A recent report by a National Academy of Science expert panel entitled """"""""Neurotoxicity: Identifying and controlling poisons of the nervous system indicates that there are thousand of chemicals in use today whose toxicity to the central nervous system (CNS) are not known. This is due, at least in part, to the lack of sensitive and general biomarkers to assess CNS neurotoxicity. Neuronal damaged caused by a number of insults has been shown to result in dose-related and region specific increases in glial fibrillary acidic protein (GFAP), an astrocyte specific protein. As a result, GFAP has been proposed as a biomarker of toxicity. The development of methods to assess GFAP levels in brain tissue represent important advances on the field of CNS biomarkers, but there are limitations. A major limitation of these methods is that they can not be applied for in vivo assessment of neurotoxicity. Thus, the development of a biomarker that can detect generalized neuronal damage, it's quantitative, provides topographical information of CNS damage, and can be applied for in vivo studies would be advantageous. We believe that the measurement of radiolabeled PK11195 to peripheral benzodiazepine (BDZ) receptors may be such a biomarker. The proposed studies will use quantitative methods to measure peripheral BDZ receptors as a biomarker of neurotoxicity. We propose to validate the use of in vitro [3H]-PKI 1195 and [125I]-PK11195 autoradiography to measure peripheral BDZ receptors in the brain of animals exposed to prototypical neurotoxins. The method is quantitative and provides excellent topographical information of brain damage. The proposed method will be compared in the same animals with GFAP levels, classical histological methods, or biochemical methods when appropriate. The second approach is the in vivo measurement of [125-I]-PK11195 radioactivity in the living mouse brain using a commercially available single photon radiation detection system (i.e., probe). This method is quantitative and is an important aspect of the proposed work since it may extend the use of the biomarker to study human populations. These approaches are feasible and will provide new and important information on the and important information on the development of a biomarker of CNS neurotoxicity.
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