Edaravone Modulates Neuron Cuproptosis in Ischemic Stroke by Targeting NF-kB Signaling Pathway

Background: Edaravone (EDA) is a neuroprotective and antioxidant drug that widely used for improving the symptoms of patients with ischemic stroke. Cuproptosis is a recently identified cell death form that caused by intracellular copper accumulation and regulated by FDX1. Increasing number of studies indicated that cuproptosis is involved in the progression of ischemic stroke. This study aimed to investigate the effects of EDA on cuproptosis during ischemic stroke. Methods: PC12 neurons were induced with OGD-R model to mimic the ischemic stroke in vitro. Mouse middle cerebral artery occlusion (MCAO) model was established and treated with EDA. Brain damage was measured by TCC staining. The in vitro cell viability was measured by cell counting kit-8 (CCK-8). Cuproptosis was measured by the intracellular levels of copper (Cu), pyruvic acid (PA) and α-ketoglutarate (α-KG), as well as the protein expression of FDX1 and lipoylation of DLST and DLAT. The NF-κB activation was measured by western blot assay. Results: Treatment with EDA improved the proliferation, suppressed the accumulation of Cu, elevated the levels of PA and α-KG, and downregulated the expression of FDX1, lipid-DLAT, and lipid-DLST, indicating the alleviated cuproptosis. Besides, EDA treatment suppressed the activation of NF-κB signaling pathway. Treatment with NF-κB activator reversed the effects of EDA on PC12 cell viability and cuproptosis. EDA treatment alleviated the infarct size and improved neurological function, which were reversed by the cuproptosis inducer elesclomol. Conclusion: EDA improved the brain function and recovered neuron viability through targeting the NF-κB signaling pathway in ischemic stroke.