Edaravone attenuates ACSL4-dependent ferroptosis in spinal motor neurons following cardiac arrest in rats.

The contribution of acute spinal motor neuron injury following cardiac arrest (CA) remains poorly understood. This study aimed to investigate the role of ferroptosis in CA-induced spinal cord injury and to evaluate the neuroprotective effects of edaravone. Asphyxial CA was induced in rats for 5 min, followed by resuscitation. Edaravone was administered immediately after the return of spontaneous circulation (ROSC). At 24 h post-ROSC, The CA group exhibited significant hindlimb motor deficits and reduced survival rates. Histological analysis revealed selective injury of choline acetyltransferase (ChAT)-positive motor neurons in the lumbar spinal cord, accompanied by mitochondrial shrinkage and membrane rupture, which are characteristic of ferroptosis. Immunofluorescence demonstrated a selective upregulation of the pro-ferroptotic enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) specifically in ChAT-positive motor neurons, whereas glutathione peroxidase 4 (GPX4) expression remained relatively preserved. Edaravone treatment significantly improved neurological outcomes and survival, attenuated lipid peroxidation (evidenced by decreased malondialdehyde and preserved glutathione levels), and effectively suppressed ACSL4 upregulation in the motor neurons. Furthermore, edaravone mitigated neuroinflammation by reducing astrogliosis and microglial activation. These findings provide the first evidence that ACSL4-mediated ferroptosis is a key driver of acute spinal motor neuron injury following CA. Edaravone exerts potent neuroprotection by targeting this pathway, suggesting its therapeutic potential for ameliorating spinal cord injury in patients with CA.