Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay.
Stem cells, through their ability to both self-renew and differentiate, can produce a virtually limitless supply of specialized cells that behave comparably to primary cells. We took advantage of this property to develop an assay for small-molecule-based neuroprotection using stem-cell-derived motor neurons and astrocytes, together with activated microglia as a stress paradigm. Here, we report on the discovery of hit compounds from a screen of more than 10,000 small molecules. These compounds act through diverse pathways, including the inhibition of nitric oxide production by microglia, activation of the Nrf2 pathway in microglia and astrocytes, and direct protection of neurons from nitric-oxide-induced degeneration. We confirm the activity of these compounds using human neurons. Because microglial cells are activated in many neurological disorders, our hit compounds could be ideal starting points for the development of new drugs to treat various neurodegenerative and neurological diseases.
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Susanne
S
Höing
York
Y
Rudhard
Peter
P
Reinhardt
Michael
M
Glatza
Martin
M
Stehling
Guangming
G
Wu
Christiane
C
Peiker
Alexander
A
Böcker
Juan A
JA
Parga
Eva
E
Bunk
Jens C
JC
Schwamborn
Mark
M
Slack
Jared
J
Sterneckert
Hans R
HR
Schöler
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D017348:Microscopy, Electron, Scanning Transmission; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D054852:Small Molecule Libraries; D009569:Nitric Oxide