Dihexa

This is the foundational report identifying Dihexa as a metabolically stabilized, hydrophobic angiotensin IV analog designed for oral activity and blood-brain-barrier penetration. In cultured hippocampal neurons Dihexa reportedly promoted dendritic arborization and synaptogenesis at sub-nanomolar to picomolar concentrations, and reversed scopolamine-induced deficits in the Morris water maze in rats. INTEGRITY CAVEAT: This article carries a 2021 Notice of Concern from the journal, and its companion mechanistic paper (Benoist et al., J Pharmacol Exp Ther. 2014;351:390-402) was formally RETRACTED in 2025 for fabricated/falsified data; the specific quantitative claims should therefore be treated as unverified.

This is the original paper that introduced Dihexa and reported it could grow new connections between brain cells and improve memory in rats. Importantly, this paper was later flagged with a formal Notice of Concern, and a closely related follow-up paper from the same lab was fully retracted for containing faked data. So while it launched the field, its results are not considered reliable on their own.

In the APP/PS1 transgenic mouse model of Alzheimer's-like amyloid pathology, Dihexa improved spatial learning and memory in the Morris water maze and increased neuronal survival and synaptophysin expression. It reduced astrocyte and microglial activation, lowered pro-inflammatory IL-1b and TNF-a, and raised anti-inflammatory IL-10. Effects were attributed to PI3K/AKT activation, since the PI3K inhibitor wortmannin reversed the anti-inflammatory and anti-apoptotic actions.

In a mouse model of Alzheimer's disease, Dihexa improved memory and helped protect brain cells while calming inflammation in the brain, apparently through a cell-survival signaling pathway (PI3K/AKT). This is a more recent study from a group independent of the compound's original developers, which adds some weight, though it remains an animal study.

This review lays out the mechanistic rationale for Dihexa as a hepatocyte growth factor (HGF)/c-Met system potentiator rather than a classic receptor agonist, arguing that HGF/c-Met signaling drives dendritic spine formation and synaptogenesis and that augmenting it could counter loss of connectivity in Alzheimer's. It is authored by the compound's originating investigators and should be read as hypothesis-framing rather than independent confirmatory data, particularly given subsequent integrity actions against some primary reports it cites.

This review explains the theory behind Dihexa: that it works by boosting a natural growth-factor system (HGF/c-Met) that helps brain cells form and keep connections, which are lost in Alzheimer's. It is a useful overview of the reasoning, but it is written by the drug's own inventors and summarizes early lab work rather than proving anything new.