Neurotoxic injury is a model of peripheral nerve damage in which degeneration and regeneration occur at the same time. It provides, therefore, a useful way to study, at the cellular level, metabolic disease processes in which a similar equilibrium between injury and repair occurs. The mechanism and prevention of neurotoxicity is interesting in its own right because it may be caused by therapeutically useful drugs in humans. Cis-platinum produces specific injury to sensory neurons which we have reproduced in tissue culture models using dorsal root ganglion neurons and PC12 cells. We have also demonstrated that this cellular injury may be prevented or ameliorated by simultaneous exposure of cells to NGF or analogs of ACTH. For ACTH peptide fragment 4-9, this protection begins to occur with molar ratios of cis-platinum to peptide of 14,000 to one implying induction of a protective mechanism within the cell rather than a non-specific interaction of the molecules outside of the cell. For the first time, we have definitively demonstrated that cis-platinum neurotoxicity is separable from its chemotherapeutic effect. It is most toxic to rapidly dividing cancer cells because of damage to DNA, therefore, we predict that damage to post-mitotic DRG neurons occurs by a different mechanism . In this proposal we will study the cellular mechanism of cis-platinum induced neuronal injury and the mechanism by which the identified molecules prevent this injury. Initial studies will focus on determining whether these compounds interact at the extracellular, cell membrane receptor, or post-receptor (intracellular) level. If interaction is at the intracellular level, then subcellular distribution, and prevention of DNA damage and the neuron specific process of axonal transport will be studied. This system provides an ideal model in which a specific type of neuronal injury and its prevention may be studied at the molecular level.
|Effective start/end date||10/1/86 → 9/30/96|
- National Institute of Neurological Disorders and Stroke
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