Neuroscience Research Compound · For laboratory research use only
Also known as PNB-0408
Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, also designated PNB-0408) is a small peptidomimetic developed at Washington State University from the angiotensin IV analogue norleucine(1)-angiotensin IV. It was designed by modifying the N-terminal tripeptide Nle-Tyr-Ile to improve metabolic stability and barrier permeability1.
The compound has been studied in rodent models of cognitive impairment and neurodegeneration, in a zebrafish hair cell model and in a rat peripheral nerve repair model1,4,5,6,7. Researchers should note the status of the originating literature: the 2013 paper describing dihexa carries an expression of concern published in 20211, and two related papers from the same group, including the 2014 study that tied its activity to the hepatocyte growth factor (HGF)/c-Met system, were retracted in 20253.
As described in the research literature
As described in the research literature, the originating group proposed that dihexa acts through the HGF/c-Met receptor system, inducing dendritic arborisation and synaptogenesis, and reviewed this hypothesis in 20152. Because the key primary study for this mechanism has since been retracted3, the HGF/c-Met account should be treated as unconfirmed.
Independent and later work has examined other pathways. In a zebrafish lateral line model, protection of hair cells from aminoglycosides was attenuated by an HGF antagonist and by inhibitors of Akt, TOR and MEK4. In APP/PS1 transgenic mice, a separate group examined glial activation, inflammatory cytokines and PI3K/AKT signalling, reporting that a PI3K inhibitor reversed the effects observed5.
What published studies have examined
The 2013 study evaluated metabolically stabilised angiotensin IV analogues, including dihexa, in scopolamine-treated and aged rat models and measured hippocampal synaptogenesis1. This paper carries an expression of concern, and related work from the group has been retracted3.
A 2021 study in APP/PS1 mice examined spatial learning in the Morris water maze, neuronal counts, synaptophysin expression, astrocyte and microglial activation, and the PI3K/AKT pathway5.
Sources [5]
A 2024 study tested PNB-0408 against 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats and reported that it did not protect against the motor and cognitive deficits measured7. A rat sciatic nerve transection-repair model examined limb sensory and motor function with dihexa alone and in combination with mesenchymal stem cells6.
Larval zebrafish lateral line hair cells were used to examine protection from the ototoxins neomycin and gentamicin, including whether protection depended on HGF signalling and downstream kinases4.
Sources [4]
Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.
McCoy AT, Benoist CC, Wright JW, et al. The Journal of Pharmacology and Experimental Therapeutics, 2013.
The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease.
Wright JW, Harding JW Journal of Alzheimer's Disease, 2015.
Retraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System" [J Pharmacol Exp Ther 351 (2014) 390-402].
Benoist CC, Kawas LH, Zhu M, et al. The Journal of Pharmacology and Experimental Therapeutics, 2025.
Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure.
Uribe PM, Kawas LH, Harding JW, et al. Frontiers in Cellular Neuroscience, 2015.
AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.
Sun X, Deng Y, Fu X, et al. Brain Sciences, 2021.
Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies.
Weiss JB, Phillips CJ, Malin EW, et al. Annals of Medicine and Surgery, 2021.
Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.
Wells RG, Azzam AF, Hiller AL, et al. Journal of Huntington's Disease, 2024.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.