title: Pterocarpanquinone LQB-118 induces apoptosis in Leishmania (Viannia) braziliensis and controls lesions in infected hamsters.
abstract: Previous results demonstrate that the hybrid synthetic pterocarpanquinone LQB-118 presents antileishmanial activity against Leishmania amazonensis in a mouse model. The aim of the present study was to use a hamster model to investigate whether LQB-118 presents antileishmanial activity against Leishmania (Viannia) braziliensis, which is the major Leishmania species related to American tegumentary leishmaniasis. The in vitro antileishmanial activity of LQB-118 on L. braziliensis was tested on the promastigote and intracellular amastigote forms. The cell death induced by LQB-118 in the L. braziliensis promastigotes was analyzed using an annexin V-FITC/PI kit, the oxidative stress was evaluated by 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) and the ATP content by luminescence. In situ labeling of DNA fragments by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis in the intracellular amastigotes. L. braziliensis-infected hamsters were treated from the seventh day of infection with LQB-118 administered intralesionally (26 µg/kg/day, three times a week) or orally (4,3 mg/kg/day, five times a week) for eight weeks. LQB-118 was active against the L. braziliensis promastigotes and intracellular amastigotes, producing IC50 (50% inhibitory concentration) values of 3,4±0,1 and 7,5±0,8 µM, respectively. LQB-118 induced promastigote phosphatidylserine externalization accompanied by increased reactive oxygen species production and ATP depletion. Intracellular amastigote DNA fragmentation was also observed, without affecting the viability of macrophages. The treatment of L. braziliensis-infected hamsters with LQB-118, either orally or intralesionally, was effective in the control of lesion size, parasite load and increase intradermal reaction to parasite antigen. Taken together, these results show that the antileishmanial effect of LQB-118 extends to L. braziliensis in the hamster model, involves the induction of parasite apoptosis and shows promising therapeutic option by oral or local routes in leishmaniasis.
authors.affiliation: Laboratório de Imunofarmacologia Parasitária, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Costa
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Roberta O
authors.initials: RO
authors.lastname: Pinheiro
authors.affiliation: Laboratório de Bioquímica de Protozoários e Imunofisiologia do Exercício, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Patrícia M L
authors.initials: PM
authors.lastname: Dutra
authors.affiliation: Laboratório de Imunofarmacologia Parasitária, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Rosiane F
authors.initials: RF
authors.lastname: Santos
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Edézio F
authors.initials: EF
authors.lastname: Cunha-Júnior
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Torres-Santos
authors.affiliation: Laboratório de Catálise Orgânica, Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alcides J M
authors.initials: AJ
authors.lastname: da Silva
authors.affiliation: Laboratório de Química Bioorgânica - Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Paulo R R
authors.initials: PR
authors.lastname: Costa
authors.affiliation: Laboratório de Imunofarmacologia Parasitária, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Silvia A G
authors.initials: SA
authors.lastname: Da-Silva
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006224:Cricetinae; D005260:Female; D007892:Leishmania braziliensis / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008647:Mesocricetus; D009285:Naphthoquinones / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D036343:Pterocarpans / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; C569361:LQB 118; D009285:Naphthoquinones; D010718:Phosphatidylserines; D036343:Pterocarpans