Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Oxid Med Cell Longev. 2020 Apr 15;2020:7879629. doi: 10.1155/2020/7879629. eCollection 2020.
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.
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.
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-) 1 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.
In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-B pathway activities. VX765 may have a good therapeutic effect on TBI.
创伤性脑损伤（TBI）是指穿透性物体或钝性创伤导致的暂时或永久性脑功能损害。TBI 激活炎症小体介导的途径和其他细胞死亡途径，以清除失活和受损的细胞，但它们也对中枢神经系统有害。新发现的细胞死亡模式称为细胞焦亡，已成为研究热点。它主要依赖于半胱氨酸天冬氨酸蛋白酶-1（caspase-1）介导的途径，导致细胞死亡。
我们的研究重点是 VX765，这是一种已知的 caspase-1 抑制剂，在 TBI 后可能具有神经保护作用。我们建立了控制性皮质撞击（CCI）小鼠模型，然后用 VX765 控制 TBI 中的细胞焦亡程度。研究了 caspase-1 抑制对炎症反应、细胞焦亡、血脑屏障（BBB）、细胞凋亡和小胶质细胞激活以及神经功能缺损的影响。
我们发现 TBI 导致 NOD 样受体（NLRs）和黑色素瘤 2（AIM2）炎症小体介导的损伤大脑皮层中的细胞焦亡。VX765 抑制了必需炎症亚基（半胱氨酸天冬氨酸蛋白酶-1和关键下游促炎细胞因子白细胞介素（IL）-1 和 IL-18）的表达。它还抑制了损伤皮层中 Gasdermin D（GSDMD）的切割和凋亡相关斑点样蛋白（ASC）寡聚化。除此之外，VX765 还抑制了高迁移率族盒 1/Toll 样受体 4/核因子-κB（HMGB1/TLR4/NF-κB）通路的炎症活性。通过抑制细胞焦亡和炎症介质表达，我们证明 VX765 可以减少血脑屏障（BBB）渗漏、细胞凋亡和小胶质细胞极化，从而发挥其神经保护作用。
总之，VX765 通过降低细胞焦亡和 HMGB1/TLR4/NF-B 途径活性来对抗 TBI 后的神经损伤。VX765 可能对 TBI 具有良好的治疗效果。
