title: Amelioration of cognitive impairment in the type-2 diabetic mouse by the angiotensin II type-1 receptor blocker candesartan.
abstract: Angiotensin II type-1 receptor blockers are widely used with the expectation of prevention of stroke, potential effects to ameliorate of type-2 diabetes, which seems to be closely associated with the impairment of cognitive function in humans. Recently, we have reported that an angiotensin II type-1 receptor blocker prevented cognitive impairment in mice after focal cerebral ischemia, at least partly through an angiotensin II type-2 receptor-mediated increase in a neuroprotective factor, methyl methanesulfonate sensitive-2. Here, we examined the possibility that an angiotensin II type-1 receptor blocker could improve cognitive function in a type-2 diabetic mouse model, KK-A(y). KK-A(y) mice subjected to 20 trials of a passive avoidance task every week from 8 weeks exhibited a significantly impaired avoidance rate, and moreover, its age-dependent decline, especially after 14 weeks of age, compared with age-matched C57BL6 mice. Oral administration of candesartan at a nonhypotensive dose (0.005% in laboratory chow) in KK-A(y) mice improved cognitive function and inhibited the impairment of cognitive decline. Methyl methanesulfonate sensitive-2 expression in the brain was lower in KK-A(y) mice than in C57BL6 mice. Treatment with candesartan markedly increased mRNA expression of angiotensin II type-2 receptor and methyl methanesulfonate sensitive-2 in the brain in KK-A(y) mice, determined by quantitative RT-PCR. In KK-A(y) mice treated with candesartan, age-dependent increases in blood glucose and insulin were significantly suppressed. Our results suggest that candesartan ameliorates the impaired cognitive function in type-2 diabetes mice, at least because of an increased expression of methyl methanesulfonate sensitive-2, a neuroprotective factor, in addition to improvement of glucose intolerance.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakata
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujita
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001786:Blood Glucose / Q000032:analysis; D003072:Cognition Disorders / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000523:psychology*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000502:physiology; D013777:Tetrazoles / Q000627:therapeutic use*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C511778:Ube2v2 protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; C081643:candesartan