Severe traumatic brain injury (TBI) can result in persistent complications, including circadian rhythm disorder, that substantially affect not only the injured people, but also the mood and social interactions with the family and the community. Pyroptosis in GFAP-positive astrocytes plays a vital role in inflammatory changes post-TBI. We determined whether VX-765, a low molecular weight caspase-1 inhibitor, has potential therapeutic value against astrocytic inflammation and pyroptosis in a rodent model of TBI plus hemorrhagic shock and resuscitation (HSR). A weight-drop plus bleeding and refusion model was used to establish traumatic exposure in rats. VX-765 (50 mg/kg) was injected via the femoral vein after resuscitation. Wheel-running activity was assessed, brain magnetic resonance images were evaluated, the expression of pyroptosis-associated molecules including cleaved caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18) in astrocytes in the region of anterior hypothalamus, were explored 30 days post-trauma. VX-765-treated rats had significant improvement in circadian rhythm disorder, decreased mean diffusivity (MD) and mean kurtosis (MK), increased fractional anisotropy (FA), an elevated number and branches of astrocytes, and lower cleaved caspase-1, GSDMD, and IL-18 expression in astrocytes than TBI + HSR-treated rats. These results demonstrated that inhibition of pyroptosis-associated astrocytic activations in the anterior hypothalamus using VX-765 may ameliorate circadian rhythm disorder after trauma. In conclusion, we suggest that interventions targeting caspase-1-induced astrocytic pyroptosis by VX-765 are promising strategies to alleviate circadian rhythm disorder post-TBI.

Graphical Abstract

中文翻译：

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VX-765 可缓解创伤性脑损伤、失血性休克和复苏啮齿动物模型中的昼夜节律紊乱

严重创伤性脑损伤 (TBI) 可导致持续性并发症，包括昼夜节律紊乱，这不仅会严重影响受伤者，还会影响与家庭和社区的情绪和社交互动。 GFAP 阳性星形胶质细胞的焦亡在 TBI 后的炎症变化中起着至关重要的作用。我们确定了低分子量 caspase-1 抑制剂 VX-765 在 TBI 加上失血性休克和复苏 (HSR) 的啮齿动物模型中是否具有对抗星形胶质细胞炎症和细胞焦亡的潜在治疗价值。使用体重下降加出血和回流模型来建立大鼠的创伤暴露。复苏后经股静脉注射VX-765 (50 mg/kg)。评估车轮行驶活动，评估脑磁共振图像，下丘脑前部星形胶质细胞中焦亡相关分子的表达，包括裂解的 caspase-1、gasdermin D (GSDMD) 和白介素-18 (IL-18) ，在创伤后 30 天进行了探索。 VX-765 治疗的大鼠昼夜节律紊乱显着改善，平均扩散率 (MD) 和平均峰度 (MK) 降低，分数各向异性 (FA) 增加，星形胶质细胞的数量和分支增加，以及裂解 caspase-1、GSDMD 降低和IL-18在星形胶质细胞中的表达高于TBI+HSR治疗的大鼠。这些结果表明，使用 VX-765 抑制下丘脑前部焦亡相关的星形胶质细胞激活可能会改善创伤后的昼夜节律紊乱。总之，我们认为 VX-765 针对 caspase-1 诱导的星形细胞焦亡的干预措施是缓解 TBI 后昼夜节律紊乱的有前途的策略。

图形概要