Abstract
Amyloid-β peptide (Aβ) 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 Aβ 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 Aβ. Furthermore, Aβ toxicity has been identified as a trigger of pyroptosis and BBB damage, suggesting an amplified effect of Aβ 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 Aβ 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-1β and abated astrocytic pyroptosis after cerebral I/R. Moreover, TXL intervention facilitated to restore AQP-4 polarization and accordingly relieve Aβ accumulation around astrocytes in ischemic cortex and hippocampus as well as the formation of toxic Aβ (Aβ1–42 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 Aβ 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.
Highlights
Ischemic stroke, a common cerebrovascular disease, constitutes approximately 80% of stroke cases and is among the leading causes of long-term disability and dementia worldwide [1, 2]
As a detrimental factor exacerbating cerebral I/R injuries, amyloid-β peptide (Aβ) massively accumulates around astrocytes in ischemic brain tissues, accounting for the occurrence of dementia induced by ischemic stroke [4,5,6,7]
Emerging research studies have indicated that neuroinflammation-related Aβ massively accumulates around astrocytes in ischemic brain tissue after cerebral I/R and accounts for the occurrence of dementia induced by ischemic stroke [6, 7, 26]
Summary
A common cerebrovascular disease, constitutes approximately 80% of stroke cases and is among the leading causes of long-term disability and dementia worldwide [1, 2]. Us, pyroptosis signaling molecules are becoming potential therapeutic targets to reduce cerebral I/R injuries and neuroinflammation-related accumulations of toxic metabolites including Aβ. Z20060322) and has become a common TCM prescription which is widely used for the prevention and treatment of cardiocerebrovascular diseases of blood stasis syndrome including ischemic stroke. In modern research studies about TCM compound prescriptions for the prevention and treatment of cerebrovascular diseases, TXL is a typical representation showing beneficial effects such as BBB protection [17]. Our studies have indicated that TXL has multiple therapeutic effects against cerebral I/R injuries including antineuroinflammation [16, 21, 22]. Erefore, based on our previous work, the present study was designed to explore the potential intervention effects of TXL on pyroptosis and Aβ accumulation induced by cerebral I/R Our studies have indicated that TXL has multiple therapeutic effects against cerebral I/R injuries including antineuroinflammation [16, 21, 22]. erefore, based on our previous work, the present study was designed to explore the potential intervention effects of TXL on pyroptosis and Aβ accumulation induced by cerebral I/R
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