Abstract: Recent studies have indicated that stroke can lead to neuronal iron overload and lipid peroxidation. Lycium barbarum glycopeptide, which has a low molecular weight and potent antioxidant properties, may mitigate ferroptosis in stroke. We hypothesized that Lycium barbarum glycopeptide can effectively mitigate iron overload within ischemic neurons due to its robust antioxidant properties. The aims of this study were to investigate the effects of Lycium barbarum glycopeptide on ferroptotic damage following brain ischemia and explore the underlying mechanisms. A rat model of middle cerebral artery occlusion was established using the intraluminal filament method, and the rats were treated with Lycium barbarum glycopeptide for 7 consecutive days, beginning 24 hours after ischemia. Liproxstatin-1, a ferroptosis inhibitor, and Erastin, a ferroptosis activator, were used as controls. We found that treatment with Lycium barbarum glycopeptide resulted in significant reductions in infarct volume (as detected by triphenyltetrazolium chloride staining staining and magnetic resonance imaging) and neuronal death (as measured by Nissl staining), as well as improvements in sensory and motor functions in rats subjected to middle cerebral artery occlusion. Furthermore, treatment with Lycium barbarum glycopeptide alleviated anxiety and depression-like behaviors and improved memory. Additionally, Lycium barbarum glycopeptide effectively reduced the iron ion content in the ischemic penumbra of the cortex. Moreover, treatment with Lycium barbarum glycopeptide downregulated the expression of ferroptotic and oxidant proteins such as transferrin receptor 1, divalent metal transporter 1, and Acyl-CoA synthetase long-chain family member 4 and upregulated the expression of anti-ferroptotic and antioxidant proteins such as ferroportin 1, solute carrier family 7 member 11, glutathione, and glutathione peroxidase 4. However, these beneficial effects were reversed when ferroptosis was induced with the activator Erastin. Therefore, the positive effects of Lycium barbarum glycopeptide in ischemic stroke are likely mediated through activation of the antiferroptotic pathway and the antioxidative System Xc-glutathione-glutathione peroxidase 4 pathway. Overall, our findings highlight the potential use of Lycium barbarum glycopeptide as a neuroprotective agent targeting both ferroptosis and oxidation to decrease ischemic brain damage.

Key words: antioxidation, anxiety, cerebral ischemic, depression, inflammation, iron overload, Lycium barbarum glycopeptide, magnetic resonance imaging, memory, neurological function, neuroprotection