Electrophysiological and pharmacological evaluation of the nicotinic cholinergic system in chagasic rats

Bonfante-Cabarcas, Rafael; Hincapié, Erlymar López; Hernández, Eliezer Jiménez; Zambrano, Ruth Fonseca; Mancini, Lady Ferrer; Mena, Marcos Durand; Rodríguez-Bonfante, Claudina

doi:10.1186/2050-6511-14-2

Cited by 9 publications

(6 citation statements)

References 24 publications

(27 reference statements)

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“…The acute phase of the disease appears shortly after infection, and the chronic phase appears after a silent asymptomatic period that can last for several years. The heart, esophagus, colon and peripheral nervous system can be irreversibly damaged during the chronic phase of Chagas disease, and the majority of patients usually die from heart failure [5,6]. …”

Section: Introductionmentioning

confidence: 99%

Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease

Wong-Baeza

Nogueda‐Torres

Serna

et al. 2015

BMC Pharmacol Toxicol

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BackgroundChagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease.MethodsThe benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.ResultsPolar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.ConclusionB-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.

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Section: Introductionmentioning

confidence: 99%

Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease

Wong-Baeza

Nogueda‐Torres

Serna

et al. 2015

BMC Pharmacol Toxicol

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“…In a different publication, we observed that rats with chronic Chagas disease had parasympathetic disturbances that could be the consequence of alterations on the muscarinic receptor distribution at different neural integration levels [15]. Recently we have also demonstrated a decrease in cardiac response to vagal stimulation in rats with chronic Chagas' disease, which was reverted by a pharmacological blockage of cholinesterase enzyme with neostigmine [16].…”

Section: Introductionmentioning

confidence: 83%

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Labrador-Hernández¹,

Jimenez²,

León³

et al. 2014

WJCD

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Background: Chagas disease is still a public health problem because of the remaining high prevalence, the expansion of the disease into developed countries and the re-emergences by oral transmission outbreaks. Chagas cardiomyopathy evolves as a consequence of an autonomic unbalance where the parasympathetic tone is undermined. Objective: To determine the functionality and expression of muscarinic cholinergic receptors in acute Chagas disease. Methodology: 62 male, 3-week-old Sprague Dawley rats were assayed; 32 were infected with Trypanosoma cruzi trypomastigotes and 30 were healthy controls. Electrocardiographic studies were conducted in the absence or presence of direct muscarinic (oxotremorine and McN-A-343) or indirect agonists (phenylephrine) or antagonist (pirenzepine). Muscarinic M1 and M2 receptor expression was determined by radioligand [ 3 H]-QNB binding assay and immunoblot. Results: Chagasic acute myocarditis was sustained by electrocardiographic signs and histopathological findings. Bradycardia induced by oxotremorine was significantly higher in healthy rats (HR) and the differences were enhanced by CsCl. In the absence of the agonist, CsCl induced a greater bradycardia in chagasic rats (ChR). In HR McN-A-343 induced tachycardia, however it induces bradycardia in the presence of a acetylcholinesterase inhibitor (neostigmine); no effects were observed in ChR. Pirenzepine induced a higher tachycardia in HR. Phenylephrine in the presence of pirenzepine induced a similar bradycardia in both groups, but recovery was faster in ChR. Muscarinic M1 and M2 receptor density was higher in HR. Conclusion: Muscarinic receptor expression and functionality are decreased * Corresponding author. M. Labrador-Hernández et al. 306in the acute Chagas disease that could impact the evolution and prognosis of the disease.

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“…30 Indeed, it seems that dysautonomy in patients with Chagas heart disease is not only related to augmented sympathetic activity, but also to loss of parasympathetic modulation. 31 Accordingly, cholinergic function is impaired in chronic Chagas disease in rats, 32 an effect that may also be caused by autoimmunological mechanisms. 33 This complex pathophysiological milieu might, at least partially, explain the lack of response of our patients to renal denervation.…”

Section: Discussionmentioning

confidence: 99%

Renal denervation in patients with heart failure secondary to Chagas' disease: A pilot randomized controlled trial

Spadaro

Bocchi

Souza

et al. 2019

Cathet Cardio Intervent

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Introduction Chagas disease is one of the most relevant endemic parasitic diseases in Latin America, affecting approximately 6 million people. Overt Chagas heart disease is an ominous condition, occurring in 20–30% of infected individuals, which has besides the persistent myocarditis a peculiar intracardiac ganglionic neuronal depletion and dysautonomy. This study aims to evaluate the safety and feasibility of renal denervation for patients with advanced symptomatic Chagas cardiomyopathy. Methods Open‐label prospective pilot study that randomized patients with Chagas heart disease to either renal denervation or conservative treatment (2:1 ratio). The primary endpoint was the incidence of major adverse events at 9 months, defined as a composite of all‐cause death, myocardial infarction, stroke, need for renal artery invasive treatment, or worsening renal function. Results A total of 17 patients were allocated for renal denervation (n = 11) or conservative treatment (n = 6). Included patients had severe symptomatic heart disease, with markedly depressed left ventricular function (average ejection fraction 26.7 ± 4.9%). For patients randomized to renal denervation, the procedure was performed successfully and uneventfully. After 9 months, the primary endpoint occurred in 36.4% of patients in the renal denervation group and 50.0% in the control arm (p = .6). After 9 months, clinical, laboratory, functional, echocardiographic, and quality of life parameters were similar between groups. Conclusions This pilot study suggests that renal denervation is safe and feasible in patients with Chagas cardiomyopathy, warranting future studies to better evaluate the clinical efficacy of the interventional strategy in improving the prognosis of this high‐risk population.

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Electrophysiological and pharmacological evaluation of the nicotinic cholinergic system in chagasic rats

Cited by 9 publications

References 24 publications

Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease

Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Renal denervation in patients with heart failure secondary to Chagas' disease: A pilot randomized controlled trial

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