g(m1)-ganglioside and Chagas-Cardiomyopathy

Chagas disease involves a cardiac impairment, being the first alterations of autonomic disorders which affect heart rate and blood pressure control. At this stage, diminished heart rate responses to atropine and propranolol are observed. Prior studies have shown that short term ganglioside treatment improves the responses to these agents, but there is no information about the long term effect of gangliosides and the evolution of antiGM1 titers. The effects of long term treatment with gangliosides on autonomic tests in patients with chagasic cardiodisautonomy and the evolution of antiGM1 titers were studied in 90 patients (57 men, 33 women, aged 25-60 years) with positive serology for Chagas disease and electrocardiogram showing sinusal bradycardia and incomplete right branch block, without cardiomegaly, with autonomic alterations by postural and Valsalva's tests. All patients were submitted to a test that consisted of intravenous injection of atropine 0.04 mg/kg followed 3 min later by intravenous injection of propranolol 0.2 mg/kg. During these tests heart rate and blood pressure were recorded continuously. Subsequently, 30 patients were treated with 100 mg/day of a mixture of gangliosides by intramuscular injection during 15 days in a row, followed by 40 mg/day during another 75 days. Another 30 patients received continuous treatment for 12 months. The remaining 30 patients were controls. The antiGM1 antibody circulating titers were determined before the treatment, at the third and 12th month. Seventy-four patients completed the study. Before treatment, the heart rate increased, though slightly, after the injection of atropine. After 3 months of ganglioside treatment a statistically significant increase in the response to atropine was recorded. In the controls at 12 months, the response to atropine remained increased without differences between the patients treated for 3 and 12 months. The control patients did not show any modification of the heart rate response during 12 months. Both ganglioside-treated groups showed an increase in the response to propranolol. The antiGM1 titer distribution was similar in both healthy subjects and chagasic patients. None of the patients had positive antiGM1 titers in basal conditions nor significant modifications after the ganglioside treatment. Chagasic cardioneuropathy was not associated in this study with high antiGM1 antibody titers. Chagasic patients showed a diminished heart rate response to atropine as well as t

Topics: Adult; Atropine; Autoantibodies; Autonomic Nervous System Diseases; Chagas Cardiomyopathy; Chronic Disease; Female; G(M1) Ganglioside; Gangliosides; Heart Rate; Humans; Injections, Intramuscular; Male; Middle Aged; Propranolol; Time Factors

Heart failure and sudden death are the most common causes of death in patients with Chagas' disease. The main drug available for Chagas treatment is benznidazole, which eradicates Trypanosoma cruzi parasites during the acute stage of infection. However, its effectiveness during the chronic phase remains unclear. Ganglioside GM1 administration in chronically infected patients resulted to be an effective treatment for the cardiac manifestations of Chagas' disease. However, the precise mechanisms of GM1-induced improvement during chronic T. cruzi infection still remain unknown. The aim of the present study was to evaluate the potential benefits of ganglioside GM1 treatment during the chronic stage of murine chagasic infection, analyzing its influence on myocardial pathology as well as its immunomodulatory effects. The results obtained showed that GM1 therapy diminished the extent of myocardial fibrosis induced by T. cruzi in chronically infected mice. In addition, GM1 treatment resulted in a significant reduction in the myocardial expression of the fibrogenic cytokine TGF-β as well as the proinflammatory cytokines and chemokines IFN-γ, TNF-α and CCL5/RANTES. Our experimental data indicate that GM1 could be a promising immunomodulatory agent with capacity to limit the inflammatory process leading to myocardial tissue damage in chronic chagasic patients.

Topics: Animals; Chagas Cardiomyopathy; Chemokine CCL5; Female; Fibrosis; G(M1) Ganglioside; Immunologic Factors; Interferon-gamma; Mice; Mice, Inbred BALB C; Myocardium; Transforming Growth Factor beta; Trypanosoma cruzi; Tumor Necrosis Factor-alpha

In a previous work, our group reported that Albino Swiss male mice inoculated with T. cruzi to develop acute lethal infection by day 15 decreased parasitemia and survived when treated with total brain gangliosides (GT; 1 mg, daily). In this paper, GT were replaced by GM1 in 0.1 mg dose that caused diminished parasitemia from day 15 to 30 and survival of 80% by day 120 p.i. Treatment with GT 0.15 mg was ineffective. This indicates that GT effect was due to GM1 and that more sialyl residues on the same lipid moiety produces adverse results. GM1 was compared to other sialylated molecules: fetuine and colominic acid. Both of them increased parasitemias and death by day 16 p.i., suggesting that sialic residues favor parasite replication. Asialo-GM1 (0.1 mg daily) was also adverse. This pointed to GM1 not to other ganglioside or sphingolipid or sialoprotein as the active agent. Gangliosides are [Ca+2]i modulators, so GM1 was compared to nifedipine which blocks calcium channels only in the host. Nifedipine treated mice behaved as controls. It is proposed that if GM1 calcium modulation is involved it must be on the parasite rather than on the host. Electrocardiographic (ECG) records show that while infected mice die with bradycardia, treated mice survive and recover normal frequency. Uninfected treated mice showed no electrocardiographic alterations.

Topics: Animals; Calcium Channel Blockers; Chagas Cardiomyopathy; Chagas Disease; Electrocardiography; G(M1) Ganglioside; Heart; Male; Mice; Nifedipine; Parasitemia