A combination of chemical and biological studies is proposed in an effort to elucidate mechanistic details associated with three selected examples of small-molecule-induced neurotoxicity. The chemical induction of neurological disorders is of interest in its own right, but especially on account of the fact that these disorders are excellent models for naturally occurring neuropathologic states. Thus, a study of the chemical toxins will likely provide important clues regarding the etiology of the naturally occurring diseases. The three areas of focus are (1) Molecular Mechanisms Responsible for the Induction of Giant Axonopathies by Alpha-Diketones and IDPN, (2) Mechanism of Toxic Action of Lathyrogens and Related Aminonitriles, and (3) Molecular Mechanisms Responsible for MPTP-Induced Parkinson Disease. In the first project analogs of 2,5-hexanedione (2,5-HD) and Beta, Beta-iminodipropionitrile (IDPN) will be synthesized, studied chemically, and biologically evaluated (by a collaborator), in an effort to clarify the structural basis of toxicity and, in the case of IDPN, the role of metabolic activation. In the latter case, the proposed toxic metabolite will be synthesized and used as a reference in an in vitro study aimed at identifying the initial IDPN metabolite(s). In the second project, a mechanism proposed to explain the observed irreversible inactivation of lysyl oxidase of Beta-aminopropionitrile (BAPN) will be tested in chemical model studies, as well as by enzymatic assay (through collaboration) of BAPN analogs. A similar mechanism proposed to explain the neurolathyrogenic properties of Beta-cyanoalanine will be tested through a chemical model and, if correct, suggests a new strategy for the design of suicide inactivators of amino acid decarboxylases. The third project will combine chemical model studies, in vitro metabolic studies, and the biological evaluation of structural analogs in an effort to identify the biochemical pathways responsible for the selective destruction by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) of dopaminergic neurons in the substantia nigra, an area in the brain which in man and higher primates, is rich in the pigment neuromelanin. The recent finding that the four-electron oxidation of MPTP to the pyridinium species (MPP+) is a prerequisite to neurotoxicity, suggests that either oxidation intermediates or a neuromelanin-mediated action of MPP+ cause the cell damage. This will be investigated in terms of the possible generation of reactive oxygen species and/or the possible depletion of glutathione.
