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Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury

ABSTRACT: 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 via 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.

SUBMITTER: Pang Y

PROVIDER: S-EPMC9318422 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rehabilitative exercise in humans with spinal cord injury aims to engage residual neural networks to improve functional recovery. We hypothesized that exercise combined with non-invasive stimulation targeting spinal synapses further promotes functional recovery. Twenty-five individuals with chronic incomplete cervical, thoracic, and lumbar spinal cord injury were randomly assigned to 10 sessions of exercise combined with paired corticospinal-motor neuronal stimulation (PCMS) or sham-PCMS. In an additional experiment, we tested the effect of PCMS without exercise in 13 individuals with spinal cord injury with similar characteristics. During PCMS, 180 pairs of stimuli were timed to have corticospinal volleys evoked by transcranial magnetic stimulation over the primary motor cortex arrive at corticospinal-motor neuronal synapses of upper- or lower-limb muscles (depending on the injury level), 1-2 ms before antidromic potentials were elicited in motor neurons by electrical stimulation of a peripheral nerve. Participants exercised for 45 min after all protocols. We found that the time to complete subcomponents of the Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) and the 10-m walk test decreased on average by 20% after all protocols. However, the amplitude of corticospinal responses elicited by transcranial magnetic stimulation and the magnitude of maximal voluntary contractions in targeted muscles increased on overage by 40-50% after PCMS combined or not with exercise but not after sham-PCMS combined with exercise. Notably, behavioural and physiological effects were preserved 6 months after the intervention in the group receiving exercise with PCMS but not in the group receiving exercise combined with sham-PCMS, suggesting that the stimulation contributed to preserve exercise gains. Our findings indicate that targeted non-invasive stimulation of spinal synapses might represent an effective strategy to facilitate exercise-mediated recovery in humans with different degrees of paralysis and levels of spinal cord injury.

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Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury

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