title: Identification of anti-inflammatory targets for Huntington's disease using a brain slice-based screening assay.
abstract: 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 HTT 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.
authors: Discovery Neuroscience, Wyeth Research, Princeton, NJ 08543, USA.
authors: Peter H
authors: PH
authors: Reinhart
authors: Linda S
authors: LS
authors: Kaltenbach
authors: Christian
authors: C
authors: Essrich
authors: Denise E
authors: DE
authors: Dunn
authors: Joshua A
authors: JA
authors: Eudailey
authors: C Todd
authors: CT
authors: DeMarco
authors: Gregory J
authors: GJ
authors: Turmel
authors: Jennifer C
authors: JC
authors: Whaley
authors: Andrew
authors: A
authors: Wood
authors: Seongeun
authors: S
authors: Cho
authors: Donald C
authors: DC
authors: Lo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents