Abstract
Nifurtimox, an antiparasitic drug, is used to treat American trypanosomiasis (Chagas disease) and has shown promise in treating central nervous system (CNS)-stage human African trypanosomiasis (HAT; sleeping sickness). In combination with other antiparasitic drugs, the efficacy of nifurtimox against HAT improves, although why this happens is unclear. Studying how nifurtimox crosses the blood-brain barrier (BBB) and reaches the CNS may clarify this issue and is the focus of this study. To study the interaction of nifurtimox with the blood-CNS interfaces, we used the in situ brain/choroid plexus perfusion technique in healthy and trypanosome-infected mice and the isolated incubated choroid plexus. Results revealed that nifurtimox could cross the healthy and infected blood-brain and blood-cerebrospinal fluid (CSF) barriers (Kin brain parenchyma was 50.8 ± 9.0 μl · min−1 · g−1). In fact, the loss of barrier integrity associated with trypanosome infection failed to change the distribution of [3H]nifurtimox to any significant extent, suggesting there is not an effective paracellular barrier for [3H]nifurtimox entry into the CNS. Our studies also indicate that [3H]nifurtimox is not a substrate for P-glycoprotein, an efflux transporter expressed on the luminal membrane of the BBB. However, there was evidence of [3H]nifurtimox interaction with transporters at both the blood-brain and blood-CSF barriers as demonstrated by cross-competition studies with the other antitrypanosomal agents, eflornithine, suramin, melarsoprol, and pentamidine. Consequently, CNS efficacy may be improved with nifurtimox-pentamidine combinations, but over time may be reduced when nifurtimox is combined with eflornithine, suramin, or melarsoprol.
Footnotes
This work was supported by The Wellcome Trust [Grants 073542, 080268].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.172981.
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ABBREVIATIONS:
- HAT
- human African trypanosomiasis
- CNS
- central nervous system
- CSF
- cerebrospinal fluid
- BBB
- blood-brain barrier
- P-gp
- P-glycoprotein
- MRP
- multidrug resistance-associated protein
- p.i.
- postinfection
- CVOs
- circumventricular organs
- T.b.
- Trypanosoma brucei
- NECT
- nifurtimox-eflornithine combination therapy
- ANOVA
- analysis of variance
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide.
- Received July 15, 2010.
- Accepted November 2, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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