Effects of Cholinergic Stimulation with Pyridostigmine Bromide on Chronic Chagasic Cardiomyopathic Mice

Abstract

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial

“…Finally, a pathophysiological link between impaired parasympathetic control, a derangement described in early phases of human Chagas disease, and abnormal neuroimmunomodulatory regulation has been recently suggested in a murine model of chronic T. cruzi infection ( Cuba et al 2014 ). These findings were based on the effect of pharmacological cholinergic stimulation using pyridostigmine, a cholinesterase inhibitor, which reduced myocardial inflammation, fibrosis, hypertrophy, and serum levels of IFN-g, but did not change IL-10 levels.…”

“…These findings were based on the effect of pharmacological cholinergic stimulation using pyridostigmine, a cholinesterase inhibitor, which reduced myocardial inflammation, fibrosis, hypertrophy, and serum levels of IFN-g, but did not change IL-10 levels. Cuba et al (2014) thought that the autonomic dysregulation caused by T. cruzi infection could abolish the normal neuroimmunomodulatory anti-inflammatory role that is normally played by the parasympathetic nervous system.…”

Parasitic (Protozoan) cardiomyopathy: A review and pooled analysis of pathophysiology, diagnosis and clinical management

“…In a majority of individuals with Chagas disease, the loss of parasympathetic cardiac control manifests prior to the onset of myocardial dysfunction [70][71][72][73][74]. Despite the parasympathicopriva Chagas cardiopathy theory postulating that catecholamine-induced CM is a consequence of parasympathetic dysfunction [75,76], it does not explain the lack of correlation between considerable individual variability of vagal denervation with severity of LV dysfunction and its detection in many patients. However, the theory is useful in explaining impaired control of the coronary microcirculation that results from dysutonomia [77,78].…”

“…Parasympathetic impairment may also be responsible for triggering malignant arrhythmia and sudden death evidence in pathological reports of highly denervated hearts of Chagasic patients with sudden death [65,79]. Nevertheless, the pathogenesis of arrhythmia in Chagasic CM patients is possibly multifactorial, also including adrenergically denervated myocardium and abnormal neuro-immunomodulatory anti-inflammatory functions of the parasympathetic nervous system [76,80,81].…”

Aplicaciones y potencial de las técnicas de diagnóstico por imagen en la investigación biomédica de la enfermedad de Chagas

“…La cardiopatía chagásica es la afección clínica más común como consecuencia de la infección por T. cruzi. La causa del daño cardiaco es multifactorial y se postulan diversos actores como: el parásito (3), la respuesta inmune-inflamatoria, autoinmunidad, (4,5) alteraciones microvasculares (6) y daño nervioso (7). Todos los anteriores se interrelacionan para contribuir al daño en el miocardio y el consecuente deterioro de la función cardiaca, el cual se manifiesta con anormalidades en la función eléctrica del corazón y miocardiopatía progresiva, que pueden provocar una insuficiencia cardíaca y, en algunos casos, la muerte (1,8,9).…”