Journal article
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system
The Journal of pharmacology and experimental therapeutics, Vol.351(2), pp.390-402
11/2014
Handle:
https://hdl.handle.net/2376/116217
PMCID: PMC4201273
PMID: 25187433
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.
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- Title
- The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system
- Creators
- Caroline C Benoist - 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.)Leen H Kawas - 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.)Mingyan Zhu - 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.)Katherine A Tyson - 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.)Lori Stillmaker - 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.)Suzanne M Appleyard - 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.)John W Wright - 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.)Gary A Wayman - 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.eduJoseph W Harding - 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
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.351(2), pp.390-402
- Academic Unit
- Psychology, Department of; Integrative Physiology and Neuroscience, Department of
- Publisher
- United States
- Grant note
- R01-MH086032 / NIMH NIH HHS R01 MH086032 / NIMH NIH HHS
- Identifiers
- 99900547582801842
- Language
- English
- Resource Type
- Journal article