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Leishmaniasis is a vector-borne neglected tropical disease that affects more than 700,000 people annually. Leishmania parasites cause the disease, and different species trigger a distinct immune response and clinical manifestations. Macrophages are the final host cells for the proliferation of Leishmania parasites, and these cells are the key to a controlled or exacerbated response that culminates in clinical manifestations. M1 and M2 are the two main macrophage phenotypes. M1 is a pro-inflammatory subtype with microbicidal properties, and M2, or alternatively activated, is an anti-inflammatory/regulatory subtype that is related to inflammation resolution and tissue repair. The present review elucidates the roles of M1 and M2 polarization in leishmaniasis and highlights the role of the salivary components of the vector and the action of the parasite in the macrophage plasticity.

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Background and purpose: Many compounds liberating NO (NO donors) have been used as therapeutic agents. Here we test two ruthenium nitrosyls, which release NO when activated by biological reducing agents, for their effects in vitro and in vivo against Trypanasoma cruzi, the agent responsible for the American trypanosomiasis (Chagas' disease). Experimental approach: Ruthenium NO donors were incubated with a partially drug-resistant strain of T. cruzi and the antiproliferative and trypanocidal activities evaluated. In a mouse model of acute Chagas' disease, trypanocidal activity was evaluated by measuring parasitemia, survival rate of infected mice and elimination of amastigotes in myocardial tissue. Key results: In vitro, the observed anti-proliferative and trypanocidal activities of trans-[Ru(NO)(NH 3 ) 4 isn](BF 4 ) 3 and trans-[Ru(NO)(NH 3 ) 4 imN](BF 4 ) 3 were due to NO liberated upon reduction of these nitrosyls. Ru(NO)isn had a lower IC 50epi (67 mM) than the NO donor, sodium nitroprusside (IC 50epi ¼ 244 mM) and Ru(NO)imN (IC 50try ¼ 52 mM) was more potent than gentian violet (IC 50try ¼ 536 mM), currently used in the treatment of blood. Both ruthenium nitrosyls eliminated, in vivo, extracellular as well as intracellular forms of T. cruzi in the bloodstream and myocardial tissue and allowed survival of up to 80% of infected mice at a dose (100 nmol kg À1 day À1 ) much lower than the optimal dose for benznidazole (385 mmol kg À1 day À1 ). Conclusions and implications: Our data strongly suggest that NO liberated is responsible for the anti-proliferative and trypanocidal activities of the ruthenium NO donors and that these compounds are promising leads for novel and effective antiparasitic drugs. (2007) British Journal of Pharmacology