Targeting liver stage malaria with metformin
| Autor: | Liliana Mancio-Silva, Sangeeta N. Bhatia, Leonardo F. Lemos Rocha, Iset Medina Vera, Maria M. Mota, Margarida T. Grilo Ruivo, Sofia Marques |
|---|---|
| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Plasmodium berghei Drug Evaluation Preclinical activated protein-kinase Primaquine Pharmacology Parasite Load ampk Mice 0302 clinical medicine Parasitic Sensitivity Tests Cells Cultured media_common Infectious disease biology heme oxygenase-1 drug General Medicine Metformin inhibition 3. Good health Mefloquine Liver 030220 oncology & carcinogenesis Drug Therapy Combination hepatocytes Drug therapy pharmacokinetics Research Article medicine.drug Drug media_common.quotation_subject Plasmodium falciparum Primary Cell Culture Microbiology Antimalarials Inhibitory Concentration 50 03 medical and health sciences Pharmacotherapy parasitic diseases medicine Animals Humans cancer business.industry Drug Repositioning biology.organism_classification medicine.disease Malaria Disease Models Animal Regimen gluconeogenesis 030104 developmental biology Infectious disease (medical specialty) Parasitology plasmodium-falciparum business |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 2379-3708 |
| Popis: | Copyright: © 2019, American Society for Clinical Investigation Despite an unprecedented 2 decades of success, the combat against malaria - the mosquito-transmitted disease caused by Plasmodium parasites - is no longer progressing. Efforts toward eradication are threatened by the lack of an effective vaccine and a rise in antiparasite drug resistance. Alternative approaches are urgently needed. Repurposing of available, approved drugs with distinct modes of action are being considered as viable and immediate adjuncts to standard antimicrobial treatment. Such strategies may be well suited to the obligatory and clinically silent first phase of Plasmodium infection, where massive parasite replication occurs within hepatocytes in the liver. Here, we report that the widely used antidiabetic drug, metformin, impairs parasite liver stage development of both rodent-infecting Plasmodium berghei and human-infecting P. falciparum parasites. Prophylactic treatment with metformin curtails parasite intracellular growth in vitro. An additional effect was observed in mice with a decrease in the numbers of infected hepatocytes. Moreover, metformin provided in combination with conventional liver- or blood-acting antimalarial drugs further reduced the total burden of P. berghei infection and substantially lessened disease severity in mice. Together, our findings indicate that repurposing of metformin in a prophylactic regimen could be considered for malaria chemoprevention. This work was supported by Fundação para a Ciência e Tecnologia (Portugal) PTDC/SAU-MET/118199/2010 to LMS and European Research Council Proof of Concept Grant to MMM (ERC-2015-PoC-DL3–713691-REUSE4MALARIA). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|