Efficacy and safety of the carbamylated erythropoietin in an animal model of chronic TNBS-induced colitis

This work was supported by the Polytechnic Institute of Lisbon [grant numbers IPL/2020/cEPO_ESTeSL]. As acknowledgments H&TRC authors gratefully acknowledge the FCT/MCTES national support through the UIDB/05608/2020 and UIDP/05608/202.Master’s degree in Pharmacy. - Specialization in Pharmacology and Advanced PharmacotherapyABSTRACT - Introduction: Inflammatory bowel disease is an immune-mediated chronic inflammatory disorder of the gastrointestinal tract. It is characterized by abdominal pain, bloody diarrhea, and an influx of neutrophils and macrophages. The current pharmacological therapies present some concerns and new approaches are required. Erythropoietin is a hormone that promotes the proliferation of erythrocytes. It also has non-erythropoietic effects, such as anti-inflammatory effects. Carbamylated erythropoietin is a modified molecule of erythropoietin with non-hematopoietic effects. Objective: To evaluate the potential anti-inflammatory effect of carbamylated erythropoietin in chronic animal models of rodents in IBD. Materials and Methods: Carbamylated erythropoietin was synthesized then, an experimental model of IBD was induced by the rectal administration of multiple doses of TNBS. To evaluate the effect and safety of cEPO the clinical symptoms, biomarkers, and the percentage of haematocrit were measured. Results: The carbamylation rate was approximately 99%. cEPO treatment presented an anti-inflammatory effect confirmed by the decrease of concentrations of pro-inflammatory cytokine (44.30 ± 4.0 pg/ml, *** p<0.001). The haematocrit was also performed and presented a similar result to the sham group. Conclusion: The cEPO 1000 UI/Kg molecule could have better efficacy and safety in the treatment of chronic TNBS-induced colitis models.RESUMO - Introdução: A doença inflamatória intestinal é uma doença inflamatória crónica imuno-mediada do trato gastrointestinal. Caracteriza-se por dor abdominal, diarreia com sangue e influxo de neutrófilos e macrófagos. As atuais terapêuticas farmacológicas apresentam algumas limitações pelo que, são necessárias novas abordagens. A eritropoietina é uma hormona que promove a proliferação dos eritrócitos. Tem também efeitos não eritropoéticos, tais como o efeito anti-inflamatório. A eritropoietina carbamilada é uma molécula modificada de eritropoietina com efeitos não hematopoiéticos. Objetivo: Avaliar o potencial efeito anti-inflamatório da eritropoietina carbamilada em modelos animais de roedores na doença inflamatória intestinal crónica. Materiais e Métodos: A eritropoietina carbamilada foi sintetizada, depois, foi feita uma administração retal com doses múltiplas de TNBS. Para avaliar o efeito e segurança da eritropoietina carbamilada foram avaliados os sintomas clínicos, biomarcadores e a percentagem de hematócrito. Resultados: A taxa de carbamilação foi de aproximadamente 99%. O tratamento com eritropoietina carbamilada apresentou efeito anti-inflamatório confirmado pela diminuição da concentração de citocinas pró-inflamatórias (44.30 ± 4.0 pg/ml, *** p<0.001). O hematócrito também foi avaliado e apresentou um resultado semelhante ao do grupo controlo. Conclusão: A eritropoietina carbamilada de 1000 UI/Kg poderá ter uma melhor eficácia e segurança no tratamento do modelo de colite crónica induzida por TNBS.N/

Potential anti-inflammatory effect of erythropoietin in non-clinical studies in vivo: a systematic review

Projeto IPL/2020/cEPO_ESTeSLErythropoietin (EPO) is a hypoxia-induced hormone produced in adult kidneys with erythropoietic and non-erythropoietic effects. In vivo studies represent an important role to comprehend the efficacy and safety in the early phase of repurposing drugs. The aim is to evaluate the potential anti-inflammatory effect of EPO observed in animal models of disease. Following PRISMA statements, electronic database Medline via PubMed platform was used to search articles with the research expression ((erythropoietin [MeSH Terms]) AND (inflammation [MeSH Terms]) AND (disease models, animal [MeSH Terms])). The inclusion criteria were original articles, studies where EPO was administered, studies where inflammation was studied and/or evaluated, non-clinical studies in vivo with rodents, and articles published in English. Thirty-six articles met the criteria for qualitative analysis. Exogenous EPO was used in models of sepsis, traumatic brain injury, and autoimmune neuritis, with an average of 3000 IU/Kg for single and multiple doses, using mice and rats. Biomarkers such as immune-related effectors, cytokines, reactive oxygen species, prostaglandins, and other biomarkers were assessed. EPO has been recognized as a multifunctional cytokine with anti-inflammatory properties, showing its significant effect both in acute and chronic models of inflammation. Further non-clinical studies are suggested for the enlightenment of anti-inflammatory mechanisms of EPO in lower doses, allowing us to understand the translational data for humans.info:eu-repo/semantics/publishedVersio

Effect of Carbamylated Erythropoietin in a Chronic Model of TNBS-Induced Colitis

Background: Inflammatory bowel disease (IBD) is a public health issue with a growing prevalence, which can be divided into two phenotypes, namely Crohn’s disease (CD) and ulcerative colitis (UC). Currently, used therapy is based only on symptomatic and/or palliative pharmacological approaches. These treatments seek to induce and maintain remission of the disease and ameliorate its secondary effects; however, they do not modify or reverse the underlying pathogenic mechanism. Therefore, it is essential to investigate new potential treatments. Carbamylated erythropoietin (cEPO) results from the modification of the Erythropoietin (EPO) molecule, reducing cardiovascular-related side effects from the natural erythropoiesis stimulation. cEPO has been studied throughout several animal models, which demonstrated an anti-inflammatory effect by decreasing the production of several pro-inflammatory cytokines. Aim: This study aimed to evaluate the efficacy and safety of cEPO in a chronic TNBS-induced colitis model in rodents. Methods: Experimental colitis was induced by weekly intrarectal (IR) administrations of 1% TNBS for 5 weeks in female CD-1 mice. Then, the mice were treated with 500 IU/kg/day or 1000 IU/kg/day of cEPO through intraperitoneal injections for 14 days. Results: cEPO significantly reduced the concentration of alkaline phosphatase (ALP), fecal hemoglobin, tumor necrosis factor (TNF)-α, and interleukin (IL)-10. Also, it demonstrated a beneficial influence on the extra-intestinal manifestations, with the absence of significant side effects of its use. Conclusion: Considering the positive results from cEPO in this experiment, it may arise as a new possible pharmacological approach for the future management of IBD