Abstract
BackgroundThe implication of nitric oxide (NO) in the development of human African trypanosomiasis (HAT) using an animal model, was examined. The manner by which the trypanocidal activity of NO is impaired in the periphery and in the brain of rats infected with Trypanosoma brucei brucei (T. b. brucei) was analyzed through: (i) the changes occurring in NO concentration in both peripheral (blood) and cerebral compartments; (ii) the activity of nNOS and iNOS enzymes; (iii) identification of the brain cell types in which the NO-pathways are particularly active during the time-course of the infection.Methodology/Principal FindingsNO concentration (direct measures by voltammetry) was determined in central (brain) and peripheral (blood) compartments in healthy and infected animals at various days post-infection: D5, D10, D16 and D22. Opposite changes were observed in the two compartments. NO production increased in the brain (hypothalamus) from D10 (+32%) to D16 (+71%), but decreased in the blood from D10 (−22%) to D16 (−46%) and D22 (−60%). In parallel with NO measures, cerebral iNOS activity increased and peaked significantly at D16 (up to +700%). However, nNOS activity did not vary. Immunohistochemical staining confirmed iNOS activation in several brain regions, particularly in the hypothalamus. In peritoneal macrophages, iNOS activity decreased from D10 (−83%) to D16 (−65%) and D22 (−74%) similarly to circulating NO.Conclusion/SignificanceThe NO changes observed in our rat model were dependent on iNOS activity in both peripheral and central compartments. In the periphery, the NO production decrease may reflect an arginase-mediated synthesis of polyamines necessary to trypanosome growth. In the brain, the increased NO concentration may result from an enhanced activity of iNOS present in neurons and glial cells. It may be regarded as a marker of deleterious inflammatory reactions.
Highlights
Human African trypanosomiasis (HAT), or sleeping sickness, is a reemerging parasitic disease caused by protozoan parasites belonging to the genus Trypanosoma
Afterwards, we focused on the original part of our approach, i.e., the changes occurring in nitric oxide (NO) concentration in the two compartments, together with an evaluation of enzymatic activity and the identification of the cell types in which the NO-pathways are active during the course of the infection
Stage determination was evaluated by measuring body weight gain, trypanosome counts in the blood and cerebrospinal fluid (CSF), and trypanosome immunostaining in the brain
Summary
Human African trypanosomiasis (HAT), or sleeping sickness, is a reemerging parasitic disease caused by protozoan parasites belonging to the genus Trypanosoma. Rhodesiense, found in East Africa, is responsible for an acute sickness (weeks to months) In both clinical entities, two distinct stages occur successively during the course of the disease. The late or meningoencephalitic stage 2 is characterized by the crossing of the blood-brain barrier (BBB) with the invasion of the central nervous system (CNS) by the parasites [1]. They may be observed throughout the course of the disease, neurological signs are most often described during stage 2, with a wide panel of sensory, motor and psychiatric disturbances, and the development of disruptions of the sleep-wake cycle, a most characteristic sign that gave its name to the illness [2]. The manner by which the trypanocidal activity of NO is impaired in the periphery and in the brain of rats infected with Trypanosoma brucei brucei (T. b. brucei) was analyzed through: (i) the changes occurring in NO concentration in both peripheral (blood) and cerebral compartments; (ii) the activity of nNOS and iNOS enzymes; (iii) identification of the brain cell types in which the NO-pathways are active during the time-course of the infection
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