title: The targets of acetone cyanohydrin neurotoxicity in the rat are not the ones expected in an animal model of konzo.
abstract: Konzo is a neurotoxic motor disease caused by excess consumption of insufficiently processed cassava. Cassava contains the cyanogenic glucoside linamarin, but konzo does not present the known pathological effects of cyanide. We hypothesized that the aglycone of linamarin, acetone cyanohydrin, may be the cause of konzo. This nitrile rapidly decomposes into cyanide and acetone, but the particular exposure and nutrition conditions involved in the emergence of konzo may favor its stabilization and subsequent acute neurotoxicity. A number of preliminary observations were used to design an experiment to test this hypothesis. In the experiment, young female Long-Evans rats were given 10mM acetone cyanohydrin in drinking water for 2 weeks, and then 20mM for 6 weeks. Nutrition deficits associated with konzo were modeled by providing tapioca (cassava starch) as food for the last 3 of these weeks. After this period, rats were fasted for 24h in order to increase endogenous acetone synthesis, and then exposed to 0 (control group) or 50 micromol/kg-h of acetone cyanohydrin for 24h (treated group) through subcutaneous osmotic minipump infusion (n=6/group). Motor activity and gait were evaluated before exposure (pre-test), and 1 and 6 days after exposure. Brains (n=4) were stained for neuronal degeneration by fluoro-jade B. Rats exposed to 50 micromol/kg-h of acetone cyanohydrin showed acute signs of toxicity, but no persistent motor deficits. Two animals showed fluoro-jade staining in discrete thalamic nuclei, including the paraventricular and the ventral reuniens nuclei; one also exhibited labeling of the dorsal endopiriform nucleus. Similar effects were not elicited by equimolar KCN exposure. Therefore, acetone cyanohydrin may cause selective neuronal degeneration in the rat, but the affected areas are not those expected in an animal model of konzo.
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, 08907 Hospitalet de Llobregat, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Soler-Martín
authors.forename: Judith
authors.initials: J
authors.lastname: Riera
authors.forename: Ana
authors.initials: A
authors.lastname: Seoane
authors.forename: Blanca
authors.initials: B
authors.lastname: Cutillas
authors.forename: Santiago
authors.initials: S
authors.lastname: Ambrosio
authors.forename: Pere
authors.initials: P
authors.lastname: Boadas-Vaello
authors.forename: Jordi
authors.initials: J
authors.lastname: Llorens
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000175:diagnosis / Q000503:physiopathology; D005260:Female; D005452:Fluoresceins; D015918:Infusion Pumps, Implantable; D008297:Male; D002365:Manihot / Q000737:chemistry* / Q000506:poisoning* / Q000633:toxicity; D020644:Midline Thalamic Nuclei / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000503:physiopathology*; D009570:Nitriles / Q000633:toxicity*; D009930:Organic Chemicals; D051381:Rats; D020318:Rats, Long-Evans; D013194:Staining and Labeling; D013788:Thalamus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D005452:Fluoresceins; D009570:Nitriles; D009930:Organic Chemicals; C435731:fluoro jade; C010833:acetone cyanohydrin