title: Kola acuminata proanthocyanidins: a class of anti-trypanosomal compounds effective against Trypanosoma brucei.
abstract: Human African trypanosomiasis is undergoing an alarming rate of recrudescence in many parts of sub-Saharan Africa. Yet, there is no successful chemotherapy for the disease due to a limited number of useful drugs, side effects and drawbacks of the existing medication, as well as the development of drug resistance by the parasite. Here we describe a new lead anti-trypanosomal compound isolated from Kola acuminata (Makasu). We purified a proanthocyanidin by chromatographic procedures and confirmed its homogeneity and structure by Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption Ionisation Time-of-Flight mass spectrometry, respectively. In vitro, this compound potently induced growth arrest and lysis of bloodstream form trypanosomes in a dose- and time-dependent manner. In a mouse model, it exhibited a trypanostatic effect that extended the life of infected, treated animals up to 8 days post-infection against the 4 days for infected, untreated animals. The proanthocyanidin showed a low cytotoxicity against mammalian cells, whereas treated-BF showed massive enlargement of their flagellar pocket and lysosome-like structures caused by an intense formation of multivesicular bodies and vesicles within these organelles. The observed ultrastructural alterations caused rupture of plasma membranes and the release of cell contents, indicative of a necrotic process rather than a programmed cell death. Interestingly, the proanthocyanidin acted against BF but not procyclic form trypanosomes. This new anti-trypanosomal compound should be further studied to determine its efficacy and suitability as an anti-trypanosomal drug and may be used as a tool to define novel specific drug targets in BF trypanosomes.
authors.affiliation: Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan. bkubata@nairobi.mimcom.net
authors.forename: B K
authors.initials: BK
authors.lastname: Kubata
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Nagamune
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Murakami
authors.forename: Patrick
authors.initials: P
authors.lastname: Merkel
authors.forename: Zakayi
authors.initials: Z
authors.lastname: Kabututu
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Martin
authors.forename: Taba M
authors.initials: TM
authors.lastname: Kalulu
authors.forename: Mostaqul
authors.initials: M
authors.lastname: Huq
authors.forename: Haq
authors.initials: H
authors.lastname: Mustakuk
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ohnishi-Kameyama
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Michael
authors.initials: M
authors.lastname: Duszenko
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
mesh_terms: D000818:Animals; D002855:Chromatography, Thin Layer / Q000379:methods; D030221:Cola; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D008517:Phytotherapy / Q000379:methods*; D010936:Plant Extracts / Q000737:chemistry / Q000627:therapeutic use; D044945:Proanthocyanidins / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D014353:Trypanosomiasis, African / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
chemical_list: D010936:Plant Extracts; D044945:Proanthocyanidins; D014344:Trypanocidal Agents