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Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory
journal contribution
posted on 2018-06-22, 16:49 authored by Wen-Ning Zhao, Balaram Ghosh, Marshall Tyler, Jasmin Lalonde, Nadine F. Joseph, Nina Kosaric, Daniel M. Fass, Li-Huei Tsai, Ralph Mazitschek, Stephen J. HaggartyThrough epigenetic and other regulatory
functions, the histone
deacetylase (HDAC) family of enzymes has emerged as a promising therapeutic
target for central nervous system and other disorders. Here we report
on the synthesis and functional characterization of new HDAC inhibitors
based structurally on tianeptine, a drug used primarily to treat major
depressive disorder (MDD) that has a poorly understood mechanism of
action. Since the chemical structure of tianeptine resembles certain
HDAC inhibitors, we profiled the in vitro HDAC inhibitory activity
of tianeptine and demonstrated its ability to inhibit the lysine deacetylase
activity of a subset of class I HDACs. Consistent with a model of
active site Zn2+ chelation by the carboxylic acid present
in tianeptine, newly synthesized analogues containing either a hydroxamic
acid or ortho-aminoanilide exhibited increased potency
and selectivity among the HDAC family. This in vitro potency translated
to improved efficacy in a panel of high-content imaging assays designed
to assess HDAC target engagement and functional effects on critical
pathways involved in neuroplasticity in both primary mouse neurons
and, for the first time, human neurons differentiated from pluripotent
stem cells. Most notably, tianeptinaline, a class I HDAC-selective
analogue of tianeptine, but not tianeptine itself, increased histone
acetylation, and enhanced CREB-mediated transcription and the expression
of Arc (activity-regulated cytoskeleton-associated protein). Systemic
in vivo administration of tianeptinaline to mice confirmed its brain
penetration and was found to enhance contextual fear conditioning,
a behavioral test of hippocampal-dependent memory. Tianeptinaline
and its derivatives provide new pharmacological tools to dissect chromatin-mediated
neuroplasticity underlying memory and other epigenetically related
processes implicated in health and disease.