blood-brain barrier significantly limits eflornithine entry into Trypanosoma brucei brucei infected mouse brain

• Published in: Journal of neurochemistry Vol. 107; no. 4; pp. 1136 - 1146
• Main Authors: Sanderson, Lisa, Dogruel, Murat, Rodgers, Jean, Bradley, Barbara, Thomas, Sarah Ann
• Format: Journal Article
• Language: English
• Published: Oxford Oxford, UK : Blackwell Publishing Ltd 01.11.2008; Blackwell; Blackwell Publishing Ltd
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette, Sub-Family B, Member 1 - deficiency; Biochemistry; Biological and medical sciences; blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - parasitology; Blood-Brain Barrier - physiopathology; Brain; Brain - drug effects; Brain - parasitology; Carbon Isotopes; Carbon Isotopes - metabolism; choroid plexus; deficiency; Disease Models, Animal; drug effects; drug therapy; Eflornithine; Eflornithine - pharmacokinetics; Eflornithine - therapeutic use; General aspects; Human protozoal diseases; Infectious diseases; Medical sciences; metabolism; Mice; Mice, Inbred BALB C; Mice, Transgenic; Neurology; Parasites; Parasitic diseases; parasitology; pathogenicity; pathology; pharmacokinetics; Pharmacology; physiopathology; Protozoal diseases; Rodents; Sucrose; Sucrose - metabolism; therapeutic use; Time Factors; Tritium; Tritium - pharmacokinetics; Trypanocidal Agents; Trypanocidal Agents - pharmacokinetics; Trypanocidal Agents - therapeutic use; Trypanosoma brucei brucei; Trypanosoma brucei brucei - pathogenicity; Trypanosomiasis; Trypanosomiasis, African; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - pathology; Drug; Choroid plexus; Ependymal organ; Animal model; Protozoal disease; Rodentia; Central nervous system; Parasitosis; African sickness; Blood brain barrier; Suramin sodium; Blood; Encephalon; Infection; Resistance; Vertebrata; eflornithine; Mammalia; Mouse; Blood-brain barrier; Dysfunction; Animal; Trypanosomiasis
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05706.x

Drugs to treat African trypanosomiasis are toxic, expensive and subject to parasite resistance. New drugs are urgently being sought. Although the existing drug, eflornithine, is assumed to reach the brain in high concentrations, little is known about how it crosses the healthy and infected blood-brain barrier. This information is essential for the design of drug combinations and new drugs. This study used novel combinations of animal models to address these omissions. Eflornithine crossed the healthy blood-CNS interfaces poorly, but this could be improved by co-administering suramin, but not nifurtimox, pentamidine or melarsoprol. Work using a murine model of sleeping sickness demonstrated that Trypanosoma brucei brucei crossed the blood-CNS interfaces, which remained functional, early in the course of infection. Concentrations of brain parasites increased during the infection and this resulted in detectable blood-brain barrier, but not choroid plexus, dysfunction at day 28 post-infection with resultant increases in eflornithine brain delivery. Barrier integrity was never restored and the animals died at day 37.9 ± 1.2. This study indicates why an intensive treatment regimen of eflornithine is required (poor blood-brain barrier penetration) and suggests a possible remedy (combining eflornithine with suramin). The blood-brain barrier retains functionality until a late, possibly terminal stage, of trypanosoma infection.