Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay

Research output: Contribution to journalResearch articleContributedpeer-review


  • Susanne Höing - , Max Planck Institute for Molecular Biomedicine (Author)
  • York Rudhard - , Evotec SE (Author)
  • Peter Reinhardt - , Max Planck Institute for Molecular Biomedicine (Author)
  • Michael Glatza - , Max Planck Institute for Molecular Biomedicine (Author)
  • Martin Stehling - , Max Planck Institute for Molecular Biomedicine (Author)
  • Guangming Wu - , Max Planck Institute for Molecular Biomedicine (Author)
  • Christiane Peiker - , Evotec SE (Author)
  • Alexander Böcker - , Evotec SE (Author)
  • Juan A. Parga - , University of Santiago de Compostela (Author)
  • Eva Bunk - , University of Münster (Author)
  • Jens C. Schwamborn - , University of Münster (Author)
  • Mark Slack - , Evotec SE (Author)
  • Jared Sterneckert - , Chair of iPS Cells and Neurodegenerative Diseases, Max Planck Institute for Molecular Biomedicine (Author)
  • Hans R. Schöler - , Max Planck Institute for Molecular Biomedicine, University of Münster (Author)


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.


Original languageEnglish
Pages (from-to)620-632
Number of pages13
JournalCell stem cell
Issue number5
Publication statusPublished - 2 Nov 2012

External IDs

PubMed 23064101
ORCID /0000-0002-7688-3124/work/142250045


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