Benznidazole blocks NF-κB activation but not AP-1 through inhibition of IKK

Manarin, Romina; Pascutti, María Fernanda; Ruffino, Juan Pablo; Heras, Beatriz de las; Revelli, Silvia; Serra, Esteban

doi:10.1016/j.molimm.2010.06.002

Cited by 23 publications

(24 citation statements)

References 30 publications

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“…Acting as an antiparasitic drug, Bz also has anti-inflammatory properties, which have been supported by previous studies (25)(26)(27). Similarly to nonsteroidal anti-inflammatory drugs (NSAIDs), BZ exerts its immunomodulatory effects by inhibiting NF-B (a key regulator of the inflammatory response), more specifically, downregulating the proinflammatory activity of macrophages (25,26).…”

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

“…Similarly to nonsteroidal anti-inflammatory drugs (NSAIDs), BZ exerts its immunomodulatory effects by inhibiting NF-B (a key regulator of the inflammatory response), more specifically, downregulating the proinflammatory activity of macrophages (25,26). Immunomodulatory effects of BZ were also evidenced by its ability to increase survival and decrease serum levels of IL-6 and TNF-␣ in C57BL/6 mice treated with lipopolysaccharide (LPS) (25,27). Apparently, this BZ effect is not restricted to LPS-mediated macrophage activation, and it is also observed when other stimuli are employed, such as proinflammatory cytokines (IL-1, TNF-␣) and H 2 O 2 , a nonradical molecule involved in reactive tissue damage (25).…”

Section: Discussionmentioning

confidence: 99%

“…Immunomodulatory effects of BZ were also evidenced by its ability to increase survival and decrease serum levels of IL-6 and TNF-␣ in C57BL/6 mice treated with lipopolysaccharide (LPS) (25,27). Apparently, this BZ effect is not restricted to LPS-mediated macrophage activation, and it is also observed when other stimuli are employed, such as proinflammatory cytokines (IL-1, TNF-␣) and H 2 O 2 , a nonradical molecule involved in reactive tissue damage (25).…”

Section: Discussionmentioning

confidence: 99%

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Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Santos

Novaes

Cupertino

et al. 2015

Antimicrob Agents Chemother

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cAlthough suramin (Sur) is suggested as a potential drug candidate in the management of Chagas disease, this issue has not been objectively tested. In this study, we examined the applicability of concomitant treatment with benznidazole (Bz) and suramin in mice infected with a virulent strain of Trypanosoma cruzi. Eighty 12-week-old male C57BL/6 mice were equally randomized in eight groups: (i) noninfected mice (negative control) and mice infected with T. cruzi Y strain receiving (ii) no treatment (positive control), (iii) Bz, 100 mg/kg of body weight per day, (iv) Sur, 20 mg/kg/day, and (v to viii) Sur, 20 mg/kg/day, combined with Bz, 100, 50, 25, or 5 mg/kg/day. Bz was administered by gavage, and Sur was administered intraperitoneally. Sur dramatically increased the parasitemia, cardiac content of parasite DNA, inflammation, oxidative tissue damage, and mortality. In response to high parasitic load in cardiac tissue, Sur stimulated the immune system in a manner typical of the acute phase of Chagas disease, increasing tissue levels of gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) and inducing a preferential IgG2a anti-T. cruzi serum pattern. When Sur and Bz were combined, the infection severity was attenuated, showing a dose-dependent Bz response. Sur therapy had a more harmful effect on the host than on the parasite and reduced the efficacy of Bz against T. cruzi infection. Considering that Sur drastically reinforced the infection evolution, potentiating the inflammatory process and the severity of cardiac lesions, the in vivo findings contradicted the in vitro anti-T. cruzi potential described for this drug.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Santos

Novaes

Cupertino

et al. 2015

Antimicrob Agents Chemother

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“…Thus, a relevant question in BZ toxicity is the direct NO production during the metabolism of this drug [3,32]. Although BZ inhibits gene transcription and inducible nitric oxide synthase (iNOS) expression,[34–36] there is evidence that BZ triggers NO synthesis independently of the conventional enzymatic mechanisms associated with NO synthase [1,3]. Hall and Wilkinson[5] described that nitroheterocyclic compounds such as BZ act as prodrugs and must undergo activation, specifically through reduction of the nitro group by nitroreductase enzymes, to mediate their toxic effects responsible for oxidative and nitrosative tissue damages [1].…”

Section: Discussionmentioning

confidence: 99%

Modulation of oxidative and inflammatory cardiac response by nonselective 1- and 2-cyclooxygenase inhibitor and benznidazole in mice

Santos

Novaes

Bastos

et al. 2015

Journal of Pharmacy and Pharmacology

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BZ triggers an oxidative and nitrosative route, which is associated with increased prostaglandin synthesis and marked damages to the lipids and proteins of the cardiac tissue. IB treatment attenuated reactive stresses triggered by BZ, which was an independent effects of this drug on the endogenous antioxidant enzymes. Individually, but not together, BZ and IB reduced the cardiac inflammatory status, indicating a beneficial and complex drug interaction.

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Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection

Manarin¹,

Villar²,

Bussy³

et al. 2013

Med Microbiol Immunol

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Leptin and glucocorticoids (GCs) are involved in metabolic functions, thymic homeostasis and immune activity through complex interactions. We recently showed that C57BL/6 mice infected with Trypanosoma cruzi revealed a fatal disease associated with a dysregulated immune-endocrine response characterized by weight loss, deleterious synthesis of pro-inflammatory cytokines and GCs-driven thymus atrophy. Extending this study, we now explored the relationship between leptin and GCs, in terms of infection outcome, thymic and metabolic changes. T. cruzi-infected mice showed a food intake reduction, together with hypoglycemia and lipolysis-related changes. Infected animals also displayed a reduction in systemic and adipose tissue levels of leptin, paralleled by a down-regulation of their receptor (ObR) in the hypothalamus. Studies in infected mice subjected to adrenalectomy (Adx) showed a worsened course of infection accompanied by even more diminished systemic and intrathymic leptin levels, for which GCs are necessary not only to decrease inflammation but also to sustain leptin secretion. Adx also protected from thymic atrophy, independently of the reduced leptin contents. Leptin administration to infected mice aggravated inflammation, lowered parasite burden and attenuated GCs release, but did not normalize thymic atrophy or metabolic parameters. Acute T. cruzi infection in C57BL/6 mice coexists with a dysregulation of leptin/hypothalamic ObR circuitry dissociated from body weight and food intake control. Endogenous GCs production attempted to reestablish systemic leptin concentrations, but failed to improve leptin-protective activities at the thymic level, suggesting that the leptin/GCs intrathymic relationship is also altered during this infection.

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Benznidazole blocks NF-κB activation but not AP-1 through inhibition of IKK

Cited by 23 publications

References 30 publications

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Modulation of oxidative and inflammatory cardiac response by nonselective 1- and 2-cyclooxygenase inhibitor and benznidazole in mice

Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection

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