Dihexa

Dihexa (PNB-0408) is a small-molecule, orally active angiotensin IV analog developed at Washington State University that functions as a potent hepatocyte growth factor (HGF) mimetic. It binds with high affinity to HGF (Kd=65 pM) and potentiates its activity at the c-Met receptor, stimulating synaptogenesis and neurogenesis at picomolar concentrations. Preclinical research demonstrates that Dihexa is seven orders of magnitude more potent than brain-derived neurotrophic factor (BDNF) at promoting synaptic connectivity. The compound crosses the blood-brain barrier, making it highly bioavailable compared to native HGF. In animal models, Dihexa has shown remarkable efficacy in reversing cognitive deficits, restoring motor function in Parkinson's disease models, and protecting against neurodegeneration through activation of the PI3K/AKT signaling pathway. The prodrug fosgonimeton (ATH-1017) entered clinical trials for Alzheimer's and Parkinson's disease but failed Phase 2/3 trials in 2024. Despite promising preclinical data, no human studies of Dihexa itself have been published, and significant safety concerns exist regarding potential cancer risk from c-Met activation. Dihexa remains an experimental research compound without regulatory approval in any country.

Synaptogenesis and Neuroplasticity

• Extreme Potency: Demonstrated to be seven orders of magnitude (10 million times) more potent than BDNF at stimulating neurotrophic activity in preclinical assays ^[1][2]
• Dendritic Spine Formation: In rat hippocampal neuronal culture, 5-day administration increased dendritic spine density nearly 3-fold (41 spines per 50-µm of dendrite versus 15 spines in vehicle controls) ^[3]
• Mechanism: Binds to HGF with high affinity (Kd=65 pM) and induces c-Met phosphorylation in the presence of subthreshold HGF concentrations, stimulating synaptogenesis through the HGF/c-Met pathway ^[4][5]
• Blood-Brain Barrier Penetration: Unlike native HGF, Dihexa is orally bioavailable, chemically stable, and crosses the blood-brain barrier, enabling direct CNS access ^[6][7]

Cognitive Enhancement and Memory

• Alzheimer's Disease Model: In APP/PS1 transgenic mice, Dihexa restored spatial learning and cognitive functions in Morris water maze testing, increased neuronal cell density, and elevated synaptic protein (SYP) expression ^[8]
• Scopolamine-Induced Amnesia: Completely reversed scopolamine-induced memory deficits in rodent models at doses of 2.0 mg/kg, with treated animals performing equivalently to vehicle controls in spatial memory tasks ^[9][10]
• Hippocampal Synaptogenesis: C-terminal truncated Nle1-angiotensin IV analogs (dihexa precursors) facilitated spatial memory and augmented hippocampal synaptic connectivity, with effects as small as tetrapeptide and tripeptide fragments demonstrating procognitive activity ^[10]

Neuroprotection and Anti-Inflammatory Effects

• Neuroinflammation Reduction: In APP/PS1 mice, Dihexa decreased astrocyte and microglia activation, reduced pro-inflammatory cytokines IL-1β and TNF-α, and increased anti-inflammatory cytokine IL-10 ^[8]
• PI3K/AKT Pathway Activation: Increased expression of PI3K and phosphorylated AKT in brain tissue, with PI3K inhibitor wortmannin reversing Dihexa's anti-inflammatory and anti-apoptotic effects, confirming mechanism of action ^[8]
• Neuronal Survival: Promoted neuronal cell survival and reduced apoptosis in ischemic brain injury models through activation of neuroprotective signaling cascades ^[11]

Parkinson's Disease Motor Function

• Complete Motor Recovery: In 6-hydroxydopamine (6-OHDA)-induced substantia nigra lesioned rats, Dihexa administered either by injection or orally completely restored lost motor function over 34-48 days of treatment ^[12]
• Dopaminergic Neuron Restoration: Tyrosine hydroxylase (TH) staining, a marker for dopamine neurons, returned to near-normal levels after 34 days of treatment in lesioned animals ^[12]
• Functional Improvements: Significantly improved rope hang times and stride length over 48-day treatment period in parkinsonian rat models ^[12]

Ototoxicity Protection

• Hair Cell Protection: Dihexa protected lateral line hair cells from acute aminoglycoside-induced ototoxicity through HGF-mediated mechanisms involving Akt, TOR, and MEK signaling pathways ^[13]
• Non-Interference with Antibiotics: Pretreatment did not affect fluorescently tagged gentamicin uptake into hair cells, indicating protection occurs through intracellular anti-apoptotic mechanisms rather than blocking drug entry ^[13]

Mechanisms Supporting Therapeutic Potential

• Neurogenesis Promotion: Stimulates formation of new neurons through HGF/c-Met receptor system activation, critical for brain repair and functional recovery ^[1][14]
• Structural Brain Changes: Creates lasting changes in neural circuitry through enhanced dendritic arborization and synaptic density rather than temporary neurotransmitter modulation ^[3][5]
• Multi-Target Effects: Modulates expression of immune-related genes, vascular system genes, and neurotrophic factors, providing comprehensive neuroprotective benefits ^[8][11]

Critical Safety Concerns

• No Human Safety Data: No studies in humans have been published to date for Dihexa itself. All available safety information comes from preclinical animal studies ^[1][2]
• Cancer Risk: Activation of HGF and c-Met is a key signaling pathway in many cancers, raising theoretical concerns about oncogenic potential with chronic use. No long-term studies in animals or humans have examined cancer risk ^[1][3]
• Long-Term Safety Unknown: No studies in animals or humans have examined the long-term safety of Dihexa. Most preclinical studies involved short-term administration (5-48 days) ^[1][10][12]

Clinical Trial Failures

• Fosgonimeton (ATH-1017): The phosphate prodrug of Dihexa failed its Phase 2/3 LIFT-AD trial in September 2024, missing primary and secondary endpoints for mild-to-moderate Alzheimer's disease treatment ^[15]
• Limited Efficacy: In the LIFT-AD trial of 549 participants, neither the Global Statistical Test (primary endpoint) nor key secondary endpoints (ADAS-Cog11, ADCS-ADL23) reached statistical significance compared to placebo at 26 weeks ^[15]
• ACT-AD Trial: Earlier Phase 2 trial failed to meet primary endpoint, with post-hoc analysis suggesting cholinesterase inhibitors may have diminished fosgonimeton's effects ^[15]
• Parkinson's SHAPE Trial: Phase 2 trial in Parkinson's disease dementia and dementia with Lewy bodies failed to meet primary goals, though fosgonimeton was well tolerated with good safety profile and no treatment-linked serious adverse events ^[16]

Regulatory Status

• No Regulatory Approval: Dihexa has never been approved as a medication in any country. It is not approved by the FDA, EMA, or any other major regulatory agency ^[1]
• Research Chemical Status: Available only as a research chemical labeled "not for human consumption." Legal status varies by jurisdiction ^[1]
• Gray Market Access: Some vendors sell Dihexa as a nootropic research compound, but all such sales are for laboratory research purposes only ^[1]

Theoretical Risks and Concerns

• Maladaptive Brain Wiring: By activating powerful growth pathways non-selectively, Dihexa could potentially create inappropriate neural connections or strengthen maladaptive circuits ^[3]
• Unknown Neurotoxicity: The long-term effects of chronic c-Met activation in the brain are unknown. Excessive neurotrophin signaling can paradoxically cause neuronal damage under certain conditions ^[3]
• Drug Interactions: Potential interactions with cholinesterase inhibitors have been suggested based on fosgonimeton clinical trial results, though mechanisms are unclear ^[15]
• Dose-Response Concerns: Optimal dosing in humans is completely unknown. Preclinical studies used varied doses (50 μg/kg to 2.0 mg/kg) depending on administration route and outcome measures ^[9][10]

Research Integrity Concerns

• Retractions and Concerns: Multiple foundational papers on angiotensin IV analogs and HGF/c-Met mechanisms have been retracted or carry expressions of concern, including key 2014 paper (PMID: 25187433) retracted in April 2025 and 2012 paper (PMID: 22129598) retracted ^[4][17]
• Data Reliability: The retraction of foundational research raises questions about the reliability of the proposed mechanism of action and efficacy claims ^[4][17]

Preclinical Tolerability

• Animal Studies: In rodent studies, Dihexa was generally well tolerated at doses used (up to 2.0 mg/kg) with no reported acute toxicity or serious adverse events during short-term administration ^[9][10][12]
• Ototoxicity in Mice: The related compound MM-201 (another HGF mimetic) was found to be ototoxic to mice across the dose range tested, though Dihexa showed protective effects in vitro ^[13]

Special Populations

• Pregnancy and Lactation: No data available. Given c-Met's role in development and cancer, use during pregnancy would be extremely high risk ^[1]
• Pediatric Use: No studies in developing organisms. The impact on brain development is completely unknown ^[1]
• Hepatic/Renal Impairment: No studies have examined safety or pharmacokinetics in organ dysfunction ^[1]

Summary

Dihexa remains a highly experimental compound with promising preclinical data but significant safety unknowns. The failure of its prodrug fosgonimeton in multiple Phase 2/3 clinical trials, combined with retractions of key mechanistic research and complete absence of human safety data for Dihexa itself, make it an extremely high-risk compound. The theoretical cancer risk from chronic c-Met activation and unknown long-term neurological effects make any human use outside controlled clinical trials inadvisable.