[Rich66]

HDACs, thought to help defeat cancer stem cells, compared to Fluoxetine.

A recent paper in the Journal of
Neuroscience has shown that inhibitors
of histone deacetylases (HDACs)
— enzymes that affect the acetylation
status of histones and regulate the
remodelling of chromatin — have
antidepressant actions.
Although currently used antidepressants
rapidly modulate
mono aminergic systems in the
brain, the emergence of their moodelevating
effects requires several
weeks of administration, which
suggests that altered gene expression
is involved in antidepressant action.
So, compounds that modulate
the epigenetic regulation of gene
expression, such as HDAC inhibitors,
might have antidepressant actions.
Nestler and colleagues used a
mouse model of chronic social defeat
to investigate histone acetylation in
depression and the effect of HDAC
inhibitors in the nucleus accumbens,
which is a brain region implicated in
the development of depression and
antidepressant action.
Immunohistochemical analysis
showed that, although acetylation
levels of histone H3 at lysine
residue 14 (acH3K14) decreased
transiently by ~50% 1 hour after
the final stress event, there was an
increase at 24 hours and 10 days.
Expression levels of HDAC2, but
not of HDAC1 or HDAC3, were
decreased 24 hours and 10 days after
the final stress event, suggesting that
this could mediate the increase in
acH3K14 levels. A similar increase
in acH3K14 levels, accompanied
by a decrease in HDAC2 levels,
was present in postmortem
samples
of the nucleus accumbens from
depressed humans.
Infusion of the HDAC inhibitors
vorinostat (a class I and II HDAC
inhibitor) or MS275
(a class I
HDAC inhibitor) into the nucleus
accumbens of mice that were
subjected to chronic socialdefeat
stress reversed stressinduced
social
avoidance and increased the amount
of time that the mice spent socially
interacting. In forcedswim
tests,
which are often used as an acute
screen for antidepressants, both
inhibitors showed antidepressantlike
effects but had no effect on anxietylike
behaviour.
As chronic socialdefeat
stress
leads to distinctive patterns of gene
expression in the nucleus acumbens,
which can almost be normalized by
fluoxetine treatment, the authors
tested the effects of MS275
on gene
expression using microarray analysis.
Like fluoxetine, MS275
mostly
reversed stressinduced
genomic
changes, and both fluoxetine and
MS275
treatment caused similar
changes in the expression patterns
of many genes. The regulation of
certain genes by chronic stress
was reversed by MS275
but not
fluoxetine, which might reveal new
targets for antidepressant action.
These included genes encoding gap
junction membrane channel protein
α5 (which is involved in gap junction
formation), discs largeassociated
protein 1 (which assembles postsynaptic
density complexes) and
the α1αadrenergic
receptor.
So, although selectivity and
delivery issues remain to be resolved,
HDAC inhibitors, which are in
clinical trials for cancer indications,
might also have therapeutic potential
in depression.
Charlotte Harrison
ORIGINAL RESEARCH PAPER
Covington, H. E. et al. Antidepressant actions of
histone deacetylase inhibitors. J. Neurosci. 29,
11451–11460 (2009)
FuRtHER REAdING Kazantsev, A. G. &
Thompson, L. M. Therapeutic application of
histone deacetylase inhibitors for central
nervous system disorders. Nature Rev. Drug
Discov. 7, 854–868 (2008)
MOOd dISORdERS
Antidepressant action
through gene regulation
ReseaRch highlights
NATurE rEvIEwS | Drug Discovery voLuME 8 | NovEMbEr 2009
© 2009 Macmillan Publishers Limited. All rights reserved