Identification of anti-inflammatory targets for Huntington's disease using a brain slice-based screening assay

Neurobiol Dis. 2011 Jul;43(1):248-56. doi: 10.1016/j.nbd.2011.03.017. Epub 2011 Mar 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Drug Delivery Systems / methods*
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Huntington Disease / drug therapy*
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Organ Culture Techniques
  • Rats
  • Rats, Sprague-Dawley


  • Anti-Inflammatory Agents, Non-Steroidal
  • Neuroprotective Agents