery occlusion (MCAO) model and were treated with different dosage of Z-GS. Morphological results showed that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in MCAO rats. A total of 8276 differentially expressed genes were identified based on microarray analysis. Oxidation-reduction process and inflammatory response were enriched as the significant gene ontology items. TXNIP and NLRP3 were screened as the potential target genes by Series Test of Cluster (STC) analysis. The results were validated by immunohistochemistry and immunofluorescence staining. Besides, Z-GS successfully inhibited oxidative stress and inflammatory response in oxygen-glucose deprivation (OGD) treated neurons. Knockdown of TXNIP significantly decreased the expression of NLRP3 in OGD-induced neurons. In addition, Z-GS treatment scarcely changed the expressions of NLRP3 in siRNA-TXNIP pretreated cells compared with the siRNA-TXNIP alone treatment group, suggesting that the neuroprotective effect of Z-GS was dependent on TXNIP-NLRP3 axis. Taken together, this study revealed that Z-GS exerted neuroprotective property through alleviated oxidative stress and inflammation via inhibiting the TXNIP/NLRP3 axis. Z-GS could be considered as a promising candidate for the treatment of ischemic stroke.