PMID- 24361310 OWN - NLM STAT- MEDLINE DCOM- 20141014 LR - 20140210 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 724 DP - 2014 Feb 5 TI - Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice. PG - 9-15 LID - S0014-2999(13)00942-4 [pii] LID - 10.1016/j.ejphar.2013.12.015 [doi] AB - Type 2 diabetes mellitus (T2DM) is known to be associated with increased risk of cognitive impairment including Alzheimer disease. Recent studies have suggested an interaction between angiotensin II and N-methyl-d-aspartic acid (NMDA) glutamate receptors. We previously reported that stimulation of the angiotensin II type 2 (AT2) receptor exerts brain protective effects. A newly developed AT2 receptor agonist, compound 21 (C21), has enabled examination of the direct effect of AT2 receptor stimulation in vivo. Accordingly, we examined the possible synergistic effect of C21 and memantine on cognitive impairment in T2DM mice, KKAy. KKAy were divided into four groups; (1) control, (2) treatment with C21 (10 mug/kg/day), (3) treatment with memantine (20mg/kg/day), and (4) treatment with both for 4 weeks, and subjected to Morris water maze tasks. Treatment with C21 or memantine alone at these doses tended to shorten escape latency compared to that in the control group. C21 treatment increased cerebral blood flow (CBF), but memantine did not influence CBF. Treatment with C21 or C21 plus memantine increased hippocampal field-excitatory postsynaptic potential (f-EPSP). Moreover, treatment with memantine or C21 increased acetylcholine level, which was lower in KKAy than in wild-type mice, and C21 plus memantine treatment enhanced memantine or C21-induced acetylcholine secretion. This study provides an insight into new approaches to understand the interaction of angiotensin II and neurotransmitters. We can anticipate a new therapeutic approach against cognitive decline using C21 and memantine. CI - Copyright (c) 2013 Elsevier B.V. All rights reserved. FAU - Iwanami, Jun AU - Iwanami J AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Mogi, Masaki AU - Mogi M AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Tsukuda, Kana AU - Tsukuda K AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Jing, Fei AU - Jing F AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Ohshima, Kousei AU - Ohshima K AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Wang, Xiao-Li AU - Wang XL AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Nakaoka, Hirotomo AU - Nakaoka H AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Kan-no, Harumi AU - Kan-no H AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Chisaka, Toshiyuki AU - Chisaka T AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Bai, Hui-Yu AU - Bai HY AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Min, Li-Juan AU - Min LJ AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. FAU - Horiuchi, Masatsugu AU - Horiuchi M AD - Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. Electronic address: horiuchi@m.ehime-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131218 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cytokines) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide) RN - 0 (Receptor, Angiotensin, Type 2) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Sulfonamides) RN - 0 (Thiophenes) RN - W8O17SJF3T (Memantine) SB - IM MH - Animals MH - Brain/drug effects/physiology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cerebrovascular Circulation/drug effects MH - Cognition Disorders/*drug therapy/etiology/metabolism/physiopathology MH - Cytokines/metabolism MH - Diabetes Mellitus, Type 2/complications/*drug therapy/metabolism/physiopathology MH - Drug Synergism MH - Excitatory Amino Acid Antagonists/pharmacology/therapeutic use MH - Excitatory Postsynaptic Potentials/drug effects MH - Maze Learning MH - Memantine/pharmacology/*therapeutic use MH - Mice MH - Receptor, Angiotensin, Type 2/*agonists/metabolism MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Sulfonamides/pharmacology/*therapeutic use MH - Thiophenes/pharmacology/*therapeutic use OTO - NOTNLM OT - AT(2) receptor OT - Acetylcholine OT - Cerebral blood flow OT - Diabetes mellitus OT - Memantine EDAT- 2013/12/24 06:00 MHDA- 2014/10/15 06:00 CRDT- 2013/12/24 06:00 PHST- 2013/06/07 00:00 [received] PHST- 2013/12/04 00:00 [revised] PHST- 2013/12/11 00:00 [accepted] PHST- 2013/12/24 06:00 [entrez] PHST- 2013/12/24 06:00 [pubmed] PHST- 2014/10/15 06:00 [medline] AID - S0014-2999(13)00942-4 [pii] AID - 10.1016/j.ejphar.2013.12.015 [doi] PST - ppublish SO - Eur J Pharmacol. 2014 Feb 5;724:9-15. doi: 10.1016/j.ejphar.2013.12.015. Epub 2013 Dec 18.