The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

This study published in the Journal of Pharmacology and Experimental Therapeutics was fundamental in elucidating the mechanism of action of Dihexa, a hexapeptide derived from angiotensin IV developed at Washington State University by the group of Joseph Harding and John Wright. Dihexa (N-hexanoic-Tyr-Ile-6-aminohexanoic amide) was designed as a stable, blood-brain barrier-permeable analog of angiotensin IV.

In the behavioral model, Dihexa administered orally at a dose of 2 mg/kg completely reversed the scopolamine-induced cognitive deficit (a muscarinic antagonist that simulates aspects of cognitive impairment) in rats assessed by the Morris water maze test. Oral efficacy is particularly notable for a peptide, as most peptides are degraded in the gastrointestinal tract.

The central mechanistic advance of the study was the demonstration that Dihexa's procognitive and synaptogenic effects are dependent on activation of the HGF/c-Met system (hepatocyte growth factor and its receptor tyrosine kinase). Dihexa acts as an allosteric potentiator of c-Met receptor dimerization, amplifying HGF signaling in the hippocampus — a brain region crucial for memory and learning.

The researchers demonstrated that pharmacological or genetic blockade of the c-Met receptor completely abolished Dihexa's effects, confirming the specificity of the mechanism. The HGF/c-Met pathway promotes synaptogenesis (formation of new synapses), neuroprotection, and synaptic plasticity. The authors suggested that Dihexa is 10 million times more potent than BDNF (brain-derived neurotrophic factor) in promoting synaptogenesis, making it one of the most potent procognitive compounds ever described.