Description

How This Works
Dihexa is an orally active, blood-brain barrier-permeable angiotensin IV analog. The proposed mechanism involves binding to hepatocyte growth factor (HGF) and augmenting HGF-induced dimerization of the c-Met receptor, thereby potentiating downstream PI3K/AKT and MAPK signaling, ultimately promoting dendritic spinogenesis and synaptogenesis in hippocampal neurons.-
Critical caveat: The primary mechanistic paper (Benoist et al., 2014) describing this HGF/c-Met mechanism has been retracted. What non-retracted literature does establish is that Dihexa reverses scopolamine-induced spatial learning deficits in rats via multiple routes (i.c.v., i.p., oral), increases hippocampal dendritic spine density ~3-fold in vitro, and improves spatial learning in aged rats at 2 mg/kg/day oral. The precise molecular target therefore remains uncertain.-

Potential Benefits & Side Effects
Potential Benefits (preclinical only):
• Cognitive enhancement: Reverses scopolamine-induced spatial learning deficits and improves spatial learning in aged rats. In APP/PS1 Alzheimer’s model mice, Dihexa rescued cognitive impairment via PI3K/AKT signaling.-
• Neuroprotection: In a mouse intracerebral hemorrhage model, Dihexa dose-dependently reduced neuronal apoptosis and inflammatory markers (TNF-α, IL-1β) and improved neurological function scores, with effects linked to PI3K-AKT pathway regulation. In a zebrafish model, Dihexa protected lateral line hair cells from aminoglycoside ototoxicity through an HGF-dependent mechanism.-
• Spinogenesis/synaptogenesis: Induces dendritic spine formation and functional synapse formation in cultured hippocampal neurons.
Side Effects & Limitations:
• No human clinical trial data available. All efficacy evidence comes from animal models and in vitro studies.
• The compound has “a very thin safety database relative to the potency claims made in its promotional framing”.
• No specific adverse effects are documented in the non-retracted animal literature, but this does not establish human safety.