MECHANISMS OF ACTION OF SMALL-MOLECULE NEUROTOXINS

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This RCDA application is an updated version of a regular research proposal submitted by the PI in November 1984, and funded as of July 1985. This previous proposal involved a collaborative effector aimed at the elucidation of mechanistic details associated with three selected examples of chemically-induced neurotoxic syndromes that resemble naturally-occurring neurological disorders). The current proposal emphasizes the experiments to be carried out in chemistry by the PI, and describes the interactions between the PI and his biomedical collaborators in correlating the chemical and biological studies. The three areas of focus are (1) molecular mechanisms responsible for the induction of neurofilamentous 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 in an effort to clarify the structural basis of toxicity, particularly in respect to the direct chemical modification of neurofilament proteins by the neurotoxic chemical (or metabolite hereof). Additionally, in the case of IDPN, the pathway of metabolic activation will be clarified by a combination of chemical model studies and in vitro metabolism experiments. In the second project, a mechanism proposed to explain the observed irreversible inactivation of lysyl oxidase by beta-aminopropionitrile (BAPN) will be tested in chemical model studies, and correlated with enzymatic activities of BAPN analogs. A related mechanism proposed to explain the neurolathyrogenic properties of beta-cyanoalanine will be similarly tested, and may lead to a new strategy for the design of suicide inactivators of amino acid decarboxylases. The third project is directed at elucidating the molecualr basis of the selective toxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) to dopaminergic neurons in the substantia nigra. This project will combine chemical model studies, in vitro metabolic studies and the biochemical and ultrastructural in vivo evaluation of structural analogs of the suspected cytotoxic MPTP metabolites, focussing on the role of "redox cycling" (02 activation) and inhibition of mitochondrial oxidative metabolism as candidate mechanisms for cytotoxicity.