2. Academic Validation
  3. A slow-releasing donor of hydrogen sulfide inhibits neuronal cell death via anti-PANoptosis in rats with spinal cord ischemia‒reperfusion injury

A slow-releasing donor of hydrogen sulfide inhibits neuronal cell death via anti-PANoptosis in rats with spinal cord ischemia‒reperfusion injury

  • Cell Commun Signal. 2024 Jan 12;22(1):33. doi: 10.1186/s12964-023-01457-x.
Lei Xie # 1 2,  Hang Wu # 2 3,  Qiuping He 1 2,  Weipeng Shi 2 3,  Jing Zhang 2 3,  Xiao Xiao 4,  Tengbo Yu 5
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
  • 2 Institute of Sports Medicine and Health, Qingdao University, Qingdao, China.
  • 3 Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.
  • 4 Central Laboratories, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China. [email protected].
  • 5 Department of Orthopedic Surgery, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China. [email protected].
  • # Contributed equally.
PMID: 38217003 DOI: 10.1186/s12964-023-01457-x
Abstract

Background: 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 (H2S) exerts a neuroprotective effect in many neurodegenerative diseases. However, whether H2S is anti-PANoptosis and neuroprotective in the progression of acute SCIRI remains unclear. Thus, in this study we aimed to explore the role of H2S in SCIRI and its underlying mechanisms.

Methods: Measurements of lower limb function, neuronal activity, microglia/macrophage function histopathological examinations, and biochemical levels were performed to examine the efficacy of H2S and to further demonstrate the mechanism and treatment of SCIRI.

Results: The results showed that GYY4137 (a slow-releasing H2S 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.

Conclusions: H2S 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.

Keywords

Hydrogen sulfide; Inflammation; Microglia/macrophage; PANoptosis; Spinal cord ischemia‒reperfusion injury.

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