Dihexa dosage protocol

What the compound is

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a synthetic small molecule that is an analog of Angiotensin IV (AngIV) (PMID 23055539, PMID 25649658). It is described as a metabolically stabilized version of the N-terminal tripeptide Nle-Tyr-Ile, derived from norleucine(1)-angiotensin IV (PMID 23055539, PMID 25187433). Unlike native hepatocyte growth factor (HGF), Dihexa is chemically stable and can cross the blood-brain barrier (PMID 25674052, PMID 25649658, PMID 25187433). It is considered a first-in-class compound that is orally active (PMID 25649658, PMID 25187433).

How it is thought to work

Dihexa functions as a mimetic of hepatocyte growth factor (HGF) and activates the HGF/c-Met receptor system (PMID 25674052, PMID 25649658, PMID 25187433). It forms a functional ligand by dimerizing with endogenous HGF to activate the HGF receptor and downstream signaling cascades (PMID 25674052). Dihexa binds with high affinity to HGF (in cells) and induces c-Met phosphorylation in the presence of subthreshold concentrations of HGF (in cells) (PMID 25187433). This activation of the c-Met receptor system is thought to stimulate processes such as mitogenesis, motogenesis, morphogenesis, stem cell differentiation, neurogenesis, and protection against tissue insults (PMID 25649658). Its protective effects are likely mediated by intracellular events rather than inhibiting entry of toxins (in cells) (PMID 25674052). Downstream HGF targets like Akt, TOR, and MEK appear to be involved in its mechanism (in cells) (PMID 25674052).

What laboratory and animal studies report

In animal studies, Dihexa exhibited antidementia activity in scopolamine and aged rat models, and marked synaptogenic activity (in animals) (PMID 23055539). It also facilitated the formation of new functional synaptic connections and augmented memory consolidation in animal models of Alzheimer's disease (in animals) (PMID 25649658). The procognitive and antidementia capacity of orally delivered Dihexa was blocked by an HGF antagonist delivered intracerebroventricularly (in animals) (PMID 25187433). Dihexa also induced hippocampal spinogenesis and synaptogenesis similar to HGF itself (in cells and animals) (PMID 25187433). Additionally, Dihexa (1 µM) protected hair cells from aminoglycoside toxicity in larval zebrafish (in animals), a protective effect attenuated by an HGF antagonist (PMID 25674052). Small changes to the molecule, such as adding an amino group to its N-terminus, attenuated its protective response (in cells) (PMID 25674052). Dihexa has also been used in combination with other small molecules to efficiently generate functional hepatic cells from human pluripotent stem cells (in cells), supporting their differentiation, expansion, and maturation into hepatocyte-like cells (PMID 35410439, PMID 27532814). However, in a rat model of Huntington's disease, Dihexa did not protect against deficits induced by 3-nitropropionic acid neurotoxicity (in animals) (PMID 38489193).

Human evidence so far

The available abstracts do not describe any human clinical trials or specific human evidence for Dihexa (PMID 41490200).

Open questions and limitations

While preclinical studies show promise, there is a current lack of clinical trials for therapeutic peptides like Dihexa (PMID 41490200). The efficacy of Dihexa may vary across different neurodegenerative conditions, as evidenced by its lack of protective effects in a rat model of Huntington's disease (in animals) (PMID 38489193). Further research is needed to explore its potential in alternative models or approaches for such conditions (PMID 38489193).

Key terms explained

**Angiotensin IV (AngIV):** A peptide related to the renin-angiotensin system, some analogs of which have shown procognitive activity (PMID 23055539, PMID 25187433).

**Hepatocyte Growth Factor (HGF):** A growth factor that activates the c-Met receptor system, stimulating various cellular processes including neurogenesis and protection against tissue insults (PMID 25674052, PMID 25649658, PMID 25187433).

**c-Met receptor:** The receptor for HGF, important in cellular signaling pathways related to growth, survival, and tissue repair (PMID 25674052, PMID 25649658, PMID 25187433).

**Synaptogenesis:** The formation of new synaptic connections between neurons, crucial for learning and memory (PMID 23055539, PMID 25649658, PMID 25187433).

**Blood-brain barrier:** A protective layer of cells that controls the passage of substances from the blood into the brain (PMID 25674052, PMID 23055539, PMID 25649658, PMID 25187433).