What Is Dihexa? The Angiotensin IV Analogue and What the Research Showed

Cognitive & Nootropic Research

Dihexa is a small, metabolically stabilised compound built from angiotensin IV, designed to switch on the brain’s hepatocyte growth factor (HGF) system, which supports the growth of dendrites and the formation of new synapses. It was developed at Washington State University and introduced in 2013 as a molecule that survived in serum, was active when given by mouth and reached the brain, where the parent peptides could not. Laboratory studies since then have linked it to new synaptic connections, better learning in cognitive-deficit models and recovery of working memory after brain injury. Vistara Labs supplies it as a Dihexa 10 mg lyophilised vial.

What is Dihexa?

Dihexa is a synthetic angiotensin IV analogue with the chemical name N-hexanoic-Tyr-Ile-(6) aminohexanoic amide. It also appears in the literature as PNB-0408. Its formula is C27H44N4O5 and its molecular weight is about 504.7, which makes it smaller than most research peptides: at its centre sit just two amino acids, tyrosine and isoleucine, with a hexanoic acid cap on one end and a 6-aminohexanoic amide on the other.

From angiotensin IV to Dihexa

Angiotensin IV (Val-Tyr-Ile-His-Pro-Phe) is a six-amino-acid fragment of the renin-angiotensin system. Angiotensin IV and related peptides had long been recognised as procognitive, but they were broken down quickly and could not cross the gut or the blood-brain barrier, which kept them in the laboratory (McCoy et al., J Pharmacol Exp Ther, 2013).

The Washington State University group, led by Joseph Harding and Jay Wright, had shown that the procognitive activity of the analogue norleucine¹-angiotensin IV lived in its first three amino acids, Nle-Tyr-Ile. They then modified the ends of that core to make it more stable, and later more hydrophobic with fewer hydrogen bonds, so it could pass biological barriers. The result was Dihexa, described as an orally active, blood-brain-barrier-permeant, metabolically stabilised analogue with marked synaptogenic activity (McCoy et al., 2013).

How stable is it?

Stability was the point of the design, and the numbers bear it out. In serum, Dihexa had a half-life of about 335 minutes, against about 1.4 minutes for norleucine¹-angiotensin IV. In liver microsomes its half-life was about 509 minutes, which the authors described as very low phase I metabolism. After the compound was infused into the carotid artery, every brain region measured concentrated Dihexa relative to blood (McCoy et al., 2013).

How Dihexa works: the HGF/c-Met system

Hepatocyte growth factor was named for its effect on liver cells, but it acts throughout the body through its receptor, c-Met (also written MET). Activation of c-Met stimulates cell growth, movement and differentiation, supports neurogenesis and protects many cell types, including neurons, against injury. In the brain, the system has been shown to drive dendritic branching and synapse formation (Wright and Harding, J Alzheimers Dis, 2015).

Its developers describe Dihexa as a positive modulator of this system: it works with the body’s own HGF to strengthen c-Met signalling. The angiotensin IV receptor had been a long-running puzzle, and the group’s view, set out in their reviews, is that the brain angiotensin IV system coincides with the HGF/c-Met system (Wright et al., Prog Neurobiol, 2015).

Independent support for the HGF link

Some of the clearest support for Dihexa’s HGF-like activity comes from outside neuroscience. A stem-cell group at the University of Oslo built a growth-factor-free method for turning human pluripotent stem cells into liver-like cells, using Dihexa at 100 nM in the final maturation stage in place of recombinant HGF. The cells matched those made with growth factors on albumin and other liver markers (Siller et al., Stem Cell Reports, 2015). A Chinese group later combined vitamin C, Dihexa and forskolin to replace growth factors at the liver-specification stage (Pan et al., Stem Cell Res Ther, 2022).

In a 2025 brain-injury study at Rowan University, Dihexa’s working-memory benefit disappeared when a MET antagonist was given first, which ties the behavioural effect to the receptor (Martino et al., Neurotrauma Rep, 2025).

What the research has shown

The published work on Dihexa itself to date is laboratory research, and it covers synapses, learning, brain injury and tissue protection.

New synapses

In cultured hippocampal neurons, five days of Dihexa at 10^-12 M raised spine density to about 41 spines per 50 micrometres of dendrite, against about 15 with vehicle, a near three-fold increase. Dendritic spines are where most excitatory synapses form, and the new spines were functional: the frequency of AMPA-type synaptic currents rose 1.6-fold, from 3.06 to 4.82 Hz. Dihexa also increased spine counts in organotypic hippocampal slices, from about 7 to about 11 per 50 micrometres (McCoy et al., 2013).

Learning and memory in cognitive-deficit models

Scopolamine blocks acetylcholine signalling and is a standard way to produce a learning deficit in the Morris water maze. Dihexa given directly into the brain prevented that deficit, and Dihexa given by mouth fully reversed it. In an ageing model, daily oral Dihexa significantly improved water maze performance on most test days (McCoy et al., 2013).

The wider field agrees. A 2018 systematic review from the University of Southern California found that in models of cognitive deficit, eight of nine studies of angiotensin IV and its analogues, Dihexa among them, reported improved performance on spatial working memory and passive avoidance tasks (Ho and Nation, Neurosci Biobehav Rev, 2018).

Alzheimer’s disease model

A group at China Pharmaceutical University gave Dihexa for three months in an Alzheimer’s disease model. Dihexa restored spatial learning in the water maze, increased the number of neurons and the synaptic protein synaptophysin, reduced the activation of astrocytes and microglia, lowered the pro-inflammatory cytokines IL-1β and TNF-α, and raised the anti-inflammatory cytokine IL-10. Brain angiotensin IV levels rose after treatment, and blocking PI3K reversed the anti-inflammatory and anti-apoptotic effects, which points to the PI3K/AKT pathway downstream of c-Met (Sun et al., Brain Sci, 2021).

Working memory after brain injury

Repeated mild traumatic brain injury produces lasting problems with working memory. In a closed-head injury model, working memory fell to 67.1% correct on a delayed task with vehicle. With Dihexa it rose to 81.5% correct, above the pre-injury baseline of about 77%, and the rescue was dose-dependent. Pretreatment with a MET antagonist removed the benefit (Martino et al., 2025).

Motor function and Parkinson’s disease models

The Washington State University group has reviewed its work on small angiotensin IV analogues in models of both Alzheimer’s and Parkinson’s disease, describing Dihexa as promising for overcoming memory and motor dysfunction by forming new functional synapses (Wright et al., Prog Neurobiol, 2015; Wright et al., Front Endocrinol, 2013).

Protection beyond the brain

• Sensory hair cells, 2015. In a laboratory model of sensory hair cells, counterparts of the hair cells of the inner ear, Dihexa protected against the antibiotics neomycin and gentamicin, with optimal protection at 1 micromolar. An HGF antagonist reduced the protection, and Dihexa did not change how much antibiotic entered the cells, which points to protection from inside the cell (Uribe et al., Front Cell Neurosci, 2015).
• Nerve repair, 2021. In a peripheral nerve transection-and-repair model, mesenchymal stem cells combined with Dihexa, given into the target muscle, significantly improved walking-based motor function scores 8 to 16 weeks after repair and reduced contractures (Weiss et al., Ann Med Surg, 2021).

Dihexa at a glance

Question	Answer
Origin	Washington State University, from angiotensin IV
Structure	Capped Tyr-Ile core, C27H44N4O5
Pathway	HGF and its receptor c-Met
Serum half-life	About 335 minutes (2013)
Key findings	New synapses; learning in deficit models; working memory after injury
Research stage	Laboratory research

How Dihexa compares with other cognitive compounds

Dihexa works through HGF and c-Met, while Semax is a seven-amino-acid ACTH analogue studied around BDNF, with human stroke research behind it (Dihexa vs Semax). Cerebrolysin is a peptide preparation with neurotrophic-factor-like activity and a large clinical trial record (Dihexa vs Cerebrolysin). The wider field is on our Cognitive & Nootropic Research page.

How Vistara Labs supplies Dihexa

Dihexa comes as a 10 mg lyophilised vial. It has limited solubility in plain water; the concentration arithmetic and handling notes are in how much bacteriostatic water for a Dihexa 10 mg vial. Certificates of analysis are on the lab reports page, and the ordering details are in Buy Dihexa.

Frequently asked questions

What is Dihexa?

Dihexa is N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, a small, metabolically stabilised analogue of angiotensin IV developed at Washington State University. It is studied as a positive modulator of hepatocyte growth factor and its receptor c-Met.

What has Dihexa research shown?

In laboratory studies, Dihexa nearly tripled dendritic spine counts in cultured neurons, reversed a drug-induced learning deficit, improved learning in an ageing model (2013), restored spatial learning in an Alzheimer’s disease model (2021) and rescued working memory after repeated mild brain injury (2025).

How does Dihexa work?

Its developers describe it as working with the body’s own hepatocyte growth factor to strengthen signalling through the c-Met receptor, a system that drives dendrite growth and synapse formation. Stem-cell groups have used it in place of recombinant HGF, and a MET antagonist blocked its working-memory effect in 2025.

What did the research show about Dihexa and the blood-brain barrier?

Dihexa was designed to cross biological barriers. In the 2013 study it was active when given by mouth, and after it entered the circulation every brain region measured concentrated it relative to blood.

What did the 2021 Alzheimer’s model study find?

Dihexa restored spatial learning, raised neuron counts and the synaptic protein synaptophysin, lowered the inflammatory cytokines IL-1 beta and TNF-alpha and raised IL-10, through the PI3K/AKT pathway.

Product details from vistaralabs.ca, October 2026. Compound data from PubChem (CID 129010512). Sources: McCoy AT et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013. PMID 23055539. Wright JW et al. A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Front Endocrinol. 2013. PMID 24298267. Wright JW, Harding JW. The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer’s disease. J Alzheimers Dis. 2015. PMID 25649658. Wright JW et al. The development of small molecule angiotensin IV analogs to treat Alzheimer’s and Parkinson’s diseases. Prog Neurobiol. 2015. PMID 25455861. Siller R et al. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Reports. 2015. PMID 25937370. Uribe PM et al. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Front Cell Neurosci. 2015. PMID 25674052. Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): a systematic review of experimental studies. Neurosci Biobehav Rev. 2018. PMID 29733881. Sun X et al. AngIV-analog Dihexa rescues cognitive impairment and recovers memory via the PI3K/AKT signaling pathway. Brain Sci. 2021. PMID 34827486. Weiss JB et al. Stem cell, granulocyte-colony stimulating factor and/or Dihexa to promote limb function recovery in a sciatic nerve damage-repair model. Ann Med Surg. 2021. PMID 34703584. Pan T et al. Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy. Stem Cell Res Ther. 2022. PMID 35410439. Martino KA et al. Hepatocyte growth factor/MET activator rescues working memory deficits after repeated mild traumatic brain injury. Neurotrauma Rep. 2025. PMID 42825082.

More on this: Dihexa vs Semax: How They Differ.