Colivelin Research

Colivelin is a synthetic 26-residue hybrid peptide first reported in 2005. Colivelin research has run for two decades without a single human subject. No published study has administered colivelin to a human being. This article reviews the peer-reviewed record, including findings that cut against the compound's neuroprotective reputation.

What colivelin is

Colivelin is wholly synthetic, and it is neither a natural peptide nor humanin.

Its N-terminal portion is ADNF9 (SALLRSIPA), the nine-residue active core of activity-dependent neurotrophic factor ^[2]. Its C-terminal portion is AGA-(C8R)HNG17, itself a triple-modified 17-residue derivative of humanin ^[1]. Colivelin is therefore two removes from humanin, and humanin's own evidence base does not transfer to it.

That separation is empirical rather than semantic. A biophysical study found colivelin's secondary structure resembles ADNF9 and not humanin, and found colivelin stable and monomeric in buffer while humanin self-associated strongly ^[2].

On PubChem, colivelin is CID 90477169, CAS 867021-83-8, formula C119H206N32O35, molecular weight 2645.1. A second CAS number, 2803948-60-7, circulates for the trifluoroacetate salt and resolves to a different record, CID 145707784. The two numbers identify different materials. Colivelin

Proposed mechanism

The originating paper describes two signaling arms, with the ADNF portion acting through CaMKIV and the humanin-derived portion through STAT3 ^[1]. Most later work treats colivelin as a JAK2/STAT3 activator.

That description is not universal. In a mouse sepsis model, colivelin treatment was associated with STAT3 inhibition and AMPK activation in aorta and lung ^[3]. The direction of effect on STAT3 appears to depend on tissue and context.

Preclinical colivelin research

Every efficacy finding below comes from animal or in vitro work. None involved human subjects.

In the founding study, colivelin suppressed neuronal death caused by familial Alzheimer's genes and amyloid-beta in vitro, roughly a hundredfold more potently than its own humanin-derived fragment ^[1]. In mice, delivery into the cerebral ventricles blocked amyloid-induced spatial working memory impairment ^[1].

In transgenic ALS model mice, colivelin dose-dependently improved motor performance and prolonged survival, with higher motoneuron survival in spinal cord than in saline-treated or ADNF-treated animals ^[4]. The same paper reports, from the group's earlier work, that ADNF alone improved motor performance without significantly prolonging survival ^[4]. The parent molecule therefore does not predict the hybrid's results, and the hybrid's results do not transfer back to the parent.

Other rodent and cell findings include:

• Intranasal delivery reached the mouse CNS via the olfactory bulb and improved memory in Alzheimer's models, tracking with septohippocampal STAT3 phosphorylation ^[5].
• Colivelin prevented alcohol-induced apoptosis in fetal mouse brain, reducing caspase-3 activation and JNK phosphorylation ^[6].
• In rats, hippocampal injection improved amyloid-induced deficits in spatial memory, long-term potentiation and calcium homeostasis ^[7].
• In APP/PS1 transgenic mice, chronic intranasal colivelin improved cognition and reduced hippocampal amyloid deposition ^[8].
• In a mouse stroke model, colivelin reduced neurological deficit and infarct volume and increased axonal growth ^[9].
• Outside neurology, in a mouse sepsis model, colivelin reduced endothelial injury and glycocalyx shedding and improved lung architecture ^[3]. The same study reports colivelin attenuating plasma syndecan-1, TNF-alpha, MIP-1alpha and IL-10 ^[3].

One measurement qualifies the brain-exposure picture. The founding study inferred blood-brain-barrier passage from a behavioral effect after systemic delivery ^[1]. In healthy mice, a radiolabeled colivelin derivative later placed only 0.58 percent of administered radioactivity in brain shortly after injection ^[10]. That is the one direct measurement of brain uptake in the corpus.

There is no oral data on colivelin at all. Every animal result above rests on injection or intranasal delivery.

Human research

There is no human evidence for colivelin.

ClinicalTrials.gov returns zero studies for colivelin, by search term and by intervention. PubMed publication-type filters for clinical trials of any phase return zero records. No first-in-human study, pharmacokinetic study or single-patient report has been published.

Colivelin holds no regulatory approval in any jurisdiction, and no evidence of an application exists. It was never withdrawn and never refused, because nothing was ever filed, and development stopped at the preclinical stage. A 2010 Japanese-language review is titled as though it concerned patient therapy ^[11]. It is a single-author review proposing a drug candidate, and no patient has ever received colivelin.

The literature runs in both directions

Colivelin's dominant modern use is not as a drug candidate. It is an off-the-shelf STAT3 activator that other groups add as a positive control, to test whether their own drug or gene knockdown acts by blocking that pathway. In that role it repeatedly makes outcomes worse across animal and in vitro studies.

In chronic cerebral hypoperfusion rats, pathway activation by colivelin exacerbated neuronal damage and cognitive decline ^[12]. A spinal cord injury study using rat models and cultured macrophages describes a pro-apoptotic action of colivelin ^[13]. In LPS-exposed mice, colivelin partially reversed a gut metabolite's neurorestorative effect on cognition ^[16]. In cultured pancreatic cancer cells, colivelin partially restored proliferation, migration and invasion after gene knockdown ^[15]. In an ovarian cancer study using cultured cells and mice, colivelin partially reversed a plant-derived JAK inhibitor's antitumor effect and its downregulation of MYC, CCND1 and TWIST1 ^[21]. In melanoma cells, colivelin attenuated the anti-proliferative effect of KIF22 knockdown ^[22]. In cultured peritoneal cells, colivelin attenuated allicin's suppression of fibrosis and epithelial-mesenchymal transition ^[23].

One recent paper puts colivelin itself under test rather than using it as a reagent, and it also reports harm. In an in vitro age-related macular degeneration model, a low concentration was cytoprotective while a tenfold higher concentration activated pro-apoptotic cascades, a dose-dependent biphasic response ^[14].

Two of the reagent reports are rodent cognition studies published in 2025 and 2026 ^[12][16]. They sit in the same broad domain as the older papers and point the other way.

Limitations

The PubMed corpus for colivelin looks larger than it is: a search returns 185 records, but only 15 carry colivelin in the title, and all 15 are preclinical. 160 of the 185 records date from 2020 onward, and that recent bulk is overwhelmingly reagent use rather than colivelin research. Claims that colivelin has been extensively studied are not supported by the record.

Conflicts of interest inside the literature matter here, because colivelin was invented in Ikuo Nishimoto's group at Keio University School of Medicine. The foundational efficacy papers and the reviews promoting colivelin as a drug candidate come from that same group ^{[1][4][5][11][18][19][20]}. The independent record is thinner than a citation count suggests, and even the fetal-alcohol study led from Indiana University carries three Keio inventors as co-authors ^[6]. Animal efficacy work from other laboratories is limited to the rat and mouse cognition studies ^[7][8], the stroke study ^[9] and the sepsis study ^[3].

A 2016 mouse Alzheimer's efficacy paper has been retracted, and it is excluded from the evidence above ^[17]. That notice states no reason, so the reason for the 2016 retraction is not on the public record. A second retracted record sits in the reagent literature, a lung injury study that used colivelin as a pathway activator rather than studying it ^[24]. It is not one of the harm signals cited above, but it shows the wider reagent literature is not uniformly clean.

Several of the key results rest on single papers from the originating laboratory and have not been reproduced by anyone else. The ALS survival result is one of them, and no other laboratory has published an ALS efficacy study of colivelin ^[4]. Later rodent work from other laboratories reports positive results in different models ^[7][8][9], so this is not blanket non-replication. No systematic review, meta-analysis or replication program exists, and no failed replication has been published. That is not reassurance, but a reflection of a field too small and too inactive to have produced any of them.

Conclusion

Colivelin is a well-characterized synthetic peptide with a real and reproducible signaling activity. Its neuroprotection literature is thin, and its foundational results come from its inventors' own laboratory, with a small body of later work from others. Its modern literature is largely reagent use containing repeated harm signals. Human evidence does not exist.

Frequently Asked Questions

Has colivelin been studied in humans?

No published study has administered colivelin to a human being, and ClinicalTrials.gov and PubMed clinical-trial filters both return zero records. Animal and in vitro studies of colivelin do exist and are described above.

Is colivelin the same as humanin?

No. Colivelin is a synthetic hybrid of ADNF9 and AGA-(C8R)HNG17, itself a triple-modified humanin derivative ^[1]. A biophysical study found colivelin's secondary structure resembles ADNF9 rather than humanin ^[2].

Have the core neuroprotection findings been replicated independently?

Not by any independent replication program, and the foundational efficacy papers come from the inventors' own group ^[1][4][5]. Later rodent work from other laboratories reports positive results in different models ^[7][8][9], while separate studies report colivelin worsening outcomes ^{[12][13][14][16]}.

Is colivelin approved anywhere?

No. Colivelin holds no regulatory approval in any jurisdiction, and no evidence of an application exists. It was never withdrawn and never refused, because nothing was ever filed.

References

1. 1

   Chiba T, Yamada M, Hashimoto Y, et al. Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against Alzheimer's disease-relevant insults in vitro and in vivo. J Neurosci. 2005;25(44):10252-61. PMID 16267233. doi:10.1523/JNEUROSCI.3348-05.2005
2. 2

   Arakawa T, Niikura T, Arisaka F, Kita Y. Activity-dependent neurotrophic factor, ADNF, determines the structure characteristics of Colivelin, a fusion protein of ADNF9 and Humanin analog. J Pept Sci. 2008;14(5):631-6. PMID 17994638. doi:10.1002/psc.959
3. 3

   Urban C, Hayes HV, Piraino G, et al. Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice. Front Immunol. 2022;13:984298. PMID 36119052. doi:10.3389/fimmu.2022.984298
4. 4

   Chiba T, Yamada M, Sasabe J, et al. Colivelin prolongs survival of an ALS model mouse. Biochem Biophys Res Commun. 2006;343(3):793-8. PMID 16564029. doi:10.1016/j.bbrc.2006.02.184
5. 5

   Yamada M, Chiba T, Sasabe J, et al. Nasal Colivelin treatment ameliorates memory impairment related to Alzheimer's disease. Neuropsychopharmacology. 2008;33(8):2020-32. PMID 17928813. doi:10.1038/sj.npp.1301591
6. 6

   Sari Y, Chiba T, Yamada M, Rebec GV, Aiso S. A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice. Neuroscience. 2009;164(4):1653-64. PMID 19782727. doi:10.1016/j.neuroscience.2009.09.049
7. 7

   Wu MN, Zhou LW, Wang ZJ, et al. Colivelin ameliorates amyloid beta peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats. Hippocampus. 2015;25(3):363-72. PMID 25332198. doi:10.1002/hipo.22378
8. 8

   Wu M, Shi H, He Y, et al. Colivelin ameliorates impairments in cognitive behaviors and synaptic plasticity in APP/PS1 transgenic mice. J Alzheimers Dis. 2017;59(3):1067-1078. PMID 28731445. doi:10.3233/JAD-170307
9. 9

   Zhao H, Feng Y, Wei C, et al. Colivelin rescues ischemic neuron and axons involving JAK/STAT3 signaling pathway. Neuroscience. 2019;416:198-206. PMID 31374230. doi:10.1016/j.neuroscience.2019.07.020
10. 10

    Kostomoiri M, Zikos C, Benaki D, et al. New labeled derivatives of the neuroprotective peptide colivelin: synthesis, characterization, and first in vitro and in vivo applications. Arch Biochem Biophys. 2015;567:83-93. PMID 25575783. doi:10.1016/j.abb.2014.12.027
11. 11

    Matsuoka M. [Colivelin--drug therapy for patients with Alzheimer's disease]. Nihon Yakurigaku Zasshi. 2010;135(6):263. PMID 20556918. (Review, Japanese)
12. 12

    Liu C, Gao Y. Berberine targets the STAT3 signaling pathway to improve cognitive impairment in chronic cerebral hypoperfusion rats. AIMS Neurosci. 2026;13(1):119-136. PMID 42004572. doi:10.3934/Neuroscience.2026005
13. 13

    Shi Y, Chen X, Luo S, et al. Panax notoginseng saponins ameliorate spinal cord injury by inhibiting JAK2/STAT3-mediated macrophage polarization. Phytomedicine. 2026;152:157856. PMID 41643451. doi:10.1016/j.phymed.2026.157856 (Erratum: Phytomedicine. 2026;157:158321)
14. 14

    Güçlü H, Doğanlar Z, Şambel Aykutlu M, Köse G, Doğanlar O. The role of STAT3-targeted therapy created with COLIVELIN in the cross-talk between IL6/JAK2/STAT3 and TGF-beta/SMAD2/SMAD3 signaling in a hyperinflammation and ROS-induced in vitro AMD model and its effect on retinal apoptosis. Int Ophthalmol. 2026;46(1):250. PMID 42240907. doi:10.1007/s10792-026-04112-9
15. 15

    Li P, Wang K, Song J, et al. THBS1 knockdown suppresses pancreatic cancer progression through JAK2/STAT3 signaling pathway. Mol Cell Probes. 2025;79:102003. PMID 39710065. doi:10.1016/j.mcp.2024.102003
16. 16

    Hao Z, Ji R, Su Y, et al. Indole-3-propionic acid attenuates neuroinflammation and cognitive deficits by inhibiting the RAGE-JAK2-STAT3 signaling pathway. J Agric Food Chem. 2025;73(9):5208-5222. PMID 39992888. doi:10.1021/acs.jafc.4c08548
17. 17

    Yin R, Yin K, Guo Z, et al. Protective effects of colivelin against Alzheimer's disease in a PDAPP mouse model. Cell Physiol Biochem. 2016;38(3):1138-46. PMID 26964005. **RETRACTED.** Retraction notice: Cell Physiol Biochem. 2022;56(3):315. PMID 35771817. Listed for transparency only; not cited as evidence.
18. 18

    Matsuoka M, Hashimoto Y, Aiso S, Nishimoto I. Humanin and colivelin: neuronal-death-suppressing peptides for Alzheimer's disease and amyotrophic lateral sclerosis. CNS Drug Rev. 2006;12(2):113-22. PMID 16958985. (Review)
19. 19

    Chiba T, Nishimoto I, Aiso S, Matsuoka M. Neuroprotection against neurodegenerative diseases: development of a novel hybrid neuroprotective peptide Colivelin. Mol Neurobiol. 2007;35(1):55-84. PMID 17519506. (Review)
20. 20

    Chiba T, Yamada M, Aiso S. Targeting the JAK2/STAT3 axis in Alzheimer's disease. Expert Opin Ther Targets. 2009;13(10):1155-67. PMID 19663649. (Review)
21. 21

    Wang J, He P, Liu C, et al. Discovery of natural compound α-Hederin via large-scale screening as a targeted JAK/STAT3 inhibitor for ovarian cancer therapy. Adv Sci (Weinh). 2025;12(38):e17278. PMID 40667652. doi:10.1002/advs.202417278
22. 22

    Zhong Z, Zhong H. KIF22 promotes the proliferation and glycolysis of melanoma by activating EGFR/STAT3 signaling. Clinics (Sao Paulo). 2023;78:100307. PMID 37944197. doi:10.1016/j.clinsp.2023.100307
23. 23

    Gan L, Geng L, Li Q, Zhang L. Allicin ameliorated high-glucose peritoneal dialysis solution-induced peritoneal fibrosis in rats via the JAK2/STAT3 signaling pathway. Cell Biochem Biophys. 2025;83(2):1847-1859. PMID 39448419. doi:10.1007/s12013-024-01593-2
24. 24

    Wang X, Yang B, Li Y, Luo J. AKR1C1 alleviates LPS-induced ALI in mice by activating the JAK2/STAT3 signaling pathway. Mol Med Rep. 2021;24(6):833. PMID 34590152. **RETRACTED.** Retraction notice: Mol Med Rep. 2025;31(4):84. PMID 39886970. Listed for transparency only; not cited as evidence.