Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation

Abstract

Ischemic cerebral infarction represents a significant cause of disability and death worldwide. Caspase-1 is activated by the NLRP3/ASC pathway and inflammasomes, thus triggering pyroptosis, a programmed cell death. In particular, this death is mediated by gasdermin D (GSDMD), which induces secretion of interleukin (IL)-1β and IL-18. Accordingly, inhibition of caspase-1 prevents the development and worsening of multiple neurodegenerative diseases. However, it is not clear whether inhibition of caspase-1 can preserve blood-brain barrier (BBB) integrity following cerebral infarction. This study therefore aimed at understanding the effect of caspase-1 on BBB dysfunction and its underlying mechanisms in permanent middle cerebral artery occlusion (MCAO). Our findings in rat models revealed that expression of caspase-1 was upregulated following MCAO-induced injury in rats. Consequently, pharmacologic inhibition of caspase-1 using vx-765 ameliorated ischemia-induced infarction, neurological deficits, and neuronal injury. Furthermore, inhibition of caspase-1 enhanced the encapsulation rate of pericytes at the ischemic edge, decreased leakage of both Evans Blue (EB) and matrix metalloproteinase (MMP) proteins, and upregulated the levels of tight junctions (TJs) and tissue inhibitors of metalloproteinases (TIMPs) in MCAO-injured rats. This in turn improved the permeability of the BBB. Meanwhile, vx-765 blocked the activation of ischemia-induced pyroptosis and reduced the expression level of inflammatory factors such as caspase-1, NLRP3, ASC, GSDMD, IL-1β, and IL-18. Similarly, vx-765 treatment significantly reduced the expression levels of inflammation-related receptor for advanced glycation end products (RAGE), high-mobility family box 1 (HMGB1), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB). Evidently, inhibition of caspase-1 significantly improves ischemia-associated BBB permeability and integrity by suppressing pyroptosis activation and the RAGE/MAPK pathway.

Vagus nerve stimulation alleviated cerebral ischemia and reperfusion injury in rats by inhibiting pyroptosis via α7 nicotinic acetylcholine receptor

“…Caspase-1 expression was considerably enhanced after ischemic stroke as a critical molecule in initiating pyroptosis, and its suppression resulted in neuroprotection against I/R injury. It has been reported that vx-765, an inhibitor of caspase-1, can ameliorate blood-brain-barrier dysfunction and integrity after I/R injury [ 26 ]. GSDMD is an essential factor in pyroptosis, and its role has been reported in I/R injury.…”

Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

“…330,433,434 VX-765, a caspase-1 inhibitor, can ameliorate infarct volumes, neurological deficits, and neuronal injury after MCAO. 435 The specific NLRP3 inflammasome inhibitor MCC950 significantly improved neurologic outcomes and reduced infarct volume when administered before or after MCAO. 436 Studies have also shown that meisoindigo, a generally water soluble and well-tolerated second-generation indirubin derivative, reduces inflammation by inhibiting leukocyte chemotaxis and migration.…”

Saposhnikoviae Radix Enhanced the Angiogenic and Anti-Inflammatory Effects of Huangqi Chifeng Tang in a Rat Model of Cerebral Infarction

“…As an important inflammatory regulator of CI, HIF-1α can stimulate the activation of the NLRP3 inflammasome [12]. However, overactivation of the NLRP3 inflammasome triggers a series of caspase 1 signaling cascades and intensifies the release of IL-1β and IL-18, leading to the formation of a vicious cycle and aggravating CI [33][34][35]. Additionally, IL-6 and TNF-α play a crucial role in the inflammatory responses induced by CI [13].…”