Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis

Rodgers, J. , Stone, T.W., Barrett, M.P., Bradley, B.M. and Kennedy, P.G.E. (2009) Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis. Brain, 132(5), pp. 1259-1267. (doi:10.1093/brain/awp074)

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Abstract

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites <i>Trypanosoma brucei rhodesiense</i> or <i>Trypanosoma brucei gambiense</i>, and is a major cause of systemic and neurological disability throughout sub-Saharan Africa. Following early-stage disease, the trypanosomes cross the blood-brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. Treatment of human African trypanosomiasis currently relies on a limited number of highly toxic drugs, but untreated, is invariably fatal. Melarsoprol, a trivalent arsenical, is the only drug that can be used to cure both forms of the infection once the central nervous system has become involved, but unfortunately, this drug induces an extremely severe post-treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. Since it is unlikely that any new and less toxic drug will be developed for treatment of human African trypanosomiasis in the near future, increasing attention is now being focussed on the potential use of existing compounds, either alone or in combination chemotherapy, for improved efficacy and safety. The kynurenine pathway is the major pathway in the metabolism of tryptophan. A number of the catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of central nervous system inflammation is well documented. In the current study, Ro-61-8048, a high affinity kynurenine-3-monooxygenase inhibitor, was used to determine the effect of manipulating the kynurenine pathway in a highly reproducible mouse model of human African trypanosomiasis. It was found that Ro-61-8048 treatment had no significant effect (P = 0.4445) on the severity of the neuroinflammatory pathology in mice during the early central nervous system stage of the disease when only a low level of inflammation was present. However, a significant (P = 0.0284) reduction in the severity of the neuroinflammatory response was detected when the inhibitor was administered in animals exhibiting the more severe, late central nervous system stage, of the infection. <i>In vitro</i> assays showed that Ro-61-8048 had no direct effect on trypanosome proliferation suggesting that the anti-inflammatory action is due to a direct effect of the inhibitor on the host cells and not a secondary response to parasite destruction. These findings demonstrate that kynurenine pathway catabolites are involved in the generation of the more severe inflammatory reaction associated with the late central nervous system stages of the disease and suggest that Ro-61-8048 or a similar drug may prove to be beneficial in preventing or ameliorating the PTRE when administered as an adjunct to conventional trypanocidal chemotherapy

Item Type:Articles
Keywords:Trypanosomiasis, brain, kynurenine pathway, mice; Ro-61-8048
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stone, Professor Trevor and Kennedy, Professor Peter and Bradley, Mrs Barbara and Barrett, Professor Michael and Rodgers, Dr Jean
Authors: Rodgers, J., Stone, T.W., Barrett, M.P., Bradley, B.M., and Kennedy, P.G.E.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Brain
ISSN:0006-8950
ISSN (Online):1460-2156
Published Online:31 March 2009
Copyright Holders:Copyright © 2009 The Authors.
First Published:First published in Brain 132(5): 1259-1267.
Publisher Policy:This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
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