Cyclo(his-pro)
Also known as: CHP, Cyclo‑His‑Pro, Cyclo(His‑Pro), Cyclo(L-histidyl-L-proline), Histidyl-proline diketopiperazine, TRH dipeptide metabolite
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Summary
Cyclo(His-Pro) (also called CHP or cyclo(L-histidyl-L-proline)) is an endogenous cyclic dipeptide found in blood, cerebrospinal fluid, brain and other tissues. Research, largely pre‑clinical, has explored its ability to modulate oxidative stress, inflammation and protein‑folding pathways, suggesting a potential role in protecting neurons from degeneration seen in disorders such as amyotrophic lateral sclerosis and other protein‑misfolding diseases.
Mechanism of Action
The dipeptide crosses the blood‑brain barrier, likely via organic cation transporters, and influences the Nrf2‑NF‑κB signaling axis. Activation of Nrf2 promotes antioxidant gene expression, while inhibition of NF‑κB reduces inflammatory cytokine production. In cell models, Cyclo(His-Pro) also up‑regulates small heat‑shock proteins and appears to stimulate proteostatic pathways including the unfolded protein response, ubiquitin‑proteasome system and autophagy, collectively supporting neuronal survival under stress.
What the Research Shows
Early work identified Cyclo(His-Pro) as a naturally occurring metabolite of thyrotropin‑releasing hormone, present in multiple human fluids. Animal and in‑vitro studies have demonstrated neuroprotective effects in models of spinal‑cord injury, oxidative stress, and protein‑misfolding. Reviews from 2016 and 2018 highlight its capacity to activate Nrf2, dampen NF‑κB, and improve proteostasis, proposing therapeutic relevance for neurodegenerative diseases. Additional reports note synergistic effects with zinc on glycaemic control. No human clinical trials have been published; evidence remains limited to experimental models and expert commentary.
Reported Benefits
Pre‑clinical evidence suggests Cyclo(His-Pro) can reduce oxidative damage, suppress neuroinflammation, and enhance cellular mechanisms that maintain proper protein folding. In rodent and cell‑culture models, these actions translate into improved neuronal survival after injury and may attenuate disease‑related protein aggregation. Early observations also indicate a possible benefit on metabolic regulation when combined with zinc. All reported benefits are confined to laboratory settings and have not been validated in patients.
Limitations of the Evidence
The literature consists of reviews and animal or cell studies; no randomized human trials or safety assessments are available. The exact biosynthetic origin, optimal dosing, and pharmacokinetic profile in humans remain undefined. Reported mechanisms are inferred from indirect markers, and conflicting data on the magnitude of neuroprotection exist. Consequently, the therapeutic potential of Cyclo(His‑Pro) is speculative and requires rigorous clinical investigation.
Safety Considerations
No adverse events have been reported in the animal or in‑vitro studies cited. Human safety data are absent, and the compound’s metabolism, potential off‑target effects, and long‑term tolerance are unknown. Until formal toxicology and phase‑I trials are conducted, caution is warranted for any experimental use, especially in vulnerable populations.
How It Is Administered
Research has employed intranasal, intraperitoneal, intravenous and oral routes in animal models, demonstrating that the peptide can reach the brain after systemic administration. Formulation details (e.g., solubility enhancers or carriers) are not described in the cited literature. Oral delivery has been combined with zinc in metabolic studies, but bioavailability data are lacking.
Routes of Administration
Goals & Uses
- Prolactin inhibitionEndocrineModerate
- anti‑inflammatoryTherapeuticModerate
- NeuroprotectionNeurologyModerate
- anti‑agingWell‑beingLow
- Appetite and body weight regulationMetabolic / EndocrineLow
- Glucose homeostasisMetabolicLow
- Ethanol intake modulationNeurological / AddictionLow
Contraindications
- Hypersensitivity to cyclic dipeptidesAllergicHigh
- PregnancyPopulationModeratePotential fetal risk or insufficient safety data
Adverse Effects
- Gastrointestinal upsetGastrointestinalUncommon
- Endocrine disruptionEndocrineUnknown
- NauseaGastrointestinalUnknownFeeling of sickness or urge to vomit
Drug Interactions
- None documentedLow
- Thyrotropin-releasing hormone (TRH) analoguesLow
- Dopaminergic agentsModerate
Population Constraints
- PregnancyReproductive SafetyRelative
- Pediatric populationsAgeRelative
- Patients with prolactinomas or pituitary disordersEndocrineRelative
- ChildrenPediatricRelative
Regulatory Status
- European UnionUnapprovedMarketed as food supplement; no medicinal authorization.
- United StatesUnapprovedAvailable as dietary supplement; not FDA‑approved as drug.
- United KingdomUnapprovedNot authorized by MHRA; research use only.
Not approved as a pharmaceutical drug in major jurisdictions; marketed in some regions as a dietary supplement with limited clinical data.
Evidence & Sources
- Journal ArticleModerateGrottelli S, et al.2016-01-01T00:00:00.000000Z
- Journal ArticleModeratePrasad C1989-01-01T00:00:00.000000Z
- Journal ArticleModeratePrasad C1995-01-01T00:00:00.000000Z
- Journal ArticleModeratePrasad C1988-01-01T00:00:00.000000Z
- Journal ArticleModerateGrottelli S, et al.2018-01-01T00:00:00.000000Z
- Journal ArticleModerateMinelli A, et al.2008-01-01T00:00:00.000000Z
Frequently Asked Questions
Is Cyclo(His‑Pro) an approved drug for neurodegenerative diseases?
No. It is currently classified as a research compound. All evidence to date comes from pre‑clinical studies and review articles; it has not received regulatory approval for any therapeutic indication.
Can Cyclo(His‑Pro) be taken as a dietary supplement?
The abstracts do not provide information on commercial availability or safety in humans. Without clinical data, its use as a supplement cannot be recommended.
How does Cyclo(His‑Pro) differ from other antioxidant peptides?
Unlike many linear peptides, Cyclo(His‑Pro) is a cyclic dipeptide that resists proteolysis and can cross the blood‑brain barrier. It uniquely activates the Nrf2 pathway while concurrently inhibiting NF‑κB, linking antioxidant and anti‑inflammatory actions.
What are the next steps for research on Cyclo(His‑Pro)?
Future work should include detailed pharmacokinetic profiling, toxicity testing, and controlled animal studies that model specific neurodegenerative disorders, followed by early‑phase human trials to assess safety and efficacy.
Is there any evidence that Cyclo(His‑Pro) improves blood sugar control?
One 2008 report noted that oral Cyclo(His‑Pro) together with zinc improved glycaemic control in diabetic models, suggesting a possible metabolic effect, but this finding remains preliminary and has not been replicated in clinical settings.
What is Cyclo(his-pro)?
Cyclo(His-Pro) (also called CHP or cyclo(L-histidyl-L-proline)) is an endogenous cyclic dipeptide found in blood, cerebrospinal fluid, brain and other tissues. Research, largely pre‑clinical, has explored its ability to modulate oxidative stress, inflammation and protein‑folding pathways, suggesting a potential role in protecting neurons from degeneration seen in disorders such as amyotrophic lateral sclerosis and other protein‑misfolding diseases.
What is Cyclo(his-pro) used for?
Cyclo(his-pro) is educationally associated with: Prolactin inhibition, anti‑inflammatory, Neuroprotection, anti‑aging, Appetite and body weight regulation, Glucose homeostasis, Ethanol intake modulation. Educational only — not medical advice.
How is Cyclo(his-pro) administered?
Recorded routes of administration: Intranasal, Intraperitoneal, Intravenous, Oral.
What are the potential side effects of Cyclo(his-pro)?
Reported adverse effects include: Gastrointestinal upset, Endocrine disruption, Nausea. This list is not exhaustive — consult a qualified clinician.
Who should avoid Cyclo(his-pro)?
Recorded contraindications: Hypersensitivity to cyclic dipeptides, Pregnancy. Consult a qualified clinician before use.