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 (Nle1-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, dihexa and Nle1-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.
Footnotes
- Received July 29, 2014.
- Accepted September 2, 2014.
C.C.B. and L.H.K. contributed equally to this work.
This work was supported by grants from the Michael J. Fox Foundation and M3 Biotechnology, Inc. (to J.W.H.); the National Institutes of Health National Institute of Mental Health [Grant R01-MH086032] (to G.A.W.); a Hope for Depression Research Foundation grant (to G.A.W.); a grant from the Edward E. and Lucille I. Lainge Endowment for Alzheimer’s Research (to J.W.W.); and the State of Washington.
J.W.H. and J.W.W. are cofounders and major shareholders of M3 Biotechnology, Inc., which is developing hepatocyte growth factor mimetics and antagonists for the treatment of various disorders including dementia. L.H.K. is the CEO of M3 Biotechnology, Inc.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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