Erythropoietin, or Epo for short, is a notorious doping agent.
It promotes the formation of red blood cells, leading thereby to enhanced physical performance – at least, that is what we have believed until now.
However, as a growth factor, it also protects and regenerates nerve cells in the brain. Researchers at the Max Planck Institute of Experimental Medicine in Göttingen have now revealed how Epo achieves this effect.
They have discovered that cognitive challenges trigger a slight oxygen deficit (termed ‘functional hypoxia’ by the researchers) in the brain’s nerve cells.
This increases production of Epo and its receptors in the active nerve cells, stimulating neighbouring precursor cells to form new nerve cells and causing the nerve cells to connect to one another more effectively.
The growth factor erythropoietin is among others responsible for stimulating the production of red blood cells.
In anaemia patients it promotes blood formation. It is also a highly potent substance used for illegal performance enhancement in sports.
“Administering Epo improves regeneration after a stroke (termed ‘neuroprotection’ or ‘neurogeneration’), reducing damage in the brain.
Patients with mental health disorders such as schizophrenia, depression, bipolar disorder or multiple sclerosis who have been treated with Epo have shown a significant improvement in cognitive performance,” says Hannelore Ehrenreich of the Max Planck Institute of Experimental Medicine.
Along with her colleagues, she has spent many years researching the role played by Epo in the brain.
Ehrenreich and her team have been using mice in animal studies for a systematic investigation into which bodily mechanism lies at the root of Epo’s effect on enhanced brain performance.
The results of her research indicate that in adult mice, there is a 20 percent increase in the formation of nerve cells in the pyramidal layer of the hippocampus – a brain region crucial for learning and memory – after the growth factor is administered.
“The nerve cells also form better networks with other nerve cells, and do this more quickly, making them more efficient at exchanging signals”, says Ehrenreich.
The growth factor erythropoietin is among others responsible for stimulating the production of red blood cells.
In anaemia patients it promotes blood formation. It is also a highly potent substance used for illegal performance enhancement in sports. The image is in the public domain.
The researchers gave the mice running wheels with irregularly-spaced spokes.
“Running in these wheels requires the mice to learn complex sequences of movement that are particularly challenging for the brain,” explains Ehrenreich.
The results demonstrate that the mice learn the movements required for the wheels more quickly after Epo treatment. The rodents also show significantly better endurance.
Higher oxygen requirements
It was important to the Göttingen researchers to understand the mechanisms behind these potent Epo effects.
They wanted to track down the physiological significance of the Epo system in the brain. In a series of targeted experiments, they were able to prove that when learning complex motor tasks, nerve cells require more oxygen than is normally available to them.
The resulting minor oxygen deficiency (relative hypoxia) triggers the signal for increased Epo production in the nerve cells.
“This is a self-reinforcing process: Cognitive exertion leads to minor hypoxia, which we term ‘functional hypoxia’, which in turn stimulates the production of Epo and its receptors in the corresponding active nerve cells.
Epo subsequently increases the activity of these nerve cells, induces the formation of new nerve cells from neighbouring precursor cells, and increases their complex interconnection, leading to a measurable improvement in cognitive performance in humans and mice,” explained Ehrenreich.
The self-reinforcing cycle of mental and cognitive challenge, activity-induced hypoxia and Epo production can be influenced in various ways:
“Cognitive performance can be improved through consistent learning and mental training via Epo production in the stimulated nerve cells. A similar effect can be achieved in patients by administering additional Epo,” says Ehrenreich.
Erythropoietin (EPO), an evolutionarily conserved hormone mainly produced in the kidney, has been well documented for its indispensable role in erythropoiesis. EPO belongs to the type 1 cytokine superfamily and has 165 amino acids forming four α helices1. In humans, the plasma half-life of kidney-produced EPO is 5–6 h due to high levels of glycosylation.
When erythrocyte levels decline, the renal tubular interstitial cells detect relative hypoxia and secrete EPO into the circulation in a classic endocrine manner.
Then, EPO migrates to bone marrow, binds the homodimeric EPO receptor (EPOR)2 on the erythroid progenitors, and promotes erythropoiesis.
Due to the high affinity of (EPOR)2, the trace amounts of EPO in human serum regulated by a classic negative feedback loop are able to maintain the homeostasis of erythropoiesis2.
In recent years, numerous studies have shown that EPO acts far beyond erythropoiesis. In hypoxia, trauma or inflammation, many tissues produce EPO at the borders surrounding injury sites; EPO plays central roles in tissue protection and restoration.
However, recent studies have revealed that EPO and its derivatives could also directly work on the immune cells. In this review, we briefly reviewed the receptors and tissue-protective effects of EPO and the development of its nonerythropoietic derivatives. We further highlight the immunomodulatory functions and application prospects of EPO in the clinic.Go to:
What is the tissue-protective receptor (TPR)?
A remarkable characteristic of the type 1 cytokine superfamily receptors is that they are commonly composed of different subunits. The β common receptor (βCR), or CD131, is the subunit receptor shared by type 1 cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-54.
Through affinity chromatography and coimmunoprecipitation, βCR and EPOR were shown to covalently bind and form a heteromeric complex. Immunocytochemistry further showed that these two subunits colocalize5.
Notably, the tissue-protective and healing effects of EPO and its derivatives were abolished in the absence of βCR5–7. Some EPO derivatives, including carbamylate EPO (CEPO), helix B surface peptide (HBSP) and cyclic helix B peptide (CHBP), did not bind (EPOR)2 and were not erythropoietic but still showed tissue-protective effects8–10.
These studies revealed that the tissue-protective effects of EPO and its derivatives are mainly mediated by the heterodimer of EPOR/βCR; thus, this heterodimer was called tissue-protective receptor (TPR) or innate repair receptor (IRR). Recently, the receptor for vascular endothelial growth factor (VEGFR2) was also reported to be involved in the composition of TPR and is induced in hypoxia and plays a role in nitric oxide (NO) production in endothelial cells11.
The emergence of nonerythropoietic EPO derivatives makes them available for illustrating the signaling pathways of TPR. When ligands bind TPR, multiple pathways are activated and overlap some in erythropoiesis1,12,13.
The initial step is the autophosphorylation of Janus kinase 2 (Jak2), which then activates three main cascades. The first cascade is the signal transducer and activator of transcription (STAT) pathway, which includes STAT3 and STAT5, leading to upregulated survival signals and apoptotic resistance like in erythropoiesis1,14.
The second cascade involves the phosphatidylinositol 3-kinase (PI3K) and Akt pathway. The PI3K/Akt pathway phosphorylates glycogen synthase kinase 3β (GSK3β), significantly decreasing its activity, inhibiting mitochondrial permeability transition (MPT) and stabilizing mitochondria, leading to the inhibition of apoptosis15.
The inhibition of GSK3β also downregulates nuclear factor-κB (NF-κB), thus reducing inflammation and edema6,16. The third cascade is the mitogen-activated protein kinase (MAPK) pathway, which also inhibits GSK3β and attenuates inflammation14,16.
In addition, the PI3K/Akt pathway promotes the production of NO via the activation of endothelial nitric oxide synthase (eNOS), which increases blood flow, attenuates regional injury and induces endothelial cell proliferation, migration and healing6,16,17. The AMP-activated protein kinase (AMPK) pathway, which is downstream of βCR, was also reported to induce eNOS and NO production after EPO stimulation18.Go to:
TPR-mediated tissue-protective effects
When tissue suffers from pathogen invasion, trauma or hypoxia, a highly orchestrated defense program is triggered, characterized by the production of proinflammatory cytokines and chemokines. These molecules recruit circulating immune cells to destroy pathogens and remove damaged cells.
They also cause vascular thrombosis and edema, which helps isolate damage but aggravates hypoxia3. Notably, the process is self-amplifying, causing necrosis and apoptosis via a positive feedback loop, which may lead to catastrophic injury to adjacent and distant tissues1. To confine the damage, protective and anti-inflammatory process occurs just following injury.
EPO is an important regulatory factor that helps maintain immune homeostasis. In most quiescent cells, EPOR and βCR are typically localized within intracellular compartments, but hypoxic and proinflammatory cytokines can induce the rapid translocation and expression of EPOR and βCR on cell surfaces; this process occurs earlier than the synthesis of EPO19.
Hypoxia also induces the expression of hypoxia-inducible factor (HIF), which binds EPO enhancer (E-3′) and leads to the production of EPO20. In contrast, proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, inhibit EPO production21.
As a result, although cells at the central core of injuries express TPR, they lack the appropriate corresponding binding ligand due to high concentrations of proinflammatory cytokines and eventually die.
At the periphery of injuries, EPO can be synthesized due to the relatively low levels of proinflammatory cytokines. Locally produced EPO diffuses inward and binds TPR, which inhibits inflammation, rescues cells and halts spread of injury. The antagonism of these molecules determines the scale of the injury1,3.
Unlike the high-affinity receptor (EPOR)2, TPR has a much lower affinity for EPO. To initiate the tissue-protective effects of TPR, the required EPO concentration is much higher than that in circulating serum12.
Locally produced EPO is poorly sialated (hyposialated EPO; hsEPO), has a much shorter plasma half-life, and functions in a paracrine-autocrine manner1. Researchers have reported that totally enzymatically desialated EPO (asialo-EPO) has a half-life of only 1.4 min but still showed fully protective effects without erythropoiesis22. Therefore, in the microenvironment of an injury, locally produced hsEPO reaches high concentrations sufficient to activate TPR but does not influence erythropoiesis.Go to:
Do EPOR- and TPR-mediated signals directly influence immune cells?
(EPOR)2 and TPR are expressed on a variety of immune cells, such as macrophages, dendritic cells, mast cells and lymphocytes23. An increasing body of evidence demonstrates that EPO and its derivatives can directly affect the manner by which immune cells exert their immunoregulatory effects.
Innate immune system
Macrophages play an important role in innate immunity and are the main source of proinflammatory cytokines. Researchers showed that macrophages expressed TPR at baseline and that EPO treatment significantly reduced TNF-α, IL-6 and inducible nitric oxide synthase (iNOS) expression by blocking NF-κB p65 activation24.
EPO treatment led to reduced pathogen clearance in Salmonella infection and, in contrast, the amelioration of disease severity in experimental colitis24. Our group also showed that EPO suppressed the production of NO, TNF-α, IL-6 and IL-1β in dose-dependent manners in macrophages (Fig. (Fig.1)25.
Chemokines are important to the migration and recruitment of macrophages and other immune-competent cells. Studies have shown that EPO can directly influence the expression of chemokines by macrophages and modulate their migration.
The production of C-C motif chemokine ligand 2 (CCL2) by macrophages relies on the stimulation of toll-like receptor (TLR) and the activation of the MyD88/NF-κB pathway. When TPR is activated, the downstream Jak2-PI3K/Akt pathway can suppress the expression of CCL2 by macrophages24,26,27.
In vitro, EPO could decrease the levels of CCL2, CCL3, CCL11 and C-X-C motif chemokine ligand 1(CXCL1) expressed by macrophages and monocytes (Fig. (Fig.11)27. In vivo, similar results have been verified in islets transplant model26, experimental colitis mice27, pristane-induced systemic lupus erythematosus (SLE) mice28 and acute kidney injury mice25.
These results indicate that EPO reduces the prolonged infiltration of inflammatory macrophages. However, contradictory phenomena were observed on resident macrophages. EPO can facilitate CCL2 production by Kupffer cells and promote the recruitment of monocytes to injured liver29.
Similarly, increased levels of EPO can recruit more macrophages to laser-injured choroids30. This may be related to EPO-induced anti-apoptosis and proliferation effects after injury.
Macrophages can be induced to the classically activated M1 phenotype or the alternatively activated M2 phenotype. EPO and its derivatives can directly affect the polarization of macrophages and tend to shift macrophages toward the M2 phenotype to exert anti-inflammatory function and promote tissue healing (Fig. (Fig.1).1).
Our group found that EPO ameliorated acute kidney injury by reducing macrophage infiltration and promoting M2 phenotype polarization in vivo25. CD206+ M2 macrophages and mRNA of M2 markers, including arginase-1, Ym-1, Fizz-1 and CD206, were significantly increased in the EPO-treated group.
In vitro, although EPO suppressed proinflammatory cytokines secreted by M1 macrophages, EPO promoted M2 polarization only in the presence of IL-4. The EPO signaling pathway collaborated with the downstream pathway of IL-4 to promote M2 polarization; a possible mechanism may be through the Jak2/STAT3/STAT6 pathway25.
Efferocytosis is a process by which dead cells are cleared without eliciting unwanted immune responses31. Macrophages are the main phagocytic cells, but their regulation is poorly understood. Recently, EPO signaling has been reported to facilitate macrophages to clear apoptotic cells and cell debris, thus promoting immune tolerance (Fig. (Fig.1).
In self-limited peritoneal inflammation mice, EPO concentration in peritoneal fluid appeared bimodal, corresponding with the infiltration of neutrophils and macrophages accompanied with hypoxia caused by respiratory burst32. In contrast, the lack of detectable EPO in situ or the macrophage-specific EPOR knockout mice yielded chronic inflammation32.
Meanwhile, apoptotic cells released the “find me” signal sphingosine 1-phosphate (S1P), which specifically binds to S1P receptor 1 (S1PR1) and enhances the expressions of HIF-1α and EPO in macrophages. EPO further induced EPOR and activated the EPOR-Jak2-ERK-C/EBPβ-peroxisome proliferator-activated receptor-γ (PPARγ) signal, increased the expression of Mfge8, Mertk, Cd36 and Gas6, and promoted apoptotic cell clearance33.
Through effective efferocytosis, apoptotic cells can be rapidly eliminated thereby preventing a triggering of the immune system. In this way, efferocytosis promotes immune tolerance and tissue restoration (Fig. (Fig.11).
Dendritic cells (DCs) play a central role in antigen presentation and initiating adaptive immunity. In response to different stimuli, DCs show great plasticity and maintain homeostasis between protective immunity and tolerance34. EPOR is expressed on DCs, suggesting they are EPO targets35–37. Our group demonstrated that CHBP could ameliorate acute rejection (AR) in a rat kidney transplantation model via inhibition of DC maturation38.
Rats treated with CHBP showed lower levels of IL-1β and IFN-γ but higher levels of IL-4 and IL-10 in serum and in renal allografts. The expression of major histocompatibility complex class II (MHC-II) or CD86, which are markers for mature DCs, decreased on DCs in renal allografts treated with CHBP.
An in vitro study of bone marrow-derived DCs showed similar results, and the function of CHBP-treated DCs to induce the T-cell proliferation was significantly inhibited. The possible mechanism was the activation of Jak2/STAT3/suppressor of cytokine signaling 1 (SOCS1) pathway, where SOCS1 inhibited the TLR2/4 signaling pathway (Fig. (Fig.2)38.
In experimental cerebral malaria mice, the analysis of DCs from the spleen showed that recombinant human EPO (rhEPO) inhibited the maturation and activation of DCs with decreasing levels of MHC-II, CD86, TLR4 and TLR9 (Fig. (Fig.2)39. However, the specific mechanism requires further exploration.
In contrast, researchers have also found that EPO could promote the maturation of DCs and enhance their immunostimulatory ability35–37. EPO was reported to enhance antigen uptake and promote the maturation of immature monocyte-derived DCs (MoDCs). In addition, EPO treatment upregulated the expressions of MHC-II, CD80, and CD86 on immature DCs; this effect was absent on mature DCs in the spleen37.
Such effects may be associated with the activation of Akt, MAPK, and NF-κB and Tyr-phosphorylation in the STAT3 signaling pathway36. However, these results were observed from in vitro studies or mice without disease model, and EPO concentrations and in vitro stimulation schedules varied. These contradictory EPO effects on DCs require additional study.
Mast cells protect against parasitic infection and anaphylactic reaction via releasing secretory granules and activating type 2 immune responses40. Recently, mast cells have been shown to express EPOR, but they have quite different characteristics. Mast cells highly express intracellular EPOR; however, on cell surface, the basal EPOR expression is low and only a small proportion (~20%) of mast cells express EPOR at high levels41.
One possible reason may be the inefficiency of the transport system41, and another may be the specific structure of the intracellular EPOR42. The intracellular EPOR of mast cells is soluble and located in the secretory granules, being incomplete with a 43 kDa extracellular domain and lacking the intracellular domain compared with the typical EPOR42.
Interestingly, neither the typical EPOR signaling pathway nor the TPR is activated in mast cells; instead, the mast cell marker CD117, or c-kit, is involved in EPOR signaling41. In vitro, EPO decreases mast cell secretions of IL-6 and TNF-α after stimulation by LPS through the activation of the EPOR/c-kit complex41. Another study showed that the administration of EPO regulated mast cells activities and ameliorated injury caused by overactive immune responses triggered by mast cells43.
However, many questions remain. Cellular trafficking mechanisms of soluble EPOR in secretory granules, soluble EPOR functions, downstream EPOR/c-kit pathways and EPO crosstalk with other immune cells require further study.
Adaptive immune system
Previously, it was believed that lymphocytes did not express EPOR; consequently, EPO was considered to have no direct effect on lymphocytes44. However, recent findings challenged this concept45. rhEPO is routinely used to correct anemia in hemodialysis (HD) patients. As such, Lisowska et al. performed a study to explore the effects of rhEPO on CD4+ lymphocytes from HD patients and found that rhEPO normalized the proliferative ability and activation markers of CD4+ lymphocytes, including CD28 and CD6946.
Similar results were obtained in the myelodysplastic syndromes (MDS) patients whose immune system was impaired47. Through quantitative flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR), researchers confirmed the existence of EPOR on human T and B lymphocytes23. Interestingly, they found that CD4+ lymphocytes from HD patients treated with rhEPO expressed higher levels of EPOR than those without rhEPO treatment23.
However, the in vitro study showed the opposite observation, wherein peripheral lymphocytes and monocytes preincubated with rhEPO had decreased EPOR expression23. The discrepancy might be caused by the complex internal environment of HD patients, whose immune system was already impaired48. Nevertheless, these findings confirmed the fact that T lymphocytes could express EPOR and thus they could be the targets of EPO.
Very recently, a series of studies revealed that EPO had an immunoregulatory effect by acting on T cells49–51. EPO directly inhibited the proliferation of conventional T cells (Tconvs) in a dose-dependent manner without inducing apoptosis and conversely facilitated Treg proliferation49,50.
The mechanism lay in the crosstalk between EPO signaling and the proliferative signaling of T cells. After IL-2/IL-2R ligation, the proliferation of Tconvs was mainly mediated by IL-2Rβ/Akt signaling, whereas in Tregs, pAkt was maintained at a low level and proliferation was mainly mediated by IL-2Rγ/STAT5 signaling.
EPO induced the protein tyrosine phosphatase SHP-1, which uncoupled the IL-2Rβ/Akt signaling in Tconvs but had minimal impact in Tregs. In contrast, EPO enhanced IL-2Rγ/STAT5 signaling in Tregs and promoted their proliferation and stability (Fig. (Fig.33)49,50. Notably, this inhibitory effect of EPO was not mediated by the TPR, because ARA290, the nonerythropoietic derivative of EPO, did not show similar effects49.
Studies have also shown that EPO and its derivatives directly modulated T-cell differentiation. Under Th1 polarizing conditions, EPO diminished Th1 polarization but did not alter Th2 polarization or induce Tregs49. However, an in vivo study of experimental autoimmune neuritis (EAN) rats showed that the administration of ARA290 promoted the development of Th2 and Treg subsets but suppressed Th1 and Th17 subsets52,53.
An analysis of draining lymph nodes revealed that after the ARA290 intervention, the master transcription factors of the Th2 and Treg subsets, GATA3 and Foxp3, respectively increased, whereas RORγt, the transcription factor of the Th17 subset, decreased52,54. The possible EPO mechanism that inhibited Th17 induction may be through the p38/SGK1-dependent pathway, which was confirmed in Th17-dependent autoimmune kidney disease models51.
In summary, T cells, especially activated T cells, express EPOR and are directly regulated by EPO. After ligation to EPOR or TPR, EPO and its derivatives exert direct immunoregulatory effects on T cells by modulating the function and differentiation of T cells.
Erythropoiesis, bone marrow microenvironments and B-lymphopoiesis are intimately associated with EPO signaling. Along with promoting erythrocyte proliferation, EPO induces a loss of trabecular bone volume to induce hematopoiesis and reduce the number of vessels in bone marrow55.
At the same time, B cell development is impaired by EPO treatment due to significant reductions in pro-B and pre-B cells55. In humans, the short-term administration of rhEPO has shown significant decreases in B cells, mainly naïve B cells and IgD−CD27− B cells in peripheral blood56.
The suppressive effect of EPO on B cells may be related to changes in the bone marrow microenvironment or the direct ligation to EPOR on B cells23. However, the specific mechanism remains unknown.
The EPOR and TPR signalings connect innate and adaptive immune systems
The activation and differentiation of T cells require the stimulation of antigen-presenting cells (APCs), which provide MHC-peptide complex with costimulatory molecules. The effects of EPO on APCs have been discussed above, and the EPO modulated APCs can further influence the adaptive immune system.
Through binding TPR, EPO stimulated APCs, including monocytes, macrophages and kidney tubular cells, to express TGF-β, which converted naïve CD4+ T cells into functional Foxp3+Tregs (Fig. (Fig.33)50,57.
In a controlled prospective cohort study, EPO administration was confirmed to augment peripheral CD4+CD25+CD127lo Tregs in chronic kidney disease patients50. Similarly, EPO promoted T-cell suppression in a peritoneal cavity cell culture model which simulated a high myeloid to lymphoid cell ratio in the tumor microenvironment, but EPO showed no effects on spleen cells with normal myeloid to lymphoid cell ratios58.
The mechanism was through the induction of iNOS from macrophages, which caused a disturbance in arginine catabolism58. These observed EPO effect discrepancies on Th2 polarization between in vivo and in vitro studies (which have been discussed above) may be attributed to the involvement of APCs.
EPO derivatives, a promising tool of immune regulation
From erythropoiesis to immune regulation and from native EPO to nonerythropoietic derivatives, the understanding of EPO and its derivatives has been widely expanded. Generally, EPO signaling suppresses the activation of the immune system, shifts the inflammatory response to immune tolerance, protects injured tissues from apoptosis, and promotes wound healing.
These effects make EPO a promising target in autoimmune diseases, allergy, IRI, and organ transplantation. Because (EPOR)2 and TPR are expressed on a variety of immune cells, the direct effects of EPO and its derivatives on the differentiation and function of immune cells require further study.
Notably, the development of nonerythropoietic derivatives of EPO, which eliminates the side effects of EPO, removes concerns for their application. Among them, the small peptides, including HBSP and CHBP, which mimic the three-dimensional structure of helix B, show great potential for translation to clinical drugs.
A number of ongoing clinical trials on HBSP show promise (summarized in Table Table11)101–104. HBSP has been granted Orphan Drug Designation for the treatment of sarcoidosis and the prevention of graft loss in pancreatic islet transplantation in the United States and the European Union.
These peptides contain only 11 amino acids and do not undergo complicated modification, leading to lower production costs and complexity compared with traditional protein-based biopharmaceuticals. Like other star peptide drugs, such as VictozaTM from Novo Nordisk and SandostatinTM from Novartis, these small peptide EPO derivatives show good specificity, efficacy and tolerability without immunogenicity105.
Our contribution to prolonging the half-life of HBSP via thioether-cyclization, namely, CHBP, further improves the chemical and physical stability. The significant increase in half-life is more in line with clinical drug requirements with better cost effectiveness.
Furthermore, innovation in alternative administration routes, such as oral preparation, with advances in drug delivery technology may provide better prospects for clinical translation and application for these biologically active peptides.
Registered clinic trials of HBSP (ClinicalTrial and ICTRP, updated July 2019).
|Registered no.||Start date||Status||Study contents||Conditions||Study design||Study population||Phase||Locations||Publication|
|EUCTR2010-018584-41-NL||July 2010||Unknown||ARA290 as therapeutic strategy in no-option critical limb ischemia patients||Critical limb ischemia||Double-blind RCT||n = 8||2||Netherlands||Not available|
|EUCTR2010-021518-45-NL||July 2010||Unknown||Effectiveness of ARA290 in the treatment of pain in neuropathic pain patients||Neuropathic pain||Double-blind RCT||Not available||Not available||Netherlands||Not available|
|EUCTR2010-023469-22-NL||March 2011||Unknown||ARA 290 as therapeutic strategy in rheumatoid arthritis||Rheumatoid arthritis||Non-RCT||n = 12||2||Netherlands||Not available|
|EUCTR2010-024364-18-NL||April 2011||Unknown||Effects of ARA290 on the cognitive and neural processing of emotions in healthy volunteers||Emotional information processing||Double-blind RCT||Not available||Not available||Netherlands||Not available|
|NTR3081||October 2011||Completed||Effectiveness of ARA290 on pain relief in sarcoidosis patients with small-fiber neuropathy||SarcoidosisSmall fiber neuropathy||Double-blind RCT||n = 24||Not available||Netherlands||Heij et al. |
|NTR3131||October 2011||Recruiting||ARA290 and the ventilatory response to hypoxia and pain responses in healthy volunteers||Hypoxia;Hypoxic pulmonary vasoconstriction;Hypoxic ventilatory response||Crossover||n = 16||Not available||Netherlands||Not available|
|NCT02070783||February 2012||Completed||Effects of ARA290 on the cognitive and neural processing of emotions in healthy volunteers||Depression||Double-blind RCT||n = 36||1 and 2||Netherlands||Cerit et al. |
|NTR3575||July 2012||Completed||Effects of ARA 290 on the regrowth of epidermal nerve fibers in patients with sarcoidosis||Sarcoidosis small fiber;Neuropathy pain||Double-blind RCT||n = 40||Not available||Netherlands||Dahan et al. |
|EUCTR2012-003688-24-NL||December 2012||Unknown||Safety and effects of ARA 290 on pain relief in chronic pain from complex regional pain syndrome type 1||Complex regional pain syndrome||Double-blind RCT||Not available||Not available||Netherlands||Not available|
|NCT01933529||October 2013||Unknown||Effects of ARA290 on prediabetes and type 2 diabetes||Type 2 diabetes;Impaired glucose tolerance;Impaired fasting glucose||Double-blind RCT||n = 24||2||Sweden||Not available|
|NCT02039687||January 2014||Completed||Effects of ARA290 on corneal nerve fiber density and neuropathic symptoms of subjects with sarcoidosis||Neuropathy of Sarcoidosis||Double-blind RCT||n = 64||2||United States;Netherlands||Culver et al. |
HBSP helix B surface peptide, ICTRP International Clinical Trials Registry Platform, RCT randomized controlled trials.
Max Planck Institute