Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
Institute of Sports Medicine and Health, Qingdao University, Qingdao, China.
Cell Commun Signal. 2024 Jan 12;22(1):33. doi: 10.1186/s12964-023-01457-x.
Spinal cord ischemia‒reperfusion injury (SCIRI) can lead to paraplegia, which leads to permanent motor function loss. It is a disastrous complication of surgery and causes tremendous socioeconomic burden. However, effective treatments for SCIRI are still lacking. PANoptosis consists of three kinds of programmed cell death, pyroptosis, apoptosis, and necroptosis, and may contribute to ischemia‒reperfusion-induced neuron death. Previous studies have demonstrated that hydrogen sulfide (HS) exerts a neuroprotective effect in many neurodegenerative diseases. However, whether HS is anti-PANoptosis and neuroprotective in the progression of acute SCIRI remains unclear. Thus, in this study we aimed to explore the role of HS in SCIRI and its underlying mechanisms.
Measurements of lower limb function, neuronal activity, microglia/macrophage function histopathological examinations, and biochemical levels were performed to examine the efficacy of HS and to further demonstrate the mechanism and treatment of SCIRI.
The results showed that GYY4137 (a slow-releasing HS donor) treatment attenuated the loss of Nissl bodies after SCIRI and improved the BBB score. Additionally, the number of TUNEL-positive and cleaved caspase-3-positive cells was decreased, and the upregulation of expression of cleaved caspase-8, cleaved caspase-3, Bax, and Bad and downregulation of Bcl-2 expression were reversed after GYY4137 administration. Meanwhile, both the expression and activation of p-MLKL, p-RIP1, and p-RIP3, along with the number of PI-positive and RIP3-positive neurons, were decreased in GYY4137-treated rats. Furthermore, GYY4137 administration reduced the expression of NLRP3, cleaved caspase-1 and cleaved GSDMD, decreased the colocalization NeuN/NLRP3 and Iba1/interleukin-1β-expressing cells, and inhibited proinflammatory factors and microglia/macrophage polarization.
HS ameliorated spinal cord neuron loss, prevented motor dysfunction after SCIRI, and exerted a neuroprotective effect via the inhibition of PANoptosis and overactivated microglia-mediated neuroinflammation in SCIRI.
脊髓缺血再灌注损伤（SCIRI）可导致截瘫，进而导致永久性运动功能丧失。这是手术的灾难性并发症，造成了巨大的社会经济负担。然而，SCIRI 仍然缺乏有效的治疗方法。PANoptosis 由三种程序性细胞死亡（细胞焦亡、细胞凋亡和细胞坏死）组成，可能与缺血再灌注诱导的神经元死亡有关。先前的研究表明，硫化氢（HS）在许多神经退行性疾病中具有神经保护作用。然而，HS 在急性 SCIRI 进展中是否具有抗 PANoptosis 和神经保护作用尚不清楚。因此，在本研究中，我们旨在探讨 HS 在 SCIRI 中的作用及其潜在机制。
通过测量下肢功能、神经元活性、小胶质细胞/巨噬细胞功能、组织病理学检查和生化水平来评估 HS 的疗效，并进一步阐明 SCIRI 的机制和治疗方法。
结果表明，GYY4137（一种缓慢释放的 HS 供体）治疗可减轻 SCIRI 后 Nissl 体的丢失，并改善 BBB 评分。此外，GYY4137 给药可减少 TUNEL 阳性和 cleaved caspase-3 阳性细胞的数量，并逆转 GYY4137 给药后 cleaved caspase-8、cleaved caspase-3、Bax 和 Bad 表达上调以及 Bcl-2 表达下调。同时，GYY4137 处理大鼠的 p-MLKL、p-RIP1 和 p-RIP3 的表达和激活以及 PI 阳性和 RIP3 阳性神经元的数量均减少。此外，GYY4137 给药可降低 NLRP3、cleaved caspase-1 和 cleaved GSDMD 的表达，减少 NeuN/NLRP3 和 Iba1/白细胞介素-1β表达细胞的共定位，并抑制促炎因子和小胶质细胞/巨噬细胞极化。
HS 通过抑制 PANoptosis 和过度激活小胶质细胞介导的神经炎症，减轻了 SCIRI 后的脊髓神经元丢失，防止了 SCIRI 后的运动功能障碍，并发挥了神经保护作用。
