A novel angiotensin IV/AT4 receptor ligand, Nle1-AngIV (dihexa), is a potent procognitive agent that augments hepatocyte growth factor (HGF)/Met signaling
McCoy AT, Benoist CC, Wright JW, et al.
Journal of Pharmacology and Experimental Therapeutics
Summary
This study characterized dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide), a stable angiotensin IV analog, as a potent procognitive compound that operates through the HGF/c-Met receptor system. Dihexa demonstrated cognitive-enhancing effects at picomolar concentrations, approximately seven orders of magnitude more potent than BDNF, in scopolamine-induced memory impairment models.
Key Findings
- Dihexa crossed the blood-brain barrier and improved cognitive performance in scopolamine-induced amnesia models at doses as low as 2 pmol via intracerebroventricular administration
- The procognitive mechanism was identified as augmentation of HGF/c-Met receptor signaling, promoting dendritic spine formation and synaptogenesis
- Dihexa facilitated new synapse formation in hippocampal neurons at picomolar concentrations, making it approximately 10 million-fold more potent than BDNF in this assay
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