Brain Advance Access originally published online on March 31, 2009
Brain 2009 132(5):1259-1267; doi:10.1093/brain/awp074
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Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis
1 Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, UK 2 Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK 3 Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK 4 Division of Clinical Neuroscience, Faculty of Medicine, Southern General Hospital, University of Glasgow Institute of Neurological Sciences, Glasgow, UK
Correspondence to: Prof. Peter Kennedy, Division of Clinical Neurosciences, Faculty of Medicine, University of Glasgow, Institute of Neurological Sciences, Southern General Hospital, Glasgow G41 4TF, UK E-mail: p.g.kennedy{at}clinmed.gla.ac.uk
Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense, 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. In vitro 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.
Key Words: trypanosomiasis; brain; kynurenine pathway; mice; Ro-61-8048
Abbreviations: HAT, human African trypanosomiasis; IDO, indolamine-2,3-dioxygenase; PTRE, post-treatment reactive encephalopathy; KMO, kynurenine-3-monooxygenase
Received December 15, 2008. Revised February 13, 2009. Accepted February 28, 2009.