Brain Advance Access published online on June 4, 2003
Brain, doi:10.1093/brain/awg160
© 2003 by Guarantors of Brain
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Article
1 Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
* Corresponding author. E-mail: P.G.Kennedy{at}clinmed.gla.ac.uk.
Received 13 December 2002
; revised 24 February 2003
; accepted 24 February 2003
Human African trypanosomiasis, also known as sleeping sickness, affects the CNS at the late stage of the disease. Untreated the disease is invariably fatal, and melarsoprol, the only available and effective treatment for CNS disease, is associated in up to 10% of cases with a severe post-treatment reactive encephalopathy (PTRE), which can itself cause death. We used a reproducible mouse model of the PTRE to investigate the pathogenesis and treatment of this condition. Mice infected with Trypanosoma brucei brucei and treated subcuratively with diminazene aceturate develop a severe meningoencephalitis that closely resembles PTRE. We previously reported that substance P plays an important role in PTRE. We investigated the effect of disrupting the gene encoding for the NK1 receptor in mice on the clinical and neuroinflammatory response in this model. After induction of PTRE, NK1-/- mice showed a significant reduction in clinical impairment compared with NK1+/+ mice, but the severity of the neuroinflammatory response was significantly greater in NK1-/- mice. To explore the mechanisms of this dissociated phenotype, we treated infected NK1-/- mice with antagonists to NK2 and NK3 receptors, either singly or in combination. While none of these antagonist treatments altered the clinical score, combined treatment with the NK2 and NK3 antagonists significantly reduced the neuroinflammatory grading score in the NK1-/- mice. Thus, the clinical and neuroinflammatory responses to parasite invasion can be mediated by different pathways, and, importantly, the neuroinflammatory response is altered by alternative tachykinin receptor usage. These findings could be exploited to develop novel anti-inflammatory therapies in Human African trypanosomiasis by modulating the NK1 receptor as well as the parasite.
Keywords: brain; meningoencephalitis; mice; substance P; trypanosomiasis
Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice
2 Department of Veterinary Clinical Studies, University of Glasgow, Glasgow, UK
3 Department of Anatomy and Developmental Biology, University College London, London, UK
4 Department of Statistics and Modelling Science, University of Strathclyde, Glasgow, UK
5 Department of Pharmacology, Boston University School of Medicine, Boston, MA, USA
6 Instituto de Neurociencias, Universidad Miguel Hernández, San Juan, Alicante, Spain
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