The role of antioxidants in improving treatment outcome and reducing disease severity in late stage human African trypanosomiasis

Abstract

African trypanosomiasis (HAT) is a tropical disease caused by two subspecies of Trypanosoma brucei: T. b. rhodesiense and T. b. gambiense. Melarsoprol, an organic arsenical is the only drug used to treat late stage T. b. rhodesiense infection in spite of its toxic side effects. A mouse model was adapted to study the effects of melarsoprol which was apparently toxic at normal intravenous doses of 3.6mg/kg body weight. Results from this study show that melarsoprol markedly reduced blood PCV, aconitase-1 and GSH levels in the brain of uninfected mice. However, Kenyan purple tea anthocyanins or coenzyme-Q10, orally administered prevented, to a significant degree, melarsoprol-induced decline in PCV and restored aconitase-1 and GSH levels. Notably, anthocyanin metabolites were detected in brain tissue of anthocyanin fed mice using HPLC. T. b. rhodesiense infection caused significant decreases in brain aconitase-1 and GSH levels while a general decrease in PCV levels was observed. Oral administration of Kenyan purple tea anthocyanins or coenzyme-Q10 in trypanosome-infected mice was found to impede these disease-induced anomalies. In PTRE studies, coenzyme-Q10 or Kenyan purple tea anthocyanins raised brain GSH and aconitase-1 levels when compared to untreated groups, coenzyme-Q10 treatment producing more beneficial effects compared to anthocyanin treatment. However, co-administration of both antioxidants caused a reduction of these beneficial effects implying a negative interaction. A histological study in the brain tissue of T. b. rhodesiense infected mice demonstrated neuroinflammatory pathology which was highly amplified in the PTRE groups. A prominent reduction in the severity of the neuroinflammatory response was detected when Kenyan purple tea anthocyanins or coenzyme-Q10 were administered separately. Moreover, degenerative changes in brain tissue of coenzyme-Q10 treated mice were less pronounced when compared to those given anthocyanins. Results of the present study provide evidence that oxidative stress in blood and brain is associated with the pathogenesis of HAT and PTRE. The present study also demonstrates a role of ROS-sensitive aconitase-1 and GSH in late stage HAT and PTRE. Evidence provided in this study implicates melarsoprol and T. b. rhodesiense parasites with interference of brain antioxidant systems and proposes that therapeutic intervention with Kenyan purple tea anthocyanins or coenzyme-Q10 may be useful in reducing disease severity and improve treatment outcome in late stage HAT and reduce PTRE occurrence.