Abstract
Currently, there is no efficient therapy for spinal cord injury (SCI). Anoxemia after SCI is a key problem, which leads to tissue destruction, while hypoxia after SCI induces cell injury along with inflammation. Mixed-lineage kinase domain-like protein (MLKL) is a critical signal molecule of necroptosis, and mitochondrial dysfunction is regarded as one of the most pivotal events after SCI. Based on the important role of MLKL in cell damage and potential role of mitochondrial dysfunction, our study focuses on the regulation of MLKL by Necrosulfonamide (NSA) in mitochondrial dysfunction of oxygen-glucose deprivation (OGD)-induced cell damage and SCI-mice, which specifically blocks the MLKL. Our results showed that NSA protected against a decrease in the mitochondrial membrane potential, adenosine triphosphate, glutathione, and superoxide dismutase levels and an increase in reactive oxygen species and malonyldialdehyde levels. NSA also improved the locomotor function in SCI-mice and OGD-induced spinal neuron injury through inhibition of MLKL activation independently of receptor-interacting protein kinase 3 (RIP3) phosphorylation. Besides the protective effects, NSA exhibited a therapeutic window. The optimal treatment time was within 12 h after the injury in the SCI-mice model. In conclusion, our data suggest a close association between the NSA level inhibiting p-MLKL independently of RIP3 phosphorylation and induction of neurological impairment by improving antioxidative capacity after SCI. NSA ameliorates neurological impairment in SCI through inhibiting MLKL-dependent necroptosis. It also provides a theoretical basis for further research and application of NSA in the treatment of SCI.
Highlights
Spinal cord injury (SCI) represents a serious trauma to the central nervous system (CNS) and often causes a devastating impact on the motor function and many essential physiological functions (Courtine and Sofroniew, 2019)
Treatment with necrostatin-1 (Nec-1), a receptor-interacting protein kinase 1 (RIP1) kinase inhibitor, prevents cell death and improves functional outcomes after injury (Wang et al, 2014b; Liu et al, 2015). Researchers found that both receptor interacting protein kinase-3 (RIP3) and mixed-lineage kinase domain-like (MLKL) accumulated in neurons immediately after SCI and peaked at day 1, which is consistent with neuronal necroptosis observed post-SCI (Liu et al, 2018)
Based on the important role of MLKL in cell damage and the potential role of mitochondrial dysfunction in SCI, our study focused on the regulation of MLKL by necrosulfonamide (NSA), which blocks the MLKL, for preventing mitochondrial dysfunction after SCI
Summary
Spinal cord injury (SCI) represents a serious trauma to the central nervous system (CNS) and often causes a devastating impact on the motor function and many essential physiological functions (Courtine and Sofroniew, 2019). Treatment with necrostatin-1 (Nec-1), a RIP1 kinase inhibitor, prevents cell death and improves functional outcomes after injury (Wang et al, 2014b; Liu et al, 2015) Researchers found that both RIP3 and MLKL accumulated in neurons immediately after SCI and peaked at day 1, which is consistent with neuronal necroptosis observed post-SCI (Liu et al, 2018). We examined the protective effects of NSA in oxygen-glucose deprivation (OGD)induced cell damage assay that replicates the pathological condition of SCI in vitro through RIP3 and MLKL activation (Wang et al, 2018b; Li et al, 2019; Zhang et al, 2019). The results showed that NSA protected against a decrease in mitochondrial membrane potential (MMP), ATP, glutathione (GSH), and superoxide dismutase (SOD), and an increase in reactive oxygen species (ROS) and malonyldialdehyde (MDA) It improved the locomotor function in SCI-mice and OGD-induced spinal neuron injury through inhibition of MLKL activation. These findings provide a theoretical basis for research and application of NSA in SCI therapy
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