PRE-CLINICAL RESEARCH
Phenyl- -tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats
Jian-Jun Wen, PhD*,
Shivali Gupta, PhD*,
Zhangjun Guan, MD ,
Monisha Dhiman, PhD*,
David Condon*,
Charles Lui, MD and
Nisha Jain Garg, PhD*, , ,*
* Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
Department of Internal Medicine-Cardiology, University of Texas Medical Branch, Galveston, Texas
Department of Pathology, University of Texas Medical Branch, Galveston, Texas
Institute for Human Infections and Immunity, Center for Biodefense and Emerging Infectious Diseases, and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas
Manuscript received July 28, 2009;
revised manuscript received February 9, 2010,
accepted February 15, 2010.
* Reprint requests and correspondence: Dr. Nisha Jain Garg, 3.142C Medical Research Building, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1070 (Email: nigarg{at}utmb.edu).
Objectives: 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- -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, β-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, -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.
Key Words: antioxidant • benzonidazole • Chagas disease • mitochondrial oxidative stress • Trypanosoma cruzi
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Abbreviations and Acronyms
| | sk actin = -skeletal actin | | ANOVA = analysis of variance | | ANP = atrial natriuretic peptide | | ATP = adenosine triphosphate | | BNP = B-type natriuretic peptide | | BZ = benzonidazole | | HNE = 4-hydroxynonenal | | LV = left ventricular | | MDA = malonyldialdehyde | | MPO = myeloperoxidase | | NOX = β-nicotinamide adenine dinucleotide phosphate oxidase | | PBN = phenyl--tert-butylnitrone | | PCR = polymerase chain reaction | | P-V = pressure-volume | | pyr/mal = pyruvate/malate | | ROS = reactive oxygen species | | XOD = xanthine oxidase |
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