title: Melatonin attenuates Leishmania (L.) amazonensis infection by modulating arginine metabolism.
abstract: Acute inflammatory responses induced by bacteria or fungi block nocturnal melatonin synthesis by rodent pineal glands. Here, we show Leishmania infection does not impair daily melatonin rhythm in hamsters. Remarkably, the attenuated parasite burden and lesion progression in hamsters infected at nighttime was impaired by blockage of melatonin receptors with luzindole, whereas melatonin treatment during the light phase attenuated Leishmania infection. In vitro studies corroborated in vivo observations. Melatonin treatment reduced macrophage expression of Cat-2b, Cat1, and ArgI, genes involved in arginine uptake and polyamine synthesis. Indeed, melatonin reduced macrophage arginine uptake by 40%. Putrescine supplementation reverted the attenuation of infectivity by melatonin indicating that its effect was due to the arrest of parasite replication. This study shows that the Leishmania/host interaction varies in a circadian manner according to nocturnal melatonin pineal synthesis. Our results provide new data regarding Leishmania infectiveness and show new approaches for applying agonists of melatonin receptors in Leishmaniasis therapy.
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Laranjeira-Silva
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Zampieri
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Muxel
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Lucile Maria
authors.initials: LM
authors.lastname: Floeter-Winter
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Regina P
authors.initials: RP
authors.lastname: Markus
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D007891:Leishmania / Q000187:drug effects* / Q000472:pathogenicity; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism
chemical_list: D026923:Amino Acid Transport Systems, Basic; D011073:Polyamines; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase; D008550:Melatonin
keywords: arginase; cationic amino acid transporter; macrophage; nitric oxide synthase; polyamines