Identification of anti-inflammatory targets for Huntington's disease using a brain slice-based screening assay
- Resource Type
- Authors
- Jennifer C. Whaley; Denise E. Dunn; Donald C. Lo; Seongeun Cho; Christian Essrich; C. Todd DeMarco; Gregory J. Turmel; Linda S. Kaltenbach; Joshua Eudailey; Peter H. Reinhart; Andrew Wood
- Source
- Neurobiology of Disease, Vol 43, Iss 1, Pp 248-256 (2011)
- Subject
- congenital, hereditary, and neonatal diseases and abnormalities
Huntingtin
Adenosine
A2A
Drug Evaluation, Preclinical
Context (language use)
Biology
Neuroprotection
Article
lcsh:RC321-571
Rats, Sprague-Dawley
Drug Delivery Systems
Organ Culture Techniques
Huntington's disease
mental disorders
medicine
Huntingtin Protein
Animals
Humans
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Inflammation
CXCR3
Drug discovery
IKK
Anti-Inflammatory Agents, Non-Steroidal
Neurodegeneration
medicine.disease
Corpus Striatum
Rats
Huntington Disease
Neuroprotective Agents
Animals, Newborn
Neurology
nervous system
Nerve Degeneration
Neuropathogenesis
JNK
Microglia
Neuroscience
- Language
- English
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.