Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice.
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.
Kennedy
Peter G E
PG
Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK. P.G.Kennedy@clinmed.gla.ac.uk
Rodgers
Jean
J
Bradley
Barbara
B
Hunt
Stephen P
SP
Gettinby
George
G
Leeman
Susan E
SE
de Felipe
Carmen
C
Murray
Max
M
D000818:Animals; D004133:Diminazene; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D008590:Meningoencephalitis / Q000469:parasitology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000502:physiology; D014353:Trypanosomiasis, African / Q000150:complications* / Q000473:pathology / Q000503:physiopathology
D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D004133:Diminazene