Tongxinluo Exerts Inhibitory Effects on Pyroptosis and Amyloid-β Peptide Accumulation after Cerebral Ischemia/Reperfusion in Rats

Amyloid-beta peptide (A beta) accumulation is a detrimental factor in cerebral ischemia/reperfusion (I/R) injuries accounting for dementia induced by ischemic stroke. In addition to blood brain barrier (BBB), the glymphatic system mediated by aquaporin-4 (AQP-4) on astrocytic endfeet functions as an important pathway for the clearance of A beta in the brain. Cerebral I/R induced astrocytic pyroptosis potentially causes the AQP-4 polarization loss and dysfunctional BBB-glymphatic system exacerbating the accumulation of A beta. Furthermore, A beta toxicity has been identified as a trigger of pyroptosis and BBB damage, suggesting an amplified effect of A beta accumulation after cerebral I/R. Therefore, based on our previous work, this study was designed to explore the intervention effects of Tongxinluo (TXL) on astrocytic pyroptosis and A beta accumulation after cerebral I/R in rats. The results showed that TXL intervention obviously alleviated the degree of pyroptosis by downregulating expression levels of cleaved caspase-11/1, N-terminal gasdermin D, nucleotide-binding oligomerization domain-like receptors pyrin domain containing 3 (NLRP3), interleukin-6 (IL-6), and cleaved IL-1 beta and abated astrocytic pyroptosis after cerebral I/R. Moreover, TXL intervention facilitated to restore AQP-4 polarization and accordingly relieve A beta accumulation around astrocytes in ischemic cortex and hippocampus as well as the formation of toxic A beta (A beta(1-42) oligomer). Our study indicated that TXL intervention could exert protective effects on ischemic brain tissues against pyroptotic cell death, inhibit astrocytic pyroptosis, and reduce toxic A beta accumulation around astrocytes in cerebral I/R injuries. Furthermore, our study provides biological evidence for the potential possibility of preventing and treating poststroke dementia with TXL in clinical practice.

Automated summary

The research indicates that TXL can protect ischemic brain tissues by inhibiting astrocytic pyroptosis and reducing Aβ accumulation after cerebral ischemia/reperfusion injury, potentially offering a preventive and therapeutic approach for poststroke dementia in clinical practice.