The combination of astragaloside IV and Panax notoginseng saponins attenuates cerebral ischaemia-reperfusion injury in rats through ferroptosis and inflammation inhibition via activating Nrf2.

OBJECTIVES: This study aimed to observe the effect of the combination of astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) on cerebral ischaemia-reperfusion injury (CIRI) and explore the specific mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated combination of AST IV and PNS against CIRI based on ferroptosis and inflammatory response. METHODS: The therapeutic effect and mechanism of AST IV and PNS were evaluated by constructing a Sprague-Dawley rat middle cerebral artery ischaemia-occlusion-reperfusion model. The specific mechanism of the combination of AST IV and PNS against CIRI was revealed through the combined intervention of the Nrf2-specific inhibitor brusatol. KEY FINDINGS: After AST IV and PNS treatment, the cerebral infarction area of the rats was reduced; behavioural performance was improved; Fe2+, malondialdehyde, lipid peroxidation, interleukin-6, interleukin-1ß, tumour necrosis factor-α and myeloperoxidase levels were reduced; and glutathione and glutathione peroxidase 4 levels were increased. In addition, the expression of Nrf2 was significantly increased, the combined treatment was more effective than the single treatment, and the Nrf2 inhibitor brusatol could reverse the effects of the combined intervention of AST IV and PNS. CONCLUSIONS: The findings of this study suggest that combining AST IV and PNS attenuates CIRI by activating Nrf2 to inhibit ferroptosis and inflammatory responses.

Panax notoginseng Saponins Attenuate Cerebral Ischemia-Reperfusion Injury via Mitophagy-Induced Inhibition of NLRP3 Inflammasome in Rats.

BACKGROUND: The mitophagy/NLRP3 inflammasome pathway is a promising therapeutic target for cerebral ischemia-reperfusion (I/R). Panax notoginseng (Burkill) F.H. Chen, one of the most valuable components of traditional Chinese medicine, and Panax notoginseng saponins (PNS), the main active ingredients of P. notoginseng, are patent medicines commonly used to treat cardio- and cerebrovascular diseases. However, their effects on the mitophagy and the NLRP3 inflammasome activation in I/R remain unclear. Therefore, in this study, we investigated how PNS might affect the mitophagy/NLRP3 inflammasome pathway in I/R. METHODS: Cerebral I/R injury was induced by middle cerebral-artery occlusion, and expression levels of NLRP3 inflammasome signaling pathway-associated proteins were detected by western blot. We tested I/R injury using a neurological-deficit score, infarct volume, and hematoxylin and eosin staining, after which we detected both mitophagy- and NLRP3 inflammasome-related proteins in PNS-treated rats to determine whether PNS could attenuate I/R injury and the possible mechanisms involved. RESULTS: Our results showed that cerebral I/R could induce activation of the NLRP3 inflammasome, aggravating brain injury, whereas PNS effectively alleviated cerebral I/R injury in rats by inhibiting the NLRP3 inflammasome and promoting mitophagy via the PINK1/Parkin pathway. Moreover, mitophagy inhibited the NLRP3 inflammasome and mediated the anti-injury effects of PNS. CONCLUSIONS: In conclusion, PNS could promote mitophagy via the PINK1/Parkin pathway by inhibiting activation of the NLRP3 inflammasome, alleviating cerebral I/R injury in rats.