Side-by-side · Research reference
LL-37vsPE 22-28
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
AHuman-MechanisticHUMAN-REVIEWED15/35 cited
BAnimal-StrongHUMAN-REVIEWED16/47 cited
LL-37
Cathelicidin · Human AMP
Broad-spectrumAntimicrobial activity
Endogenous · Secreted at inflammation sites
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
01Mechanism of Action
Parameter
LL-37
PE 22-28
Primary target
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Pathway
hCAP-18 precursor → Proteinase-3 cleavage → LL-37 release → Membrane insertion/disruption
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Downstream effect
Membrane permeabilization, cytokine induction, autophagy, phagosome-lysosome fusion, chemotaxisAhmad 2026Zhang 2026
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
Endogenous human cathelicidin (37-AA fragment, residues 134–170 of hCAP-18)
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
LL-37
PE 22-28
Endogenous expression
Constitutive in neutrophils, epithelial tissues
Upregulated during infection and inflammation.Pinheiro 2026
—
Exogenous (experimental)
Dose varies by study; antimalarial ~10–50 μM in vitro
No FDA-approved exogenous formulation.
—
Plasma levels (malaria)
Elevated in infected patients and miceHe 2026
Exogenous administration reduced parasitemia in murine models.He 2026
—
Evidence basis
In vitro, animal models, human observational
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
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
LL-37
PE 22-28
Cytotoxicity (high dose)
Membrane disruption in host cells at supraphysiological concentrations
—
Pro-inflammatory signaling
Can exacerbate inflammation in certain contexts (context-dependent)Pinheiro 2026
—
Theoretical cancer risk
Immunomodulatory roles in tumor microenvironment under investigation
—
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
LL-37
—PE 22-28
- ·Human use — no clinical safety data available
Relative Contraindications
LL-37
- ·Active autoimmune disease (theoretical immune dysregulation)
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
05Administration Protocol
Parameter
LL-37
PE 22-28
1. Natural secretion
LL-37 is constitutively expressed in neutrophils and epithelial cells, cleaved from hCAP-18 by proteinase-3 at sites of infection or inflammation.
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
2. Experimental formulations
Synthetic LL-37 and derivatives (e.g., SAMP-12aa) tested in vitro and animal models. Administered via topical, intraperitoneal, or intravenous routes in research settings.
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
3. Stability considerations
LL-37 is resistant to pepsin degradation at gastric pH. Synthetic short peptides designed to retain this stability while reducing toxicity.Lu 2026
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.