2. Academic Validation
  3. Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation

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

  • Front Cell Neurosci. 2021 Jan 11:14:540669. doi: 10.3389/fncel.2020.540669.
Yubin Liang 1 2 3,  Pingping Song 2 3,  Wei Chen 2 3,  Xuemin Xie 2 3,  Rixin Luo 4,  Jiehua Su 1,  Yunhui Zhu 2 3,  Jiamin Xu 2 3,  Rongrong Liu 2 3,  Peizhi Zhu 2 3,  Yusheng Zhang 2 3,  Min Huang 5
Affiliations

Affiliations

  • 1 Department of Neurology, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China.
  • 2 Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 3 Clinical Neuroscience Institute, Jinan University, Guangzhou, China.
  • 4 Department of Stroke Center, GuangZhou Panyu Central Hospital, Guangzhou, China.
  • 5 Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
PMID: 33584203 DOI: 10.3389/fncel.2020.540669
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.

Keywords

MAPK; RAGE; blood-brain barrier; caspase-1; ischemic stroke; pyroptosis.

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