Minocycline impedes African trypanosome invasion of the brain in a murine model.
Passage of Trypanosoma brucei across the blood-brain barrier (BBB) is a hallmark of late-stage human African trypanosomiasis. In the present study we found that daily administration of minocycline, a tetracycline antibiotic, impedes the penetration of leukocytes and trypanosomes into the brain parenchyma of T. brucei brucei-infected C57BL/6 mice. The trypanosome-induced astrocytic and microglial reactions were reduced in the minocycline-treated mice, as were the levels in the brain of transcripts encoding adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and endothelial-leukocyte adhesion molecule 1 (E-selectin); the inflammatory cytokines tumor necrosis factor alpha, interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, and gamma interferon; and matrix metalloprotease 3 (MMP-3), MMP-8, and MMP-12. Loss of weight occurring during infection with T. b. brucei was not observed after treatment of the mice with minocycline; these mice also survived longer than nontreated mice. Invasion of trypanosomes and leukocytes into the brain parenchyma most likely triggered the loss of weight and death of infected animals, since minocycline did not affect the growth of T. b. brucei either in vitro or in vivo or the levels of the transcripts encoding the cytokines and MMPs in the spleen. In conclusion, our data show that T. b. brucei invasion of the brain is related to that of leukocytes and that minocycline can ameliorate the disease in trypanosome-infected mice.
Masocha
Willias
W
Department of Neuroscience, Retzius väg 8, Karolinska Institutet, SE-171 77 Stockholm, Sweden. willias.masocha@ki.se
Rottenberg
Martin E
ME
Kristensson
Krister
K
D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000166:cytology / Q000469:parasitology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014346:Trypanosoma brucei brucei / Q000502:physiology*
D000900:Anti-Bacterial Agents; D016207:Cytokines; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D020782:Matrix Metalloproteinases; D008911:Minocycline