Leishmanicidal activity of primary S-nitrosothiols against Leishmania major and Leishmania amazonensis: implications for the treatment of cutaneous leishmaniasis.
Nitric oxide (NO) is considered a key molecule in the defense against intracellular pathogens, particularly Leishmania. The expression of inducible nitric oxide synthase and consequent production of NO by infected macrophages has been shown to correlate with leishmaniasis resistance in the murine model as well as in human patients. Nitric oxide donors have been used successfully in the treatment of cutaneous leishmaniasis in humans, although their mechanisms of action are not fully understood. In the present work, the dose-dependent cytotoxic effects of the NO-donors S-nitroso-N-acetyl-l-cysteine (SNAC) and S-nitrosoglutathione (GSNO) against Leishmania were evaluated. GSNO inhibited the growth of Leishmania major and Leishmania amazonensis with in vitro 50% inhibitory concentrations (IC(50)) of 68.8+/-22.86 and 68.9+/-7.9 micromol L(-1), respectively. The IC(50) for SNAC against L. major and L. amazonensis were, respectively, 54.6+/-8.3 and 181.6+/-12.5 micromol L(-1). The leishmanicidal activity of GSNO, but not of SNAC, was reversed by ascorbic acid (AA) and dithiothreitol (DTT), suggesting that the mechanism of action of GSNO is related to the transnitrosation of parasite proteins. These results demonstrate that SNAC and GSNO have leishmanicidal activity, and are thus potential therapeutic agents against cutaneous leishmaniasis.
de Souza
Gabriela Freitas Pereira
GF
Departamento de Físico-Química, Instituto de Química, Universidade Estadual de Campinas, UNICAMP, Campinas, SP, Brazil.
Yokoyama-Yasunaka
Jenicer K U
JK
Seabra
Amedea Barozzi
AB
Miguel
Danilo Ciccone
DC
de Oliveira
Marcelo Ganzarolli
MG
Uliana
Silvia Reni B
SR
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D018320:Leishmania major / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D026422:S-Nitrosoglutathione / Q000494:pharmacology / Q000627:therapeutic use
D020030:Nitric Oxide Donors; D009569:Nitric Oxide; C024940:S-nitroso-N-acetylcysteine; D026422:S-Nitrosoglutathione; D000111:Acetylcysteine