PMID- 37075971 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20230524 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 365 DP - 2023 Jul TI - Erythropoietin ameliorates cognitive dysfunction in mice with type 2 diabetes mellitus via inhibiting iron overload and ferroptosis. PG - 114414 LID - S0014-4886(23)00098-5 [pii] LID - 10.1016/j.expneurol.2023.114414 [doi] AB - Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Guo, Tingli AU - Guo T AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Yu, Ye AU - Yu Y AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Yan, Wenhui AU - Yan W AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Zhang, Meng AU - Zhang M AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Yi, Xinyao AU - Yi X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Liu, Na AU - Liu N AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Cui, Xin AU - Cui X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Wei, Xiaotong AU - Wei X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Sun, Yuzhuo AU - Sun Y AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Wang, Zhuanzhuan AU - Wang Z AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Shang, Jia AU - Shang J AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. FAU - Cui, Wei AU - Cui W AD - The First Affiliated Hospital, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; International Obesity and Metabolic Disease Research Center, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. Electronic address: doctorweiwei.cui@126.com. FAU - Chen, Lina AU - Chen L AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an 710061, Shaanxi, China; International Obesity and Metabolic Disease Research Center, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China. Electronic address: chenlin@mail.xjtu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230417 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 11096-26-7 (Erythropoietin) RN - 64FS3BFH5W (Epoetin Alfa) SB - IM MH - Mice MH - Animals MH - *Ferroptosis MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - *Diabetes Mellitus, Experimental/complications/drug therapy/metabolism MH - *Erythropoietin/therapeutic use/pharmacology MH - *Cognitive Dysfunction/drug therapy/etiology MH - Epoetin Alfa MH - *Iron Overload/complications/drug therapy OTO - NOTNLM OT - Cognitive dysfunction OT - Erythropoietin OT - Ferroptosis OT - Iron overload OT - Type 2 diabetes mellitus COIS- Declaration of Competing Interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/04/20 00:41 MHDA- 2023/05/22 06:42 CRDT- 2023/04/19 19:26 PHST- 2023/02/08 00:00 [received] PHST- 2023/03/20 00:00 [revised] PHST- 2023/04/15 00:00 [accepted] PHST- 2023/05/22 06:42 [medline] PHST- 2023/04/20 00:41 [pubmed] PHST- 2023/04/19 19:26 [entrez] AID - S0014-4886(23)00098-5 [pii] AID - 10.1016/j.expneurol.2023.114414 [doi] PST - ppublish SO - Exp Neurol. 2023 Jul;365:114414. doi: 10.1016/j.expneurol.2023.114414. Epub 2023 Apr 17.