Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Cutrullis, Romina Andrea; Poklépovich, Tomás Javier; Postan, Miriam; Freilij, Héctor; Petray, Patricia

doi:10.1016/j.intimp.2011.02.022

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…[44] Others have shown that administration of ganglioside GM1 reduced arrhythmias in patients with Chagas disease [45] and fibrosis in T. cruzi –infected mice. [46] The antifibrotic effect was associated with a significant reduction in myocardial expression of TGF-β and in IFN-γ, TNF-α and CCL5/RANTES, all proinflammatory cytokines and chemokines. Thus, treatment with ganglioside GM1 may offer a potential therapy for modulating myocardial damage in chronic Chagas disease.…”

Section: Inflammation Oxidative Stress and Fibrosismentioning

confidence: 99%

Developments in the management of Chagas cardiomyopathy

Tanowitz

Machado

Spray

et al. 2015

Expert Review of Cardiovascular Therapy

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Over 100 years have elapsed since the discovery of Chagas disease and there is still much to learn regarding pathogenesis and treatment. Although there are antiparasitic drugs available, such as benznidazole and nifurtimox, they are not totally reliable and often toxic. A recently released negative clinical trial with benznidazole in patients with chronic Chagas cardiomyopathy further reinforces the concerns regarding its effectiveness. New drugs and new delivery systems, including those based on nanotechnology, are being sought. Although vaccine development is still in its infancy, the reality of a therapeutic vaccine remains a challenge. New ECG methods may help to recognize patients prone to developing malignant ventricular arrhythmias. The management of heart failure, stroke and arrhythmias also remains a challenge. Although animal experiments have suggested that stem cell based therapy may be therapeutic in the management of heart failure in Chagas cardiomyopathy, clinical trials have not been promising.

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Section: Inflammation Oxidative Stress and Fibrosismentioning

confidence: 99%

Developments in the management of Chagas cardiomyopathy

Tanowitz

Machado

Spray

et al. 2015

Expert Review of Cardiovascular Therapy

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“…The IFN-γ production was high in the acute phase and decreased in the chronic stage (Figure 8A,B). At the chronic stage, there is a significant amount of CD8 + T cells producing IFN-γ 45 and perforin, 46 which are responsible for the maintenance of cytokine levels, 46,47 while secreted perforin leads to late lesions in muscle fibers and cardiac alterations. 46 Our results point out that the amount of IFN-γ released at the early phase of infection was in contrast to the amount of IFN-γ induced by Bz.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Organometallic Gold(III) Complex [Au(Hdamp)(L1⁴)]⁺ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease

et al. 2019

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Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs against Trypanosoma cruzi, we evaluated both the in vitro and in vivo activity of the organometallic gold(III) complex [Au(III)(Hdamp)(L14)]Cl (L1 = SNS-donating thiosemicarbazone), henceforth denoted 4-Cl. Our results demonstrated that 4-Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In in vivo assays, 4-Cl in PBS solution loses the protonation and becomes the 4-neutral. 4-Neutral reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage at 2.8 mg/kg/day. All these changes resulted in the survival of 100% of the mice treated with the gold complex during the acute phase. Analyzing the surviving animals of the acute infection, the parasite load after 150 days of infection was equivalent to those treated with the standard dose of Bz without demonstrating the hepatotoxicity of the latter. In addition, we identified a modulation of interferon gamma (IFN-γ) levels that may be targeting the disease’s positive outcome. To the best of our knowledge, this is the first gold organometallic study that shows promise in an in vivo experimental model against Chagas disease.

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“…6B). At this late stage, there is a significant amount of CD8 T cells producing IFN-γ (43) and perforin (44), which are responsible for the maintenance of high levels of this cytokine (44, 45), while secreted perforin leads to late lesions in muscle fibres and cardiac alterations (44). Although treatment with Bz reduces the parasitic burden and, consequently, the inflammatory infiltrate, the action of Bz remains still dependent of the amount of IFN-γ produced.…”

Section: Discussionmentioning

confidence: 99%

Organometallic gold(III) [Au(Hdamp)(L1⁴)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection

Lopes

Gaspari

Oliveira

et al. 2018

Preprint

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Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs against Trypanosoma cruzi, we evaluated both the in vitro and in vivo activity of the organometallic gold(III) complex [Au(Hdamp)(L14)]Cl (L1 = SNS- donating thiosemicarbazone), which was denoted 4-Cl. Our results demonstrated that 4- Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and the intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In very-low-dose in vivo assays, 4-Cl reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage. All these changes resulted in the survival of 100% of the mice treated with 4-Cl during the acute phase. We hypothesised that 4-Cl can act directly on the parasite and may participate in the modulation of IFN-γ production at the acute stage of the disease. Molecular docking simulations showed that the compound may interact with cruzain, a thiol protease considered a possible antiparasitic drug target, primarily by hydrophobic interactions. These analyses predicted that the Cys25 residue in the cruzain binding site is approximately 3.0 Å away from the S and Au atoms of the gold compound, which could suggest formation of a possible covalent bond between cruzain and the inhibitor. Overall, we confirmed the potential of 4-Cl as a new candidate for Chagas disease treatment.

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Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Cited by 11 publications

References 38 publications

Developments in the management of Chagas cardiomyopathy

Developments in the management of Chagas cardiomyopathy

Organometallic Gold(III) Complex [Au(Hdamp)(L1⁴)]⁺ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease

Organometallic gold(III) [Au(Hdamp)(L1⁴)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection

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Immunomodulatory and anti-fibrotic effects of ganglioside therapy on the cardiac chronic form of experimental Trypanosoma cruzi infection

Cited by 11 publications

References 38 publications

Developments in the management of Chagas cardiomyopathy

Developments in the management of Chagas cardiomyopathy

Organometallic Gold(III) Complex [Au(Hdamp)(L14)]+ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease

Organometallic gold(III) [Au(Hdamp)(L14)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection

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Product

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Organometallic Gold(III) Complex [Au(Hdamp)(L1⁴)]⁺ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease

Organometallic gold(III) [Au(Hdamp)(L1⁴)]Cl (L1 =SNS-donating thiosemicarbazone) complex protects mice against acuteT. cruziinfection