Side-by-side · Research reference
DihexavsPE 22-28
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
AAnimal-StrongHUMAN-REVIEWED7/28 cited
BAnimal-StrongHUMAN-REVIEWED16/47 cited
Dihexa
Angiotensin IV Analogue · Pre-Clinical
Not established — animal studies only
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
01Mechanism of Action
Parameter
Dihexa
PE 22-28
Primary target
c-Met receptor (HGF receptor tyrosine kinase)
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Pathway
HGF/c-Met receptor activation → downstream signaling cascade → synaptogenesis and dendritic arborization
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Downstream effect
Induction of dendritic arborization, synapse formation, neurogenesis, and neuroprotection in rodent models
Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017Cong 2023Wu 2021
Feedback intact?
—
N/A — direct ion channel blockade; not receptor-mediated endocrine axis
Origin
Small-molecule angiotensin IV analogue designed to activate HGF/c-Met systemWright 2015
Synthetic truncation of spadin (PE 12-28), itself derived from the sortilin propeptide C-terminus. Residues 22-28: Val-Val-Arg-Gly-Trp-Leu-Arg.Djillani 2017Mazella 2018
Antibody development
—
Not reported in animal studies
02Dosage Protocols
Parameter
Dihexa
PE 22-28
Human dosing
Not established — no human trials
—
Animal studies
Mouse/rat models only — dosing not translatable to humans
—
Evidence basis
Pre-clinical / Rodent models
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
Clinical status
No Phase 1, 2, or 3 trials published
—
Animal dose (antidepressant)
—
0.3–3 µg/kg IP
Effective in forced swim test, tail suspension test, CUMS models.
Animal dose (neuroprotection)
—
0.03 µg/kg IPPietri 2019
Low-dose TREK-1 activation post-stroke for 7 days, then high-dose blockade.
Frequency
—
Once daily
Sustained antidepressant effect over 7+ days.
Onset (animal)
—
Within hours (acute); full effect 4–7 days
Comparison to fluoxetine
—
PE 22-28 outperforms fluoxetine in CUMS-sensitive rats by day 7
Chronic administration shows superior long-term efficacy.
Human equivalent (extrapolated)
—
Not established — no clinical trials
Allometric scaling from rodent data unavailable.
04Side Effects & Safety
Parameter
Dihexa
PE 22-28
Human safety data
None available — no human clinical trials
—
Theoretical c-Met risks
c-Met receptor activation has been implicated in tumorigenesis; unknown cancer risk profile
—
Pre-clinical tolerability
Not systematically reported in available studies
—
Toxicity (animal)
—
No adverse effects reported at therapeutic doses
Cardiovascular (theoretical)
—
TREK-1 expressed in cardiac tissue; arrhythmia risk unclear
Weight change
—
Not reported in animal studies
Neurological
—
No seizures or behavioral abnormalities noted
Long-term safety
—
Unknown — longest animal study 28 days
Absolute Contraindications
Dihexa
- ·Not approved for human use — research compound only
PE 22-28
- ·Human use — no clinical safety data available
Relative Contraindications
Dihexa
- ·Theoretical contraindication: active or history of malignancy (c-Met pathway involvement in cancer)
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
05Administration Protocol
Parameter
Dihexa
PE 22-28
1. Human administration
No established protocol. Dihexa has not been tested in human subjects. Animal studies used various routes (typically subcutaneous or intraperitoneal in rodents) not translatable to clinical use.
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
2. Legal status
Pre-clinical research compound. Not approved by FDA or any regulatory authority for human use.
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
3. BBB penetration
—
Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.
4. Human formulation
—
Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.