Cyclic Glycine-Proline
Summary
Cyclic glycine-proline (cGP) is a small cyclic dipeptide produced when the N-terminal tripeptide of IGF-1 is cleaved and cyclized. It competes with IGF-1 for IGFBP-3 binding, regulating bioavailable IGF-1. It is orally available and reaches cerebrospinal fluid; human data are a stroke biomarker cohort and an 11-patient Parkinson supplement study, with efficacy evidence still preclinical.
Also known as: cGP, cyclo(Gly-Pro), Cyclo(glycylprolyl), Cyclic Gly-Pro
Key Findings at a Glance
- • cGP is an endogenous diketopiperazine metabolite of IGF-1 that regulates IGF-1 bioavailability by competing with IGF-1 for IGF binding protein-3.
- • Unlike most peptides, cGP is orally available and reaches the human CNS: blackcurrant anthocyanin supplementation raised cerebrospinal fluid cGP in Parkinson patients within 28 days.
- • Intranasal cGP (20 mg/kg, 28 days) improved spatial memory and reduced amyloid plaque load in APP/PS1 Alzheimer mice, in a study independent of the group that built the cGP field.
- • The plasma cGP/IGF-1 ratio predicts 90-day neurological outcome after stroke, but as a biomarker association, not an intervention result.
Cyclic Glycine-Proline Overview & Molecular Profile
Cyclic glycine-proline (cGP) is a cyclic dipeptide of the 2,5-diketopiperazine family, generated endogenously when the N-terminal tripeptide of insulin-like growth factor-1 (glycine-proline-glutamate) is cleaved and cyclized. It is detectable in human plasma and cerebrospinal fluid and functions as a natural regulator of IGF-1 bioavailability: cGP retains affinity for IGF binding protein-3 (IGFBP-3) and competes with IGF-1 for binding, so the molar ratio of cGP to IGF-1 tracks functional IGF-1 in circulation. Human research is early but real: stroke patients show lower cGP/IGF-1 ratios that predict 90-day neurological outcome, and a small Parkinson disease study showed oral blackcurrant anthocyanins, a natural cGP source, raised cerebrospinal fluid cGP. In APP/PS1 Alzheimer mice, intranasal cGP improved spatial memory and reduced amyloid plaque load. Most efficacy evidence remains preclinical, and no controlled human trial of isolated cGP has been published.
Mechanism of Action: Neuroprotection & Synaptic Plasticity
cGP is produced from glycine-proline-glutamate (GPE), the N-terminal tripeptide cleaved from IGF-1, which then cyclizes into the diketopiperazine cGP. Because cGP retains the IGFBP-3 binding determinants of its parent sequence, it competes with IGF-1 for IGFBP-3 occupancy; a 2014 Scientific Reports study established this binding mechanism, and reviews by the Auckland research group frame cGP as normalizing IGF-1 function in both deficiency and excess states, though the bidirectional claim rests on modeling and association data. Unlike IGF-1, cGP is orally available and crosses into the central nervous system: blackcurrant anthocyanin supplementation raised cerebrospinal fluid cGP in Parkinson patients, with CSF levels correlating with plasma levels. This combination of central penetration and IGF-1 regulation underlies its investigation in Alzheimer, stroke, and Parkinson research.
cGP Pharmacokinetics: Oral Availability and Central Uptake, Sparse Formal Data
Formal pharmacokinetic parameters for isolated cGP (half-life, clearance, volume of distribution) have not been published. What the literature does establish is unusual for a peptide: cGP is orally available and reaches the cerebrospinal fluid, and its plasma and CSF concentrations can be measured by HPLC-MS.
Oral Availability and CSF Uptake
- • In 11 male Parkinson patients, 28 days of blackcurrant anthocyanin supplementation (300 mg twice daily, a natural cGP source) significantly increased CSF cGP (p<0.01) without changing IGF-1 or IGFBP-3; CSF cGP correlated with plasma cGP (R=0.68), indicating central uptake of circulating cGP (PMID 29865234).
- • The CSF/plasma ratio was high for cGP and low for IGF-1 and IGFBP-3 in the same study, consistent with the small cyclic peptide crossing the blood-CSF barrier far more readily than the parent growth factor (PMID 29865234).
Endogenous Turnover and Measurement
- • cGP circulates as an endogenous IGF-1 metabolite; stroke patients showed lower baseline cGP and cGP/IGF-1 ratios than age-matched controls, with ratios rising over 90 days of recovery, indicating dynamic physiological turnover (PMID 31019991).
- • In APP/PS1 mice, intranasal cGP at 20 mg/kg daily for 28 days produced behavioral and histological effects, demonstrating CNS bioactivity by the intranasal route; systemic exposure was not measured (PMID 36909366).
Research-Observed Effects
IGF-1 Bioavailability Regulation
Moderate ResearchcGP is the best-characterized endogenous regulator of IGF-1 bioavailability: it competes with IGF-1 for IGF binding protein-3 occupancy, and the cGP/IGF-1 molar ratio is used as a functional index of free IGF-1. The binding mechanism was demonstrated in a 2014 Scientific Reports study, and human cohort data show the ratio is low in stroke and age-related conditions and rises during stroke recovery. The Auckland group's reviews frame cGP as normalizing IGF-1 function bidirectionally, though that stronger claim rests on modeling rather than intervention trials.
Memory and Amyloid Reduction (Preclinical)
Preliminary ResearchIn APP/PS1 transgenic Alzheimer mice, intranasal cGP (20 mg/kg daily for 28 days) improved spatial memory in the Morris water maze and reduced amyloid plaque burden in hippocampus and cortex. This 2023 study from the National Brain Research Centre in India is independent of the New Zealand group that built the cGP field, giving it unusual weight in this literature; it remains a single mouse study without replication.
Stroke Recovery Association (Human Observational)
Preliminary ResearchIn 34 stroke patients versus 50 age-matched controls, baseline cGP and cGP/IGF-1 ratio were lower after stroke and rose over 90 days, and the admission cGP/IGF-1 ratio correlated with day-90 NIHSS scores and their improvement. The authors propose the ratio as a prognostic biomarker of recovery; this is an association study and does not show that raising cGP changes outcome.
Oral and Central Bioavailability
Preliminary ResearchA 28-day study in 11 male Parkinson patients showed that oral blackcurrant anthocyanin supplementation (a natural cGP source, 300 mg twice daily) raised cerebrospinal fluid cGP significantly, with CSF levels tracking plasma levels. This demonstrates that cGP can be delivered orally and measured in the human CNS compartment, a pharmacokinetic property most peptides lack; the study was small, open-label, and not designed to test clinical efficacy.
Safety & Tolerability
cGP is an endogenous IGF-1 metabolite present in human plasma and cerebrospinal fluid, which gives it a different starting profile from exogenous research peptides. Human exposure data are nonetheless thin: one small open-label 28-day supplement study and one observational stroke cohort. No controlled safety or efficacy trial of isolated cGP exists, and the long-term consequences of altering IGF-1 bioavailability are unstudied.
Human data: Human data consist of an 11-patient open-label supplement study (28 days, Parkinson disease) and observational biomarker cohorts in stroke and aging. No controlled interventional trial of isolated cGP has been published.
Regulatory status: Not approved as a drug anywhere; cGP-containing blackcurrant extracts are sold as dietary supplements, and isolated cGP is available as a research compound.
- PubMed 29865234
In 11 male Parkinson patients, 28 days of blackcurrant anthocyanin supplementation (300 mg twice daily) raised CSF cGP significantly with no adverse events reported in the publication; the study was small, open-label, and not powered for safety endpoints.
Human trial - PubMed 31019991
In 34 stroke patients, lower cGP and cGP/IGF-1 ratio were associated with worse 90-day outcomes; this is a biomarker association and provides no interventional safety or efficacy evidence.
Human observational - PubMed 36909366
In APP/PS1 Alzheimer mice, intranasal cGP at 20 mg/kg daily for 28 days improved memory and reduced plaque load; the study reported behavioral and histological endpoints, not a toxicological evaluation.
Animal
Research Protocol Doses Reported in Published Literature
Research Disclaimer: Doses reported below are from published preclinical research protocols. Cyclic Glycine-Proline is not approved by the US FDA for human use; regulatory status can differ in other countries, so see the regulatory status note in the safety section of this page. This information is provided for research reference only and does not constitute a dosing recommendation.
| Route | Dose | Frequency | Notes |
|---|---|---|---|
| Intranasal (mouse) | 20 mg/kg | Daily for 28 days | APP/PS1 Alzheimer model (PMID 36909366) |
| Oral (human, supplement study) | 300 mg blackcurrant anthocyanin extract | Twice daily for 28 days | 11 Parkinson patients; raised CSF cGP (PMID 29865234) |
All doses above are reported from published research protocols using laboratory subjects. Refer to the cited studies in the Research Studies section above for original source data.
Research Studies & References
Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1
Guan J, Gluckman P, Yang P, et al.
Scientific Reports (2014)
This study established the core mechanism of cGP: as the cyclized remnant of the IGF-1 N-terminus, cGP retains affinity for IGFBP-3 and competes with IGF-1 for binding, altering the equilibrium of bioavailable IGF-1. The authors position the cGP/IGF-1 molar ratio as a functional index of IGF-1 status, the framework used by all subsequent human cGP work.
Cyclic Glycine-Proline Improves Memory and Reduces Amyloid Plaque Load in APP/PS1 Transgenic Mouse Model of Alzheimer's Disease
Arora T, Sharma SK
International Journal of Alzheimer's Disease (2023)
APP/PS1 transgenic Alzheimer mice received cGP intranasally at 20 mg/kg daily for 28 days. Treatment improved spatial memory in the Morris water maze and reduced amyloid plaque load in hippocampus and cortex. Notably, this study comes from the National Brain Research Centre in India, independent of the Auckland group responsible for most cGP research.
Plasma cyclic glycine proline/IGF-1 ratio predicts clinical outcome and recovery in stroke patients
Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J
Annals of Clinical and Translational Neurology (2019)
In 34 stroke patients and 50 age-matched controls, baseline cGP and cGP/IGF-1 ratio were lower in patients and rose over 90 days of recovery; the admission cGP/IGF-1 ratio correlated with day-90 NIHSS scores and their improvement from baseline. The authors propose the ratio as a prognostic biomarker for stroke recovery, an observational finding that does not test cGP as an intervention.
Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function
Fan D, Alamri Y, Liu K, et al.
Nutrients (2018)
Eleven male Parkinson patients took blackcurrant anthocyanin extract (300 mg twice daily, 35% anthocyanins, a natural cGP source) for 28 days. CSF cGP increased significantly (p<0.01) without changes in IGF-1 or IGFBP-3, and CSF cGP correlated with plasma cGP (R=0.68, p=0.01), demonstrating oral availability and central uptake of cGP in humans. The study was small and open-label with exploratory clinical measures.
Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions
Guan J, Li F, Kang D, et al.
Molecules (2023)
This review by the Auckland group synthesizes the case that cGP normalizes IGF-1 function in the aging brain: the cGP/IGF-1 molar ratio is low in hypertension, stroke, and neurological conditions with cognitive impairment; stroke patients with higher ratios show more favorable outcomes; and elderly individuals with higher cGP show better memory retention. The normalization framework is influential but rests largely on association data and modeling.
The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders
Guan J
Expert Opinion on Therapeutic Targets (2015)
This review positions IGF-1-derived small neuropeptides, including GPE and cGP, as therapeutic targets for neurological disorders. It argues that cleavage of the IGF-1 N-terminus generates bioactive fragments whose balance regulates IGF-1 function in the brain, and that cGP's oral availability and central penetration make it a practical candidate where IGF-1 itself is undeliverable. It is a perspective review rather than new experimental data.
Frequently Asked Questions
What is cyclic glycine-proline?
Cyclic glycine-proline (cGP) is a small cyclic dipeptide in the 2,5-diketopiperazine family, produced naturally when the N-terminal tripeptide of IGF-1 (glycine-proline-glutamate) is cleaved and cyclized. It circulates in human plasma and cerebrospinal fluid and acts as an endogenous regulator of IGF-1 bioavailability. It is not one of the Khavinson bioregulator peptides; the field was built mainly by a University of Auckland research group.
How does cGP affect IGF-1?
cGP retains the IGFBP-3 binding determinants of its parent IGF-1 N-terminal sequence, so it competes with IGF-1 for occupancy of IGF binding protein-3. By displacing IGF-1 from IGFBP-3, cGP increases free, bioavailable IGF-1; the cGP/IGF-1 molar ratio is used as a functional index of IGF-1 status. A 2014 Scientific Reports study established this binding mechanism. Reviews frame cGP as normalizing IGF-1 function in both deficiency and excess, though that stronger bidirectional claim rests on modeling and association data.
Does cGP reach the brain when taken orally?
Evidence says yes, indirectly: in 11 male Parkinson patients, 28 days of oral blackcurrant anthocyanin supplementation (a natural cGP source, 300 mg twice daily) significantly raised cerebrospinal fluid cGP, and CSF levels correlated with plasma levels (R=0.68). The CSF/plasma ratio was high for cGP and low for IGF-1 itself, consistent with the small cyclic peptide crossing into the CNS far more readily than the parent growth factor.
What human evidence exists for cGP?
Two lines: an observational stroke cohort (34 patients) in which a lower cGP/IGF-1 ratio at admission predicted worse 90-day neurological outcome, and a small open-label supplement study (11 Parkinson patients) showing oral blackcurrant anthocyanins raise CSF cGP. Neither is a controlled trial of isolated cGP, and neither establishes clinical efficacy. The efficacy evidence, including the APP/PS1 Alzheimer mouse study, is preclinical.
Is cGP safe?
cGP is an endogenous compound present in human plasma and cerebrospinal fluid, and the 28-day Parkinson supplement study reported no safety signal, but it involved only 11 patients and was not designed as a safety trial. No formal toxicology or controlled safety study of isolated cGP has been published, and the consequences of chronically altering IGF-1 bioavailability have not been studied in humans.
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