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.
Highlights
Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma
To determine whether VX765 can alleviate inflammatory cytokine levels (IL-1β and IL-18) and identify the optimal dose, we examined inflammation around the injured cortex 24 h after cortical impact (CCI) mice received different drug concentrations
We found that the expression levels of IL-1β (Figure 1(a)) as well as IL-18 (Figure 1(b)) were significantly inhibited by VX765 at concentrations of 100 or 200 mg/kg
Summary
Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. 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. 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. 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 inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. 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. VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. A growing body of evidence shows that innate immunity and neuroinflammation are connected with TBI pathogenesis [5]
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