Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

Abstract

Leishmaniasis is an important neglected tropical disease, affecting more than 12 million people worldwide. The available treatments are not well tolerated and present diverse side effects in patients, justifying the search for new therapeutic compounds. In the present study, the therapeutic potential and toxicity of ursolic acid (UA), isolated from the leaves of Baccharis uncinella C. DC. (Asteraceae), were evaluated in experimental visceral leishmaniasis. To evaluate the therapeutic potential of UA, hamsters infected with L. (L.) infantum were treated daily during 15 days with 1.0 or 2.0 mg UA/kg body weight, or with 5.0 mg amphotericin B/kg body weight by intraperitoneal route. Fifteen days after the last dose, the parasitism of the spleen and liver was stimated and the main histopathological alterations were recorded. The proliferation of splenic mononuclear cells was evaluated and IFN-γ, IL-4, and IL-10 gene expressions were analyzed in spleen fragments. The toxicity of UA and amphotericin B were evaluated in healthy golden hamsters by histological analysis and biochemical parameters. Animals treated with UA had less parasites in the spleen and liver when compared with the infected control group, and they also showed preservation of white and red pulps, which correlate with a high rate of proliferation of splenic mononuclear cells, IFN-γ mRNA and iNOS production. Moreover, animals treated with UA did not present alterations in the levels of AST, ALT, creatinine and urea. Taken together, these findings indicate that UA is an interesting natural compound that should be considered for the development of prototype drugs against visceral leishmaniasis.

Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

“…Passero et al demonstrated that the production of cytokines in an in vivo model of L. infantum-infected hamsters was characterized by an increase in the IL-10 levels at all the doses tested of UA and a decrease in the IFN-γ at higher doses [35]. Our in vitro results correlate with those observed by Passero et al In the latter study, it was also remarked that even though the parasite load were reduced by 96%, the complete eradication of the parasites was not achieved, which can be related to an immunoregulator effect of the parasite on the macrophages [36].…”

“…In vitro antileishmanial activity of UA has been previously reported by other authors [35][36][37]. However, this is one of the first works that reports the in vivo leishmanicidal activity of UA against both VL and CL in different states of the disease.…”

“…The same fraction has also exhibited in vivo efficacy in tegumentary leishmaniasis, resulting in a decreased skin parasitism and increased levels of IL-12 and IFN-γ, spreading the Th1 immune response [20]. In addition, the same plant extract was effective in vivo against L. infantum [36]. UA extracted from Petiveria alliaceae showed similar activity against L. amazonensis associated with programmed cell death of parasites and an increase in NO [37].…”

In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative

“…VL is fatal if left untreated and is caused by the intracellular parasitic protists L. donovani or L. infantum (chagasi) [33]. Syrian golden hamsters (Mesocricetus auratus) have been described as a useful model of many human infectious diseases since they exhibit susceptibility to a variety of intracellular pathogens, such as different species of Leishmania, including L. infantum [34][35][36][37][38][39]; besides, this model has been used for the in vivo tests of new antileishmanial compounds [40,41]. The efficiency of compound 14e to eliminate the parasite in L. infantuminfected hamsters was also demonstrated.…”

Synthesis and Antitumor Evaluation in Vitro of NO‐Donating Ursolic Acid‐Benzylidene Derivatives

“…Meanwhile, other studies have clearly confirmed that UA displayed low toxicity. [20,21] Thus, UA is considered as a potential antitumor agent. However, the clinical application of UA is severely restricted due to its poor solubility, rapid metabolism and low bioavailability.…”