期刊
NEUROBIOLOGY OF DISEASE
卷 43, 期 1, 页码 248-256出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.03.017
关键词
Adenosine; A(2A); JNK; IKK; CXCR3; Microglia; Neurodegeneration; Neuroprotection; Biolistics; Brain slice; Drug discovery; Inflammation
资金
- High Q Foundation
- CHDI Foundation, Inc.
- Hereditary Disease Foundation
- NIH [NS048181]
Huntington's disease (HD) is a late-onset, neurodegenerative disease for which there are currently no cures nor disease-modifying treatments. Here we report the identification of several potential anti-inflammatory targets for HD using an ex vivo model of HD that involves the acute transfection of human mutant huntingtin-based constructs into rat brain slices. This model recapitulates key components of the human disease, including the formation of intracellular huntingtin protein (HTT)-containing inclusions and the progressive neurodegeneration of striatal neurons both occurring within the native tissue context of these neurons. Using this high-throughput biology screening platform, we conducted a hypothesis-neutral screen of a collection of drug-like compounds which identified several anti-inflammatory targets that provided neuroprotection against HIT fragment-induced neurodegeneration. The nature of these targets provide further support for non-cell autonomous mechanisms mediating significant aspects of neuropathogenesis induced by mutant HTT fragment proteins. (C) 2011 Elsevier Inc. All rights reserved.
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