title: The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.
abstract: A subset of angiotensin IV (AngIV)-related molecules are known to possess procognitive/antidementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier-penetrant analogs, and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, blood-brain barrier-permeable analog N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa). Therefore, the goal of this study was to elucidate the mechanism that underlies dihexa's procognitive activity. Here, we demonstrate that dihexa binds with high affinity to hepatocyte growth factor (HGF) and both dihexa and its parent compound Norleucine 1-AngIV (Nle(1)-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, dihexa and Nle(1)-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a short hairpin RNA directed at c-Met. Most importantly, the procognitive/antidementia capacity of orally delivered dihexa was blocked by an HGF antagonist delivered intracerebroventricularly as measured using the Morris water maze task of spatial learning.
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Benoist
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: Leen H
authors.initials: LH
authors.lastname: Kawas
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Tyson
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: Lori
authors.initials: L
authors.lastname: Stillmaker
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Appleyard
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.).
authors.forename: John W
authors.initials: JW
authors.lastname: Wright
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.) hardingj@vetmed.wsu.edu waymang@vetmed.wsu.edu.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Wayman
authors.affiliation: Department of Integrative Physiology and Neuroscience (C.C.B., L.H.K., M.Z., K.A.T., L.S., S.M.A., J.W.W., G.A.W., J.W.H.) and Department of Psychology (J.W.W., J.W.H.), Washington State University, Pullman, Washington; and M Biotechnology, Inc., Seattle, Washington (L.H.K., J.W.W., J.W.H.) hardingj@vetmed.wsu.edu waymang@vetmed.wsu.edu.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Harding
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003071:Cognition / Q000502:physiology*; D004285:Dogs; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D010455:Peptides; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C578458:N-hexanoic-Tyr-Ile-(6) aminohexanoic amide; D019859:Proto-Oncogene Proteins c-met; C081092:HGF activator; D012697:Serine Endopeptidases