The pathogenesis and modulation of the post-treatment reactive encephalopathy in a mouse model of Human African Trypanosomiasis.
Drug treatment of late-stage human African Trypanosomiasis (HAT) in which the central nervous system (CNS) is involved may be complicated by a severe post-treatment reactive encephalopathy (PTRE) which can be fatal in up to 10% of cases. In order to understand the immunopathogenesis of this complication, an experimental mouse model has been developed that mirrors many of the pathological features of the PTRE in humans, and which allows various anti-inflammatory therapeutic regimes to be evaluated. Following the development of the PTRE in this model a number of cytokines are increased within the CNS including tumour necrosis factor (TNF) alpha, interleukins 1, 4 and 6, and macrophage inflammatory protein (MIP)-1. These cytokines appear at the same time as astrocyte activation which is an early event occurring before the development of the marked meningoencephalitic inflammatory response. The immunosuppressant drug azathioprine prevents but does not reduce the severity of an established PTRE and has a minimal effect on astrocyte activation. The ornithine decarboxylase inhibitor eflornithine prevents the induction, and ameliorates the severity, of the PTRE, and also reduces the degree of astrocyte activation. The Substance P antagonist RP-67,580 ameliorates the severity of an established PTRE, and also reduces astrocyte activation, indicating an important role of SP in the generation of the inflammatory response. Continued use of this mouse model should lead to further enhancement of our understanding of the pathogenesis of the PTRE and to improved drug regimes to prevent and/or treat it.
Kennedy
P G
PG
Glasgow University Department of Neurology, Southern General Hospital, South Glasgow University Hospitals NHS Trust, Scotland, UK. p.g.kennedy@clinmed.gla.ac.uk
D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use; D004195:Disease Models, Animal; D000518:Eflornithine / Q000627:therapeutic use; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology; D006624:Hippocampus / Q000187:drug effects / Q000382:microbiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D054833:Isoindoles; D051379:Mice; D014344:Trypanocidal Agents / Q000627:therapeutic use; D014353:Trypanosomiasis, African / Q000150:complications* / Q000188:drug therapy
D000700:Analgesics; D007166:Immunosuppressive Agents; D007211:Indoles; D054833:Isoindoles; D014344:Trypanocidal Agents; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D001379:Azathioprine; D000518:Eflornithine