title: Direct stimulation of angiotensin II type 2 receptor enhances spatial memory.
abstract: We examined the possibility that direct stimulation of the angiotensin II type 2 (AT(2)) receptor by a newly generated direct AT(2) receptor agonist, Compound 21 (C21), enhances cognitive function. Treatment with C21 intraperitoneal injection for 2 weeks significantly enhanced cognitive function evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT(2) receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B(2) receptor antagonist. Administration of C21 dose dependently increased cerebral blood flow assessed by laser speckle flowmetry and hippocampal field-excitatory postsynaptic potential (f-EPSP) determined by electrophysiological techniques in C57BL6 mice. Furthermore, activation of the AT(2) receptor by C21 promoted neurite outgrowth of cultured hippocampal neurons prepared from fetal transgenic mice expressing green fluorescent protein. Finally, we investigated the pathologic relevance of C21 for spatial learning using an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid-β (1 to 40). We observed that treatment with C21 prevented cognitive decline in this model. These results suggest that a direct AT(2) receptor agonist, C21, enhances cognitive function at least owing to an increase in CBF, enhancement of f-EPSP, and neurite outgrowth in hippocampal neurons.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan.
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakata
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Kousei
authors.initials: K
authors.lastname: Ohshima
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Steckelings
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlöf
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D055366:Synaptic Potentials / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes