This is a second revision of a previously submitted application (R01-ES012443-01). It has recently been shown that apoptotic neurodegeneration can be triggered in the in vivo developing rodent CNS by any of several classes of drugs that have in common the property of abnormally suppressing neuronal activity. The period of vulnerability coincides with synaptogenesis, also known as the brain growth spurt period, which occurs postnatally in rodents (first 2 weeks after birth) and both prenatally and postnatally in humans (third trimester and several years after birth). Included among the offending agents are drugs that block NMDA glutamate receptors, drug that hyperactivate GABAA receptors and ethanol, which has both NMDA antagonist and GABAmimetic properties. The apoptogenic action of ethanol is a promising candidate to explain the reduced brain mass and neurobehavioral disturbances associated with the human Fetal Alcohol Syndrome. While interference with NMDA and GABAA neurotransmission during synaptogenesis is putatively responsible for much of ethanol's neurotoxic action, other mechanisms may also be operative in that ethanol kills some populations of neurons that are not affected by NMDA antagonist or GABAmimetic drugs. The applicants have recently discovered that an ethanol-like neurodegenerative syndrome can be induced in the developing rodent brain by certain solvents that are widely used in the industrial world to facilitate the manufacturing process or to dissolve and/or add functionality to marketed products, including injectable drugs used in human medicine. For example, we have found that dimethyl sulfoxide (DMSO) and propylene glycol, which are widely used throughout the world and are generally considered having a very low toxicity potential, trigger a robust neurodegenerative reaction in the developing rodent brain. This is not a property of all solvents in that polyethylene glycol, a very widely used solvent, does not display such activity.
The Aims of the proposed research are to more fully characterize the neurodegenerative reactions induced by DMSO and propylene glycol, to screen other solvents for their ability to mimic this type of neurodegenerative phenomenon, to evaluate the degree of risk associated with using these agents as solvent vehicles for drugs administered intravenously to human neonates and, by a combined in vivo/in vitro approach, attempt to elucidate mechanisms underlying these newly discovered neurotoxic phenomena.
