Phenyl-alpha-tert-butyl-nitrone and benzonidazole treatment controlled the mitochondrial oxidative stress and evolution of cardiomyopathy in chronic chagasic Rats.
OBJECTIVE
The purpose of this study was to determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction.


BACKGROUND
Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease.


METHODS
Sprague-Dawley rats were infected with T. cruzi and treated with phenyl-alpha-tert-butylnitrone (PBN), an antioxidant, and/or benzonidazole (BZ), an antiparasitic agent. We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration, and adenosine triphosphate synthesis rates, and inflammatory and cardiac remodeling responses during disease development. The cardiac hemodynamics was determined for all rats.


RESULTS
Benzonidazole (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, beta-nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronically infected hearts. PBN +/- BZ (not BZ alone) decreased the mitochondrial reactive oxygen species level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (atrial natriuretic peptide, B-type natriuretic peptide, alpha-skeletal actin), and collagen deposition and preserved the respiratory chain efficiency and energy status in chronically infected hearts. Subsequently, LV dysfunction was prevented in PBN +/- BZ-treated chagasic rats.


CONCLUSIONS
BZ treatment after the acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction, and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combination treatment (PBN + BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1070, USA.
Jian-Jun
JJ
Wen
Shivali
S
Gupta
Zhangjun
Z
Guan
Monisha
M
Dhiman
David
D
Condon
Charles
C
Lui
Nisha Jain
NJ
Garg
D000704:Analysis of Variance; D000818:Animals; D002598:Chagas Cardiomyopathy / Q000209:etiology / Q000517:prevention & control; D014355:Chagas Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002908:Chronic Disease; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006334:Heart Function Tests; D006439:Hemodynamics / Q000502:physiology; D015227:Lipid Peroxidation; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000469:parasitology; D009593:Nitroimidazoles / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014349:Trypanosoma cruzi
D003497:Cyclic N-Oxides; D009593:Nitroimidazoles; C029217:phenyl-N-tert-butylnitrone; C009999:benzonidazole