PMID- 38458310 OWN - NLM STAT- MEDLINE DCOM- 20240428 LR - 20240428 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 376 DP - 2024 Jun TI - Floralozone regulates MiR-7a-5p expression through AMPKalpha2 activation to improve cognitive dysfunction in vascular dementia. PG - 114748 LID - S0014-4886(24)00074-8 [pii] LID - 10.1016/j.expneurol.2024.114748 [doi] AB - BACKGROUND: The pathogenesis of vascular dementia (VD) is complex, and currently, no effective treatments have been recommended. Floralozone is a colorless liquid first discovered in Lagotis Gaertn. Recently, its medicinal value has been increasingly recognized. Our previous study has demonstrated that Floralozone can improve cognitive dysfunction in rats with VD by regulating the transient receptor potential melastatin 2 (TRPM2) and N-methyl-D-aspartate receptor (NMDAR) signaling pathways. However, the mechanism by which Floralozone regulates TRPM2 and NMDAR to improve VD remains unclear. AMP-activated protein kinase (AMPK) is an energy regulator in vivo; however, its role of AMPK activation in stroke remains controversial. MiR-7a-5p has been identified to be closely related to neuronal function. PURPOSE: To explore whether Floralozone can regulate the miR-7a-5p level in vivo through AMPKalpha2 activation, affect the TRPM2 and NR2B expression levels, and improve VD symptoms. METHODS: The VD model was established by a modified bilateral occlusion of the common carotid arteries (2-VO) of Sprague-Dawley (SD) rats and AMPKalpha2 KO transgenic (AMPKalpha2(-/-)) mice. Primary hippocampal neurons were modeled using oxygen and glucose deprivation (OGD). Morris water maze (MWM) test, hematoxylin-eosin staining (HE staining), and TUNEL staining were used to investigate the effects of Floralozone on behavior and hippocampal morphology in rats. Minichromosome maintenance complex component 2(MCM2) positive cells were used to investigate the effect of Floralozone on neurogenesis. Immunofluorescence staining, qRT-PCR, and western blot analysis were used to investigate the effect of Floralozone on the expression levels of AMPKalpha2, miR-7a-5p, TRPM2, and NR2B. RESULTS: The SD rat experiment revealed that Floralozone improved spatial learning and memory, improved the morphology and structure of hippocampal neurons, reduced apoptosis of hippocampal neurons and promoted neurogenesis in VD rats. Floralozone could increase the miR-7a-5p expression level, activate AMPKalpha2 and NR2B expressions, and inhibit TRPM2 expression in hippocampal neurons of VD rats. The AMPKalpha2 KO transgenic (AMPKalpha2(-/-)) mice experiment demonstrated that Floralozone could regulate miR-7a-5p, TRPM2, and NR2B expression levels through AMPKalpha2 activation. The cell experiment revealed that the TRPM2 and NR2B expression levels were regulated by miR-7a-5p, whereas the AMPKalpha2 expression level was not. CONCLUSION: Floralozone could regulate miR-7a-5p expression level by activating the protein expression of AMPKalpha2, control the protein expression of TRPM2 and NR2B, improve the morphology and structure of hippocampus neurons, reduce the apoptosis of hippocampus neurons, promote neurogenesis and improve the cognitive dysfunction. CI - Copyright (c) 2023. Published by Elsevier Inc. FAU - Song, Yu-Ting AU - Song YT AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China; JinShan Hospital of Fudan University, Shanghai 201508, China. FAU - Li, Shan-Shan AU - Li SS AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China. FAU - Chao, Chun-Yan AU - Chao CY AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China; Huang Huai University, Zhumadian 463000, China. FAU - Shuang-Guo AU - Shuang-Guo AD - Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437100, China. FAU - Chen, Gui-Zi AU - Chen GZ AD - Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Wang, Shuang-Xi AU - Wang SX AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China. FAU - Zhang, Ming-Xiang AU - Zhang MX AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China. FAU - Yin, Ya-Ling AU - Yin YL AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China. Electronic address: yalingyin@xxmu.edu.cn. FAU - Li, Peng AU - Li P AD - Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China. Electronic address: pengli@xxmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240307 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (MicroRNAs) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 2.7.11.1 (AMPK alpha2 subunit, mouse) RN - 0 (MIRN7 microRNA, mouse) RN - 0 (TRPM Cation Channels) SB - IM MH - Animals MH - *MicroRNAs/metabolism/genetics MH - Mice MH - *Dementia, Vascular/genetics/drug therapy/metabolism MH - Rats MH - *AMP-Activated Protein Kinases/metabolism/genetics MH - *Rats, Sprague-Dawley MH - Male MH - *Cognitive Dysfunction/drug therapy/etiology/metabolism/genetics MH - Hippocampus/metabolism/drug effects MH - Mice, Knockout MH - Neurons/metabolism/drug effects MH - Mice, Inbred C57BL MH - TRPM Cation Channels/genetics/metabolism OTO - NOTNLM OT - AMPKalpha2 OT - Floralozone OT - NR2B OT - TRPM2 OT - miR-7a-5p COIS- Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript was approved by all authors for publication. EDAT- 2024/03/09 10:43 MHDA- 2024/04/29 01:01 CRDT- 2024/03/08 19:13 PHST- 2023/10/24 00:00 [received] PHST- 2024/02/07 00:00 [revised] PHST- 2024/03/04 00:00 [accepted] PHST- 2024/04/29 01:01 [medline] PHST- 2024/03/09 10:43 [pubmed] PHST- 2024/03/08 19:13 [entrez] AID - S0014-4886(24)00074-8 [pii] AID - 10.1016/j.expneurol.2024.114748 [doi] PST - ppublish SO - Exp Neurol. 2024 Jun;376:114748. doi: 10.1016/j.expneurol.2024.114748. Epub 2024 Mar 7.