1. Academic Validation
  2. VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF- κ B Pathways to Improve Functional Outcomes in TBI Mice

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF- κ B Pathways to Improve Functional Outcomes in TBI Mice

  • Oxid Med Cell Longev. 2020 Apr 15;2020:7879629. doi: 10.1155/2020/7879629.
Zhezhe Sun  # 1 2 Mark Nyanzu  # 1 2 Su Yang  # 1 2 Xiaohong Zhu 1 2 Kankai Wang 1 2 Junnan Ru 1 2 Enxing Yu 1 2 Hengli Zhang 1 2 Zhenzhong Wang 3 Jie Shen 4 Qichuan Zhuge 1 2 Lijie Huang 1 2
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 2 Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 3 Department of Neurosurgery, Yuyao People's Hospital, Ningbo 315000, China.
  • 4 Department of Neurosurgery, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou 310003, China.
  • # Contributed equally.
Abstract

Background: Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed Pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death.

Methods: Our research focus is VX765, a known Caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of Pyroptosis in TBI with VX765. The effects of Caspase-1 inhibition on inflammatory response, Pyroptosis, blood-brain barrier (BBB), Apoptosis, and microglia activation, in addition to neurological deficits, were investigated.

Results: We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated Pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (Caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like Receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting Pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, Apoptosis, and microglia polarization to exhibit its neuroprotective effects.

Conclusion: In conclusion, VX765 can counteract neurological damage after TBI by reducing Pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

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