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Establishing a Mouse Contusion Spinal Cord Injury Model Based on a Minimally Invasive Technique

Using minimally invasive methods to model spinal cord injury (SCI) can minimize behavioral and histological differences between experimental animals, ...

Tianjin Medical University General Hospital

Spinal cord injury (SCI) severely and irreversibly damages the central nervous system. Neurotropin (NTP), a nonprotein extract obtained from inflamed rabbit skin inoculated with vaccinia virus, is a drug that has been used for more than sixty years to alleviate neuropathic pain. It also reportedly exerts a neuroprotective role in peripheral nerves and in response to various central nervous system diseases, such as brain injury and Alzheimer disease. However, whether NTP promotes SCI recovery remains unknown. This study evaluated NTP's effects after SCI and explored its underlying mechanisms in a rat contusion model of SCI.

Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines.

Spinal cord injury (SCI) leads to severe physical disability and sensory dysfunction. Neurotropin (NTP) has been used clinically to alleviate neuropathic pain, while nafamostat mesylate (NM) used clinical on pancreatitis patients through inhibiting synthetic serine protease. Our previous studies showed that NTP and NM were able to repair SCI. However, the underlying mechanism has not been fully explored after treatment with these 2 different drugs.

Cytokine expressions of spinal cord injury treated by neurotropin and nafamostat mesylate.

Spinal cord injury (SCI) is a serious condition that can cause physical disability and sensory dysfunction. Cytokines play an extremely important role in the acute phase of SCI. Clarifying the cytokine expression profile is of great importance.

Identification of four genes and biological characteristics associated with acute spinal cord injury in rats integrated bioinformatics analysis.

Spinal cord injury (SCI) is a traumatic disease that is associated with high morbidity, disability, and mortality worldwide. The animal spinal cord contusion model is similar to clinical SCI; therefore, this model is often used to study the pathophysiological changes and treatment strategies for humans after SCI. The present study aimed to introduce a novel, minimally invasive technique to establish an SCI model, and to evaluate its advantages compared with conventional methods.

A novel, minimally invasive technique to establish the animal model of spinal cord injury.

Nafamostat mesylate (nafamostat, NM) is an FDA-approved serine protease inhibitor that exerts anti-neuroinflammation and neuroprotective effects following rat spinal cord injury (SCI). However, clinical translation of nafamostat has been limited by an unclear administration time window and mechanism of action.

Delayed administration of nafamostat mesylate inhibits thrombin-mediated blood-spinal cord barrier breakdown during acute spinal cord injury in rats.

The FDA-approved drug edaravone has a neuroprotective effect on spinal cord injury (SCI) and many other central nervous system diseases. However, its molecular mechanism remains unclear. Since edaravone is a lipid peroxidation scavenger, we hypothesize that edaravone exerts its neuroprotective effect by inhibiting ferroptosis in SCI. Edaravone treatment after SCI upregulates glutathione peroxidase 4 (GPX4) and system Xc-light chain (xCT), which are anti-ferroptosis proteins. It downregulates pro-ferroptosis proteins Acyl-CoA synthetase long-chain family member 4 (ACSL4) and 5-lipoxygenase (5-LOX). The most significant changes in edaravone treatment occur in the acute phase, two days post injury. Edaravone modulates neuronal GPX4/ACSL4/5-LOX in the spinal segment below the lesion, which is critical for maintaining locomotion. Moreover, the GPX4/ACSL4/5-LOX in motor neuron is also modulated by edaravone in the spinal cord. Therefore, secondary injury below the lesion site is reversed by edaravone  ferroptosis inhibition. The cytokine array revealed that edaravone upregulated some anti-inflammatory cytokines such as IL-10, IL-13, and adiponectin. Edaravone reduced microgliosis and astrogliosis, indicating reduced neuroinflammation. Edaravone has a long-term effect on neuronal survival, spinal cord tissue sparing, and motor function recovery. In summary, we revealed a novel mechanism of edaravone in inhibiting neuronal ferroptosis in SCI. This mechanism may be generalizable to other neurological diseases.

Article	Year
Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines. Journal of orthopaedic translation\| PubMed ID: 33437626	2021
Cytokine expressions of spinal cord injury treated by neurotropin and nafamostat mesylate. Annals of translational medicine\| PubMed ID: 33850886	2021
Identification of four genes and biological characteristics associated with acute spinal cord injury in rats integrated bioinformatics analysis. Annals of translational medicine\| PubMed ID: 33987268	2021
A novel, minimally invasive technique to establish the animal model of spinal cord injury. Annals of translational medicine\| PubMed ID: 34164515	2021
Delayed administration of nafamostat mesylate inhibits thrombin-mediated blood-spinal cord barrier breakdown during acute spinal cord injury in rats. Journal of neuroinflammation\| PubMed ID: 35842640	2022
Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury. Frontiers in cell and developmental biology\| PubMed ID: 35903552	2022

Yilin Pang

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