Study summary · research use only
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study, the authors investigated the mechanism underlying the procognitive activity of dihexa, an orally active, blood-brain-barrier-permeable angiotensin IV (AngIV) analogue. The abstract reports that dihexa binds with high affinity to hepatocyte growth factor (HGF) and that both dihexa and its parent compound Norleucine 1-AngIV (Nle(1)-AngIV) induced c-Met phosphorylation with subthreshold HGF and augmented HGF-dependent cell scattering. It states both induced hippocampal spinogenesis and synaptogenesis similar to HGF, actions inhibited by an HGF antagonist and c-Met short hairpin RNA. In rats, the procognitive effect of oral dihexa was blocked by an intracerebroventricular HGF antagonist measured in the Morris water maze.
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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