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

Reinhart, Peter H; Kaltenbach, Linda S; Essrich, Christian; Dunn, Denise E; Eudailey, Joshua A; DeMarco, C Todd; Turmel, Gregory J; Whaley, Jennifer C; Wood, Andrew; Cho, Seongeun; Lo, Donald;

Keywords

  • 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

External Links