Cortistatin
A somatostatin cousin that binds every somatostatin receptor but also hits the ghrelin and MRGPRX2 receptors, giving it a genuinely distinct profile in slow-wave sleep, inflammation and fibrosis.
Also known as CST-14, CST-17, CORT
Animal data only — Rodent or other animal studies. Dose translation to humans is genuinely uncertain.
Thirty years of reproducible rodent work across sleep, sepsis, colitis, arthritis and fibrosis models, and a clear knockout phenotype. Not a single published human trial, and no analogue has been publicly advanced into the clinic.
How it works
Cortistatin was named for its cortical expression and its ability to depress cortical activity. It shares the core FWKT motif with somatostatin and binds SSTR1 through SSTR5 with comparable affinity, but it diverges in three important ways: it enhances slow-wave sleep whereas somatostatin does not, it binds the ghrelin receptor GHS-R1a as an antagonist or inverse agonist, and it activates MRGPRX2 on mast cells. Its most developed therapeutic angle is immunomodulation — cortistatin is produced by activated immune cells and suppresses TNF-alpha, IL-6 and IL-12 while inducing regulatory T cells, and it has shown protective effects in animal models of sepsis, colitis, arthritis, pulmonary fibrosis and pulmonary hypertension. Cortistatin-deficient mice show exaggerated inflammatory and fibrotic responses. Despite thirty years of consistently positive preclinical work, no cortistatin analogue has reached a published clinical trial.
Targets: SSTR1-SSTR5, GHS-R1a (ghrelin receptor), MRGPRX2, TNF-alpha and IL-6 signalling
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| No human protocol existsNot applicable. | — | not established | subcutaneous |
- · All published dosing is preclinical and body-weight-scaled, usually intraperitoneal. The native peptide's half-life of minutes means peripheral injection of unmodified cortistatin has no plausible sustained effect.
Cycling
Not applicable.
Pharmacology
- Half-life
- Minutes for the native peptide — like somatostatin, it is cleared almost immediately, which is why the therapeutic effort has gone into analogues.
- Onset
- Sleep and cortical effects within an hour of central administration in animals; anti-inflammatory effects over days of repeated dosing.
- Routes
- subcutaneous, intravenous
- Molecule
- Endogenous neuropeptide; human CST-17, rodent CST-14
- Sequence length
- 17 amino acids
Handling
- Diluent
- Bacteriostatic water
- Lyophilised
- Freezer at -20 C.
- Reconstituted
- Refrigerated, days only; the disulfide is vulnerable to reduction.
Mixing
Research reagent; contains an intramolecular disulfide bond that must be correctly formed for activity.
Side effects
- commonGrowth hormone suppression— Somatostatin-receptor agonism suppresses GH; it will work against any secretagogue in the stack.
- commonUnknown human profile— No published human administration study.
- uncommonMast cell degranulation and pseudo-allergic flushing— A direct consequence of MRGPRX2 activation, the same receptor that causes injection-site reactions with icatibant and vancomycin.
Do not use if
- Human use outside research.
- Concurrent mast cell activation syndrome - MRGPRX2 agonism is exactly the wrong signal.
Combining it
- conflictipamorelin — Cortistatin both agonises somatostatin receptors and antagonises GHS-R1a — it blocks GH secretagogues from two directions at once.
- conflictmk-677 — Direct antagonism at the ghrelin receptor.
What to monitor
- · Not applicable outside research.
Legal status
Research reagent. Not approved anywhere.
References
- de Lecea et al. 1996, Nature — a cortical neuropeptide with neuronal depressant and sleep-modulating properties (preclinical)
- Gonzalez-Rey et al. 2006, PNAS — cortistatin as an anti-inflammatory factor in sepsis and arthritis models (preclinical)
Mechanism in depth
Structurally close to somatostatin and binding all five somatostatin receptors, but with two activities somatostatin lacks: it binds the ghrelin receptor GHSR1a and the mast cell receptor MRGPRX2. That broader profile is why it has anti-inflammatory and sleep-modulating effects somatostatin does not, and also why its effects are harder to predict.
What usually goes wrong
Its breadth is the problem rather than the selling point: a molecule that hits five somatostatin receptors plus the ghrelin receptor plus a mast cell receptor will have endocrine effects nobody intended. MRGPRX2 activation in particular is the pathway behind pseudo-allergic mast cell degranulation.
Receptor targets
- SSTR1-5, GHSR1a, MRGPRX2 — Comparable to somatostatin at SSTRs; additional targets are the distinguishing feature
Anti-inflammatory, sleep-modulating, and endocrine effects overlapping somatostatin
Genuinely uncertain
- No human therapeutic trial has been completed.
- The endocrine consequences of chronic pan-SSTR agonism in healthy people are uncharacterised.