A novel therapeutic strategy for spinal cord injury

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• By Prama Ghosh

Spinal cord injury (SCI) is a severe injury caused by a traumatic blow to the spine and is a challenging concern for public health worldwide. SCI causes major and minor pathophysiological changes induced by several traumas, such as shear stress, torsion and compression of the spinal cord. Inflammation, tissue ischaemia, cell oedema, apoptosis, homeostasis imbalance as well as other secondary pathophysiological changes are found to largely enhance the level of acute SCI. Neuroinflammation caused by pro-inflammatory factors, such as interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), leads to neuronal death mechanisms. These factors are regulated by the activation of an inflammasome called nucleotide-binding-like receptor protein 3 (NLRP3) and apoptosis-associated speck-like protein (ASC) recruitment which subsequently mediate caspase-1. Recently, pyroptosis was identified as a newly programmed cell death mechanism regulated by the stimulation of caspase-1 or caspase-4/-5 signalling pathways that lead to a series of inflammatory responses. Evidence demonstrates that pyroptosis also plays a key role in cell swelling, plasma membrane lysis and release of intracellular pro-inflammatory factors. Cell death mediated by pyroptosis plays a critical role in the pathogenesis of SCI. Thus, if pyroptosis and inflammasome components can be inhibited, SCI could be cured in the near future.

Studies illustrate the capability of certain molecules like celastrol to inhibit pyroptosis in SCI. Celastrol (CSL) is a root extract that has substantial anti-inflammatory effects on the central nervous system (CNS) and is used to treat Parkinson’s disease. It is observed that CSL administration can decline NLRP3, ASC and caspase-1 expression levels in rat models with SCI, indicating that CSL treatment could significantly inhibit pyroptosis-regulated neuronal cell death. A selective NLRP3 inflammasome blocker, namely a sulfonylurea-based compound called MCC950 can tremendously impede the NLRP3, ASC and caspase-1 signalling pathways as well as pro-inflammatory factors including tumour necrosis factor-alpha (TNF-α), IL-1β and IL-18 expression levels in the injured spinal cord areas. Another potential treatment strategy includes the use of a carbon monoxide releasing molecule-3 (CORM-3), responsible for enhancing the concentration of carbon monoxide (CO) which is found to have substantial neuroprotective effects in animal models with SCI. Besides inhibiting neuronal cell death, CO also promotes axonal regeneration and functional recovery in SCI. Similarly, zinc, echinacoside, polydatin, rutin, methylene blue, peptide-5, etc. are some of the other compounds that can inhibit the pyroptosis-signalling pathways as well as inflammasome components and improve functional recovery of the spinal cord. However, the actual mechanism of these molecules is still unknown and the potential inhibition of pyroptosis-regulated cell death in SCI by these molecules is limited to experimental models. Hence, further detailed studies in this field are required for the use of these molecules as a novel therapeutic approach for the treatment of SCI.

Keywords: Pyroptosis, Neuroinflammation, Inflammasome, Spinal cord injury, Apoptosis

Image source:
Image by Dr. Manuel González Reyes, available under Pixabay License at https://pixabay.com/photos/x-rays-hospital-disability-doctor-1715903/

Citation:
Prama Ghosh. A novel therapeutic strategy for spinal cord injury. The Torch. 2021. 2 (26).
Available from: https://www.styvalley.com/pub/magazines/torch/read/a-novel-therapeutic-strategy-for-spinal-cord-injury/.

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