The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-CSF barriers

Jeganathan, S., Sanderson, L., Dogruel, M., Rodgers, J. , Croft, S. and Thomas, S.A. (2011) The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-CSF barriers. Journal of Pharmacology and Experimental Therapeutics, 336(2), pp. 506-515. (doi: 10.1124/jpet.110.172981)

Abstract

Nifurtimox, an anti-parasitic drug, is used to treat American trypanosomiasis (Chagas disease) and has shown promise in treating CNS-stage human African trypanosomiasis (HAT; sleeping sickness). In combination with other anti-parasitic 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-CSF barriers (Kin brain parenchyma was 50.8±9.0μl.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 anti-trypanosomal 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rodgers, Dr Jean
• Authors: Jeganathan, S., Sanderson, L., Dogruel, M., Rodgers, J., Croft, S., and Thomas, S.A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Pharmacology and Experimental Therapeutics
• ISSN: 0022-3565
• Published Online: 05 November 2010