Insulin attenuates LPS ‐induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus

作者：Miao Sun, Min Liu, Qingxiao Li, Siyuan Liu, Huikai Yang, Yuxiang Song, Mengyao Qu, Xiaoying Zhang, Yulong Ma, Weidong Mi · 发表于：CNS Neuroscience & Therapeutics · 年份：2024 · DOI：10.1111/cns.14887 · 被引用次数：14 · 研究领域：Ferroptosis and cancer prognosis、GDF15 and Related Biomarkers、Epigenetics and DNA Methylation

AIMS: Neuroinflammation is a recognized contributor to cognitive disorders like Alzheimer's disease, with ferroptosis emerging as a novel mechanism underlying cognitive dysfunction associated with neuroinflammation. Insulin, pivotal in the central nervous system, holds promise for cognitive function enhancement. This study aimed to establish a cognitive impairment model through intracerebroventricular injection of lipopolysaccharide (LPS) and explore the impact of intracerebroventricular insulin injection on cognitive function in mice. METHODS: We employed diverse experimental techniques, including animal behavior testing, molecular assays, targeted metabolomics, nuclear medicine, and electron microscopy, to assess neurodegenerative changes, brain insulin resistance (IR), glucose uptake and metabolism, and ferroptosis. The model of cognitive impairment was induced via intracerebroventricular injection of LPS, followed by intracerebroventricular administration of insulin to evaluate its effects. RESULTS: Insulin treatment effectively mitigated LPS-induced cognitive decline and safeguarded against neuronal degeneration. Furthermore, insulin alleviated LPS-induced insulin resistance, enhanced glucose uptake in the hippocampus, and promoted the Pentose Phosphate Pathway (PPP) and nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, insulin activated the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway, reducing lipid peroxidation, and mitochondri...