NEUROTOXINS AND ANIMAL MODELS OF NEUROLOGICAL DISEASES

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The objectives of this project are to identify and characterize toxins which target specific neuronal systems,determine the mechanisms of action of these toxins, and use them to produce animal models of human neurologic disorders. At present the main focus is on two toxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and beta-methylaminoalanine (BMAA). MPTP is administered via the internal carotid artery to produce hemiparkinsonism in monkeys. These animals are used to evaluate changes cerebral metabolism (as indicated by autoradiographic determination of the uptake of 14C-2-deoxyglucose) as a result of the toxin-induced neurologic disorder and to examine the efficacy of tissue implants in alleviating the neurologic deficits. Biochemical and behavioral abnormalities are examined to evaluate the efficacy of tissue implants to replace destroyed neurons or enhance sprouting of surviving neurons. In other studies, mice are treated with various doses of MPTP and with substances which may potentiate its toxic effects. Fluid obtained from gelfoam placed in MPTP and surgically damaged brain is examined for substances which stimulate growth of neurons in tissue culture. Enhancement of MPTP toxicity by low doses of ethanol or acetaldehyde is not due to any effect on MPTP metabolism or retention of its metabolite, MPP+ .This enhancement of toxicity has now been shown to be negligible in young (7-day-old) mice, but marked in older (8-week-old) animals. Furthermore, ethanol or acetaldehyde appears to enhance the specificity of the toxin in targeting specific dopaminergic neurons. Gel foam plugs removed from cavities made in the caudate nucleus of MPTP parkinsonian monkeys contains soluble substance(s) which promotes neurite outgrowth in tissue cultured neurons. Similar substances have been found in fetal tissues, including amnion. BMAA has been implicated as responsible for the putative toxicity of flour produced from cycas circinalis and cited as one etiologic factor in the Amytrophic lateral sclerosis-parkinsonism-dementia complex of Guam (Guamanian ALS-PD). Samples of a flour from Guam as well as cycad plants from various sources have been assayed (by GC-MS) Processing of the cycad to produce the flour removes greater than 80% of the BMAA (usually over 95%) and the residual BMAA content is not sufficient to reach even a small fraction of the amounts reported to be toxic in monkeys. The BMAA contents of flour from various sources have been compared with toxicity elicited in vitro using granule cell tissue cultures. At the concentrations in flour, BMAA is not toxic to these cells but some of the flour samples were toxic. High concentrations of zinc were found in only toxic samples. Galvanized metal containers might have been used in preparation of these samples of flour, implicating zinc as a toxic metal related to Guamanian ALS-PD.