Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes
Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes
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DOI：
10.1007/s12035-023-03589-0
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发表时间：
2023-09
影响因子：
5.1
通讯作者：
Nan Wang;Yujing Zhao;Meiyan Wu;Na Li;Chaoying Yan;Hongyan Guo;Qiao Li;Qing Li;Qiang Wang-Q
中科院分区：
文献类型：
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作者：
Nan Wang;Yujing Zhao;Meiyan Wu;Na Li;Chaoying Yan;Hongyan Guo;Qiao Li;Qing Li;Qiang Wang-Q
糖尿病相关认知功能障碍（daca）被认为是糖尿病的重要并发症，表现为认知障碍。星形胶质细胞对大脑能量代谢和大脑抗氧化状态至关重要。铁下垂与认知障碍有关，但尚不清楚星形胶质细胞的铁下垂是否与daca的进展有关。PPARA/PPARα（过氧化物酶体增殖物激活受体α）是一种调节大脑葡萄糖和脂质代谢的转录因子。在本研究中，我们证明了高糖通过破坏糖尿病小鼠和高糖培养的星形胶质细胞的铁代谢和抑制xCT/ gpx4调节通路，促进了星形胶质细胞的铁凋亡。在db/db小鼠中，给予已知的PPARα激动剂gemfibrozil可抑制铁凋亡并改善记忆障碍。Gemfibrozil还可以防止星形胶质细胞中铁沉积引起的脂质过氧化产物和致命活性氧的积累，并大大减少神经元和突触的损失。我们的研究结果表明，星形细胞铁下垂是daca发生的一种新机制。此外，我们的研究还揭示了吉非罗齐通过抑制铁下垂来预防和治疗daca的疗效。
Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis.