Format

Send to

Choose Destination
J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. doi: 10.1124/jpet.114.218735. Epub 2014 Sep 3.

The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.

Author information

1
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.).
2
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.

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.

PMID:
25187433
PMCID:
PMC4201273
DOI:
10.1124/jpet.114.218735
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center