Treatment of African trypanosomiasis with cordycepin and adenosine deaminase inhibitors in a mouse model.
There is an urgent need to discontinue the use of highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We show here that intraperitoneal injection of the adenosine analogue cordycepin (3'-deoxyadenosine), together with an adenosine deaminase (ADA) inhibitor (coformycin or deoxycoformycin), cures Trypanosoma brucei brucei infection in mice. Treatment was also effective at a stage when the trypanosomes had penetrated into the brain parenchyma, as determined by double immunolabeling of parasites and cerebral vessel endothelial cells in brain sections. At this stage, the parasites were eliminated not only from the blood but also from the brain parenchyma. In parallel with the elimination of parasites, in treated mice, the number of CD45+ inflammatory cells in the brain parenchyma was reduced. Treatment was not immunosuppressive. In vitro incubation with cordycepin reduced the growth of T. brucei brucei and T. cruzi, as well as Leishmania major and L. amazonensis. Administration of cordycepin plus deoxycofomycin to T. cruzi-infected mice also significantly reduced parasitemia. Accordingly, we propose nucleoside analogues resistant to ADA as candidates for treatment of late-stage HAT.
Rottenberg
Martin E
ME
Microbiology and Tumorbiology Center, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. martin.rottenberg@mtc.ki.se
Masocha
Willias
W
Ferella
Marcela
M
Petitto-Assis
Fabricio
F
Goto
Hiro
H
Kristensson
Krister
K
McCaffrey
Ronald
R
Wigzell
Hans
H
D000243:Adenosine Deaminase / Q000008:administration & dosage / Q000627:therapeutic use*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D007274:Injections, Intraperitoneal; D007891:Leishmania / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D058892:Adenosine Deaminase Inhibitors; D000981:Antiprotozoal Agents; D003839:Deoxyadenosines; D000243:Adenosine Deaminase; C058120:cordycepin