Dihexa

Overview

Dihexa (PNB-0408) is a small hexapeptide derived from angiotensin IV that exhibits extraordinarily potent synaptogenic activity—reportedly 10 million times more potent than BDNF by molar concentration in promoting synapse formation in hippocampal neuronal cultures. Developed at Washington State University, Dihexa works through a novel mechanism involving hepatocyte growth factor (HGF) and its receptor c-Met rather than through classical peptide hormone receptors. It crosses the blood-brain barrier and is orally active, making it a compelling candidate for neurodegenerative disease treatment.

Mechanism of Action

Dihexa acts by binding to and potentiating the hepatocyte growth factor (HGF) signaling system. It activates or sensitizes HGF/c-Met receptor pathway signaling in hippocampal neurons, which drives synaptic protein expression (PSD-95, synapsin), dendritic spine formation, and synaptogenesis. This occurs independently of classical angiotensin receptor signaling despite the structural relationship to angiotensin IV. The c-Met pathway activation leads to downstream ERK/MAPK and PI3K/Akt signaling, stimulating neuronal gene expression programs associated with synaptic plasticity and cognitive function.

Potential Benefits

• Extraordinary potency in synaptogenesis (10 million× BDNF by molar mass in vitro)
• Cognitive enhancement in rodent models of dementia
• Oral bioavailability with CNS penetration
• Synaptic density restoration in models of age-related cognitive decline
• Novel c-Met mechanism distinct from other nootropics

Research Dosage Notes

The following reflects doses used in published research studies. This is not medical advice.

No established human dosing. Research community reports 1–10 mg topical or subcutaneous. Extreme caution warranted given unknown safety profile.

Amino Acid Sequence

Side Effects & Safety

• Unknown long-term safety profile
• Theoretical concern: potential oncogenic signaling via c-Met activation
• Human safety data lacking

Synergistic Compounds

The following compounds have been studied alongside Dihexa for potential complementary or synergistic effects:

Related Peptides

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References & Further Reading

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