Brain-penetrant LSD1 inhibitors can block memory consolidation

Ramesh Neelamegam, Emily L. Ricq, Melissa Malvaez, Debasis Patnaik, Stephanie Norton, Stephen M. Carlin, Ian T. Hill, Marcelo A. Wood, Stephen J. Haggarty, Jacob M. Hooker

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Modulation of histone modifications in the brain may represent a new mechanism for brain disorder therapy. Post-translational modifications of histones regulate gene expression, affecting major cellular processes such as proliferation, differentiation, and function. An important enzyme involved in one of these histone modifications is lysine specific demethylase 1 (LSD1). This enzyme is flavin-dependent and exhibits homology to amine oxidases. Parnate (2-phenylcyclopropylamine (2-PCPA); tranylcypromine) is a potent inhibitor of monoamine oxidases, and derivatives of 2-PCPA have been used for development of selective LSD1 inhibitors based on the ability to form covalent adducts with flavin adenine dinucleotide (FAD). Here we report the synthesis and in vitro characterization of LSD1 inhibitors that bond covalently to FAD. The two most potent and selective inhibitors were used to demonstrate brain penetration when administered systemically to rodents. First, radiosynthesis of a positron-emitting analogue was used to obtain preliminary biodistribution data and whole brain time-activity curves. Second, we demonstrate that this series of LSD1 inhibitors is capable of producing a cognitive effect in a mouse model. By using a memory formation paradigm, novel object recognition, we show that LSD1 inhibition can abolish long-term memory formation without affecting short-term memory, providing further evidence for the importance of reversible histone methylation in the function of the nervous system.

Original languageEnglish (US)
Pages (from-to)120-128
Number of pages9
JournalACS Chemical Neuroscience
Volume3
Issue number2
DOIs
StatePublished - Feb 15 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Neelamegam, R., Ricq, E. L., Malvaez, M., Patnaik, D., Norton, S., Carlin, S. M., Hill, I. T., Wood, M. A., Haggarty, S. J., & Hooker, J. M. (2012). Brain-penetrant LSD1 inhibitors can block memory consolidation. ACS Chemical Neuroscience, 3(2), 120-128. https://doi.org/10.1021/cn200104y