Tanshinone IIA Inhibits Microglial Activation and Inflammation and Relieves Cerebral Ischemia‒Reperfusion Injury Through TGM2/PANX1

Microglial activation and induced inflammation play important roles in cerebral ischemia‒reperfusion injury (CIRI). Tanshinone IIA (Tan IIA) is a natural extract from Chinese herbal medicines that has anti-inflammatory, antioxidant, antiapoptotic and neuroprotective properties and has a protective effect against CIRI. This study aimed to investigate the effects of Tan IIA on microglial activation and inflammation under CIRI and the underlying molecular mechanism. Experimental investigations were conducted using rat and cellular models of CIRI induced by middle cerebral artery occlusion (MCAO) and oxygen‒glucose deprivation/reperfusion (OGD/R), respectively. The neuroprotective effects of Tan IIA on CIRI rats were evaluated through neurological deficit scores, TTC staining, and H&E staining. Immunofluorescence staining and ELISA were used to detect microglial activation and the expression of inflammatory molecules. In this study, treatment with Tan IIA significantly improved neurological deficits, reduced infarct size, and ameliorated pathological damage to the cerebral cortex in CIRI rats. It also decreased the expression of microglial marker Iba-1 and activation marker TSPO, as well as the expression of pro-inflammatory factors TNF-α, IL-1β and IL-6. In terms of molecular mechanisms, the expression of PANX1 and TGM2 is upregulated in this disease, and TGM2 binds to PANX1. The overexpression of PANX1 or TGM2 attenuated the inhibitory effect of Tan IIA on OGD/R-induced microglial activation and inflammation. Overall, Tan IIA inhibits the expression of PANX1 by downregulating TGM2 expression, thereby suppressing microglial activation and inflammation and alleviating CIRI. These findings provide new insights into the role of Tan IIA in the treatment of CIRI.

Cerebral ischemia‒reperfusion injury; Inflammation; Microglia; PANX1; TGM2; Tanshinone IIA.