PMID- 33709562 OWN - NLM STAT- MEDLINE DCOM- 20210715 LR - 20240226 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 35 IP - 4 DP - 2021 Apr TI - Melatonin prevents diabetes-associated cognitive dysfunction from microglia-mediated neuroinflammation by activating autophagy via TLR4/Akt/mTOR pathway. PG - e21485 LID - 10.1096/fj.202002247RR [doi] AB - Cognitive dysfunction often occurs in diabetes mellitus patients. This study aimed to investigate the efficacy of melatonin (MLT) in improving diabetes-associated cognitive decline and the underlying mechanism involved. Type 2 diabetic mice and palmitic acid (PA)-stimulated BV-2 cells were treated by MLT, and the potential mechanisms among MLT, cognition, and autophagy were explored. The results showed that type 2 diabetic mice showed obvious learning and memory impairments in the Morris water maze test compared with normal controls, which could be ameliorated by MLT treatment. Meanwhile, MLT administration significantly improved neuroinflammation and regulated microglial apoptosis. Furthermore, autophagy inhibitor 3-methyladenine (3-MA) increased the microglial inflammation and apoptosis, indicating that the treatment effect of MLT was mediated by autophagy. Lastly, MLT treatment significantly decreased the levels of toll-like receptors 4 (TLR4), phosphorylated-protein kinase B (Akt), and phosphorylated-mechanistic target of rapamycin (mTOR), indicating that blocking TLR4/Akt/mTOR pathway might be an underlying basis for the anti-inflammatory and anti-apoptosis effects of MLT. Collectively, our study suggested that MLT could improve learning and memory in type 2 diabetic mice by activating autophagy via the TLR4/Akt/mTOR pathway, thereby inhibiting neuroinflammation and microglial apoptosis. CI - (c) 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. FAU - Cui, Yixin AU - Cui Y AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. FAU - Yang, Mengmeng AU - Yang M AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. FAU - Wang, Yilin AU - Wang Y AD - Department of Traumatic Orthopedics, Peking University People's Hospital, Beijing, China. FAU - Ren, Jianmin AU - Ren J AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - Lin, Peng AU - Lin P AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - Cui, Chen AU - Cui C AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. FAU - Song, Jia AU - Song J AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. FAU - He, Qin AU - He Q AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - Hu, Huiqing AU - Hu H AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. FAU - Wang, Kexin AU - Wang K AD - Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China. FAU - Sun, Yu AU - Sun Y AD - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Anti-Inflammatory Agents) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - JL5DK93RCL (Melatonin) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology MH - Cognitive Dysfunction/metabolism/*prevention & control MH - Diabetes Mellitus, Experimental/metabolism MH - Inflammation/metabolism MH - Male MH - Melatonin/*pharmacology MH - Mice, Inbred C57BL MH - Microglia/*drug effects/metabolism MH - Proto-Oncogene Proteins c-akt/*drug effects/metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/drug effects MH - Mice OTO - NOTNLM OT - apoptosis OT - autophagy OT - cognition OT - melatonin OT - neuroinflammation EDAT- 2021/03/13 06:00 MHDA- 2021/07/16 06:00 CRDT- 2021/03/12 07:47 PHST- 2020/09/30 00:00 [received] PHST- 2021/02/10 00:00 [revised] PHST- 2021/02/15 00:00 [accepted] PHST- 2021/03/12 07:47 [entrez] PHST- 2021/03/13 06:00 [pubmed] PHST- 2021/07/16 06:00 [medline] AID - 10.1096/fj.202002247RR [doi] PST - ppublish SO - FASEB J. 2021 Apr;35(4):e21485. doi: 10.1096/fj.202002247RR.