Dihexa (PNB-0408) is a small, chemically modified analog of angiotensin IV developed by academic researchers at Washington State University. All published research is preclinical, and key early papers carry a journal expression of concern.
Researchers reported that dihexa binds hepatocyte growth factor (HGF) and increases c-Met receptor phosphorylation when HGF is present at low levels, and that its effects on neuronal spine formation were blocked by an HGF antagonist or c-Met knockdown [2]. The journal later issued an expression of concern over possible image manipulation in that paper [3]. A separate mouse study proposed involvement of PI3K/AKT signaling [4]. The mechanism should be regarded as proposed.
| Study | Model | Reported result | Source |
|---|---|---|---|
| Stabilized angiotensin IV analogs in rats [1] | Rat Scopolamine-induced memory-deficit and aged-rat models; Morris water maze | Authors reported metabolic stability, blood-brain barrier entry, improved water-maze performance vs scopolamine-only rats, and increased hippocampal synapse formation. | Peer-reviewed J Pharmacol Exp Ther 2013 |
| HGF/c-Met dependence of dihexa effects [2] | Cell Hippocampal neuron cultures and cell-scattering assays; rat water maze | Dihexa bound HGF and increased c-Met phosphorylation; spine formation was blocked by HGF antagonist. Paper is under a 2021 expression of concern. | Peer-reviewed J Pharmacol Exp Ther 2014 |
| Dihexa in APP/PS1 mice [4] | Mouse APP/PS1 transgenic amyloid mouse model, 6 months old, ~3 months exposure, n=6-12 per group | Researchers measured better water-maze performance, more Nissl-positive neurons and synaptophysin, lower TNF-α and IL-1β; PI3K inhibitor wortmannin blocked several effects. | Peer-reviewed Brain Sciences 2021 |
| PNB-0408 in 3-NP rat model [5] | Rat 3-nitropropionic acid (3-NP) toxin model, 40 male Wistar rats, randomized, 5 weeks | PNB-0408 did not change 3-NP-induced reductions in weight gain, motor function or spatial learning measures. | Peer-reviewed J Huntingtons Dis 2024 |
Human trials are listed for research context only; outcomes are reported in the linked publications. Animal and lab results do not establish effects in humans.
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