Human exposure to anthropogenic or naturally occurring chemicals contributes to the incidence of neurological disease. To estimate and minimize the human risk of neurological disease from chemical exposure, it is important to identify whether specific chemicals, or classes of chemicals, produce neurotoxicity. Biomarkers of neurotoxicity permit evaluation of exposure to an agent (i.e., dose) and the vulnerability of specific brain structures and cell populations, such as neurons and glial cells, to damage (i.e., effect). A useful approach to assess neurotoxicity is to identify marker proteins of neuronal or glial origin that are sensitive to change as a result of neurotoxic insult. Our approach to the development of a biomarker of neurotoxicity focuses on the peripheral benzodiazepine receptor (PBR), a glia-specific protein. The rationale for this strategy is that reactive gliosis is the earliest and most widespread response of the nervous system to injury. Quantification of a widespread response is needed as a generic biomarker when there is a paucity of knowledge about neuronal targets that may be damaged by a specific chemical. Although the PBR has now been used extensively by us and others as a biomarker of neurotoxicity in the adult brain, it has never been tested in the developing brain. Thus, the specific aims of this proposal are: (1) apply the PBR as a biomarker of neurotoxicity in developing animals;(2) to continue the application of the PBR as an in vivo biomarker of neurotoxicity using small animal imaging;and (3) to determine if the pharmacological activation of the PBR can prevent damage and/or promote recovery from chemical-induced brain injury. A novel aspect of the proposed work is the use of the PBR as an in vivo biomarker of neurotoxicity using state-of- the-art small animal brain imaging techniques. To the best of our knowledge, this is the first validation of a biomarker of neurotoxicity that will permit the study of the living brain in small animals following environmentally-relevant exposures to neurotoxicants. The validation of this technology may serve as a first- tier screening method in neurotoxicity testing of chemicals. Lastly, emerging evidence suggests that the pharmacological activation of the PBR may have neuroprotective effects. We will test this hypothesis in an animal model of demyelination. These studies may have important implications in the development of a novel therapeutic strategy for the treatment of brain injury.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Neurotoxicology and Alcohol Study Section (NAL)
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Kirshner, Annette G
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Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
United States
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