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Inhibition of Hippocampal Neuronal Ferroptosis by Liproxstatin-1 Improves Learning and Memory Function in Aged Mice
Liurong Lin1,2, Xin Ling1,2, Ting Chen1,2
1Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, People's Republic of China.
Background:
Perioperative neurocognitive disorders (PND) are common in elderly patients after surgery, leading to long-term cognitive decline and reduced quality of life. The mechanisms are unclear, but ferroptosis, a key cell death pathway, may be involved in the disruption of brain homeostasis during perioperative stress.
Methods:
In this study, we used the SAM-P8 mouse model to simulate brain aging and observe isoflurane-induced ferroptosis. Forty 8-month-old SAM-P8 mice were divided into four groups: control (CON), perioperative cognitive dysfunction (PND), PND with Liproxstatin-1 intervention (PND+Lip-1), and Liproxstatin-1 control (Lip-1). After 3% isoflurane anesthesia in the PND group, the PND+Lip-1 group received daily intrathecal Liproxstatin-1 injections for five days. Behavioral tests assessed spatial learning and memory. Nissl staining, transmission electron microscopy (TEM), FJB (Fluoro-Jade B), Western Blot (WB), and enzyme-linked immunosorbent assay (ELISA) evaluated neuronal morphology and levels of iron metabolism and lipid peroxidation markers.
Results:
Behavioral tests indicated a decline in learning and memory function in the PND mice. Liproxstatin-1 treatment improved cognitive performance, restored normal neuron ratios, and alleviated mitochondrial damage. In the PND group, increased Cluster of Differentiation 71 (CD71) and decreased Ferroportin 1 (FPN1) and Glutathione Peroxidase 4 (GPx4) indicated ferroptosis activation, while Liproxstatin-1 normalized these markers, reduced ferrous ion concentration, Malondialdehyde (MDA), Reactive Oxygen Species (ROS), and 4-Hydroxy-2-nonenal (4-HNE) levels, and decreased Interleukin-6 (IL-6), showing anti-inflammatory effects.
Conclusion:
The results of this study suggest that isoflurane-induced ferroptosis may play an important role in the pathologic progression of PND. The application of liproxstatin-1, a lipid peroxidation inhibitor, provides a new potential therapeutic target for perioperative neuroprotection.
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