Implication of purinergic signaling pathways in clinical management of Chagas' disease

Santos, EC; Novaes, RD; Cardoso, SA; Oliveira, LL

doi:10.13172/2052-0069-2-3-1104

Cited by 4 publications

(5 citation statements)

References 20 publications

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“…It is believed that this increased activity is related to the enzymatic modulation in the presence of high grade stimulation by T. cruzi during CD infection, leading to a high release of ATP by cells. Once into extracellular medium, ATP acts to mediate events such as stimulate astrocyte proliferation and differentiation, cytokine release, and the formation of reactive nitrogen and oxygen species [24]. These events triggered by extracellular ATP as a danger signal can protect the host from T. cruzi and induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…To survive, the parasite exploits mechanisms involving NTPDase enzymes, especially E-NTPDase-1 [23]. The parasite increases its virulence through cell adhesion, modulation of the immune system, and increases its intracellular survival in the host [24]. The enzyme in the parasite interferes with extracellular ATP signals and interrupts purinergic signaling, inhibiting host defenses [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of ectonucleotidases and purinergic receptor expression during acute Chagas disease in the cortex of mice treated with resveratrol and benznidazole

Fracasso

Reichert

Bottari

et al. 2021

Purinergic Signalling

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Chagas disease (CD) is caused by the parasite Trypanosoma cruzi. CD affects people worldwide, primarily in tropical areas. The central nervous system (CNS) is an essential site for T. cruzi persistence during infection. The protozoan may pass through the blood-brain barrier and may cause motor and cognitive neuronal damage. Once in the CNS, T. cruzi triggers immune responses that the purinergic system can regulate. Treatment for CD is based on benznidazole (BNZ); however, this agent has negative side-effects and is toxic to the host. For this reason, we investigated whether resveratrol (RSV), a potent antioxidant and neuroprotective molecule, would modulate purinergic signaling and RSV alone or in combination with BNZ would prevent changes in purinergic signaling and oxidative damage caused by T. cruzi. We infected mice with T. cruzi and treated them with RSV or BNZ for 8 days. Increases in ATP and ADP hydrolysis by NTPDase in the total cortex of infected animals were observed. The treatment with RSV in infected group diminished ATP, ADP, and AMP hydrolysis compared to infected group. The combination of RSV + BNZ decreased AMP hydrolysis in infected animals compared to the INF group, exerting an anti-inflammatory effect. RSV acted as a neuroprotector, decreasing adenosine levels. Infected animals presented an increase of P2X 7 and A 2A density of purine receptors. RSV reduced P2X 7 and A 2A and increased A1 density receptors in infected animals. In addition, infected animals showed higher TBARS and reactive oxygen species (ROS) levels than control. RSV diminished ROS levels in infected mice, possibly due to antioxidant properties. In short, we conclude that resveratrol could act as a neuroprotective molecule, probably preventing inflammatory changes caused by infection by T. cruzi, even though the mice experienced high levels of parasitemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of ectonucleotidases and purinergic receptor expression during acute Chagas disease in the cortex of mice treated with resveratrol and benznidazole

Fracasso

Reichert

Bottari

et al. 2021

Purinergic Signalling

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“…From in vitro evidence, it is understandable that ecto -NTPDase has been considered a promising molecular target in the treatment of Chagas disease [ 10 , 37 , 38 ]. However, in vitro studies also showed a contradictory response.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that the increased extracellular release of ATP (eATP) [ 37 , 49 ] from the lysis of T. cruzi -infected cells could trigger the secretion of proinflammatory cytokines and the inflammatory response from the activation of type 2 purinergic receptors (P2) in resident leucocytes [ 8 , 32 ]. In fact, this process is highly relevant in the process of death, since high eATP levels act as a molecular signal to activate immune cells, especially macrophages [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi‐Infected Mice

Novaes

Santos

Cupertino

et al. 2018

Oxidative Medicine and Cellular Longevity

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Suramin (Sur) acts as an ecto-NTPDase inhibitor in Trypanosoma cruzi and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown in vitro, limited evidence in vivo suggests that this drug can be dangerous to T. cruzi-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and T. cruzi-infected male C57BL/6 mice were randomized into five groups: SAL = uninfected; INF = infected; SR5, SR10, and SR20 = infected treated with 5, 10, or 20 mg/kg Sur. In addition to its effect on blood and heart parasitism, the impact of Sur-based chemotherapy on leucocytes myocardial infiltration, cytokine levels, antioxidant defenses, reactive tissue damage, and mortality was analyzed. Our results indicated that animals treated with 10 and 20 mg/kg Sur were disproportionally susceptible to T. cruzi, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (T. cruzi DNA)), intense protein, lipid and DNA oxidation, marked myocarditis, and mortality. Animals treated with Sur also exhibited reduced levels of nonprotein antioxidants. However, the upregulation of catalase, superoxide dismutase, and glutathione-S-transferase was insufficient to counteract reactive tissue damage and pathological myocardial remodeling. It is still poorly understood whether Sur exerts a negative impact on the purinergic signaling of T. cruzi-infected host cells. However, our findings clearly demonstrated that through enhanced parasitism, inflammation, and reactive tissue damage, Sur-based chemotherapy contributes to aggravating myocarditis and increasing mortality rates in T. cruzi-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.

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“…In addition, eATP mediates mechanisms to control the parasite as astrocyte proliferation and differentiation, cytokine release, and the ROS and RNS formation. Furthermore, ATP, ADP, and AMP hydrolysis occur in infected animals, related to the enzymatic modulation in the presence of high parasitism [111]. As mentioned, adenosine has a neuroprotective role; however, E-ADA activity is augmented in infected animals, producing iosine which is later used in the purine rescue pathway of T. cruzi [83], and in other parasites such as Trypanosoma evansi [112] and Plasmodium falciparum [113].…”

Section: Pathogens and Purinergic Signaling Mediating Immune Responsementioning

confidence: 99%

Purinergic System in Immune Response

Salvador¹

2022

Purinergic System

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In mammalian cells, the purinergic signaling and inflammatory mediators regulate each other. During microbial infection, nucleotides and nucleosides from both dying host cells and pathogens may be recognized by the host receptors. These receptors include purinergic receptors such P2X, P2Y, and A2A, as well Toll-like receptors, and NOD-like receptors. The interaction with most of these receptors activates immune responses, including inflammasome activation, releasing of pro-inflammatory cytokines, reactive nitrogen and oxygen species production, apoptosis induction, and regulation of T cell responses. Conversely, activation of adenosine receptors is associated with anti-inflammatory responses. The magnitude of resultant responses may contribute not only to the host defense but also to the homeostatic clearance of pathogens, or even to the severe progression of infectious diseases. In this chapter, we discuss how the purinergic signaling activation upregulates or downregulates mechanisms in infectious diseases caused by the bacterial, parasite, and viral pathogens, including SARS-CoV-2. As a concluding remark, purinergic signaling can modulate not only infectious diseases but also cancer, metabolic, and cardiovascular diseases, constituting a strategy for the development of treatments.

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Implication of purinergic signaling pathways in clinical management of Chagas' disease

Cited by 4 publications

References 20 publications

Involvement of ectonucleotidases and purinergic receptor expression during acute Chagas disease in the cortex of mice treated with resveratrol and benznidazole

Involvement of ectonucleotidases and purinergic receptor expression during acute Chagas disease in the cortex of mice treated with resveratrol and benznidazole

Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi‐Infected Mice

Purinergic System in Immune Response

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