MECHANISMS OF NEUROTOXIC ACTION AND METABOLIC ACTIVATION

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This is a continuation of a collaborative effort to elucidate molecular mechanisms associated with several types of chemically-induced neurotoxic syndromes that resemble naturally-occurring neurological disorders. With ongoing development of this program, the major thrust is focusing more on specific aspects of the toxic activation mechanisms and on underlying biochemical considerations. In Project I, a major issue is whether accumulation of neurofilaments (NF) in peripheral axons induced by neurotoxic chemicals such as gamma-diketones, beta, beta'-imino- dipropionitrile (IDPN), and CS2, is a consequence of (i) simple covalent modification of NF or (ii) a subsequent NF cross-linking. Studies on gamma-diketone analogs which permit a dissociation of these two factors are proposed, as are chemical studies which address the nature of potential protein cross-linking reactions. Another area of focus is the metabolic activation of IDPN, a neurotoxin which induces a Tourette-like behavioral abnormality in addition to a peripheral axonopathy, and the related bladder neurotoxin beta-(dimethylamino)propionitrile (DMAP). The first part of Project II is directed at clarifying certain details regarding the mechanism of toxic activation of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Studies are proposed (i) to gain further insight into the mechanism of and structural dependence governing the inhibition of mitochondrial respiration by the neurotoxic MPTP metabolite, 1-- methyl-4-phenylpyridinium (MPP+), (ii) to obtain a better definition of what MPTP- or MPP+-like structures could act as endogenous or exogenous neurotoxins, (iii) to clarify the propensity for free-radical production and reactive intermediate generation in MPTP metabolism, and (iv) to develop 18F-containing MPTP analogs for positron emission tomography (PET) studies on MPTP biodistribution in primate brain. The second part of Project II focuses on basic biochemical mechanisms of metabolic activation of toxic tertiary amines related to MPTP, which are associated with suicide inactivation of metabolizing enzymes and covalent binding to proteins. A combination of model chemical oxidation, enzymologic, and in vitro metabolism studies is proposed.