title: Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour.
abstract: Consumption of cycad seed products (Cycas circinalis) is one of the strongest epidemiological links to the Guamian neurological disorder amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), however, the putative toxin which causes neurodegeneration has never been identified definitively. To reexamine this issue, 6-7-mo-old, male CD-1 mice were assessed for motor and cognitive behaviours during and following feeding with pellets made from washed cycad flour. Cycad-fed animals showed early evidence of progressive motor and cognitive dysfunctions. Neurodegeneration measured using TUNEL and caspase-3 labeling was found in neocortex, various hippocampal fields, substantia nigra, olfactory bulb, and spinal cord. In vitro studies using rat neocortex have identified toxic compounds in washed cycad flour that induce depolarizing field potentials and lead to release of lactate dehydrogenase (LDH), both blocked by AP5. High-performance liquid chromatography (HPLC)/mass spectrometry of cycad flour samples failed to show appreciable amounts of other known cycad toxins, cycasin, MAM, or BMAA; only trace amounts of BOAA were present. Isolation procedures employing these techniques identified the most toxic component as beta-sitosterol beta-D-glucoside (BSSG). The present data suggest that a neurotoxin, or a toxic metabolite, not previously identified in cycad, is able to gain access to central nervous system (CNS) resulting in neurodegeneration of specific neural populations and in motor and cognitive dysfunctions. These data are consistent with a number of major features of ALS-PDC in humans.
authors.affiliation: Department of Ophthalmology, University of British Columbia, Vancouver, Canada.
authors.forename: Jason M B
authors.initials: JM
authors.lastname: Wilson
authors.forename: Iraj
authors.initials: I
authors.lastname: Khabazian
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Wong
authors.forename: Arash
authors.initials: A
authors.lastname: Seyedalikhani
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Bains
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Pasqualotto
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Simpson
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
authors.forename: Ulla-Kate
authors.initials: UK
authors.lastname: Craig
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Kurland
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Shaw
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D029784:Cycas / Q000737:chemistry*; D007794:Lameness, Animal / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010936:Plant Extracts / Q000633:toxicity*; D051381:Rats; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology
chemical_list: D009498:Neurotoxins; D010936:Plant Extracts