NEUROTOXINS AND ANIMAL MODELS OF NEUROLOGICAL DISEASES

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The objectives are to identify and use toxic substances which target specific neuronal systems to produce animal models of neurological disease and to explore the mechanisms of action of such toxins as a means of examining: (1) The biochemical basis of neuron vulnerability to damage; (2) The role of such vulnerability in the pathogenesis of neurological disease; and (3) Approaches to new therapies for diseases of the nervous system. At present, 1- methyl-4-phenyl-1-2,3-6-tetrahydropyridine (MPTP) is the toxin most intensively studied, but other toxins such as beta- methylaminoalamine (BMAA) or 2-amino-3-methylamino-propanoic acid are being examined as well. MPTP is injected into mice at various doses, after various treatments, and the effects on movements observed. Monkeys are treated with MPTP either intravenously via the internal carotid artery. These animals are used to evaluate biochemical changes in body fluids (homovanillic acid, MHPG), effects on motor activity of DOPA and dopamine receptor agonists, alterations of dopamine neurones or receptors in various areas of brain as described for mice and by PET imaging with 18F-DOPA, or 2 DG radioautography. Implants of fetal tissue from the substantia nigra region are being used in attempts to reverse dopaminergic deficits in the basal ganglia of these animals. Compounds implicated as neurotoxins are synthesized with isotopically labelled components so that the occurrence, metabolism and distribution in the body of experimental animals can be examined. In vitro studies performed with MPP + support the view that the transplantation of MPTP to MPP + occurs in astrocytes in the brain and that the product is concentrated in dopaminergic neurons by the dopamine uptake system. BMAA has been successfully synthesized using deuterum labelled methylamine and the isotopically labelled compound used to develop a gas chromatography-mass spectrometry methods for assay of the suspected toxin in food products, body fluids and tissues. The BMAA content of cycad seeds of various types from Guam and other tropical areas has been determined and the process developed for preparation of the seeds for human consumption shown to remove almost all the toxin.