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Drug screening to identify suppressors of GFAP expression.
[alexander disease]
Glial
fibrillary
acidic
protein
(
GFAP
)
is
the
major
intermediate
filament
protein
of
astrocytes
in
the
vertebrate
central
nervous
system
.
Increased
levels
of
GFAP
are
the
hallmark
feature
of
gliosis
,
a
non-
specific
response
of
astrocytes
to
a
wide
variety
of
injuries
and
disorders
of
the
CNS
,
and
also
occur
in
Alexander
disease
where
the
initial
insult
is
a
mutation
within
the
coding
region
of
GFAP
itself
.
In
both
settings
,
excess
GFAP
may
cause
or
exacerbate
astrocyte
dysfunction
.
With
the
goal
of
finding
drugs
that
reduce
the
expression
of
GFAP
,
we
have
devised
screens
to
detect
changes
in
GFAP
promoter
activity
or
protein
levels
in
primary
cultures
of
mouse
astrocytes
in
a
96
-
well
format
.
We
have
applied
these
screens
to
libraries
enriched
in
compounds
that
are
already
approved
for
human
use
by
the
FDA
.
We
report
that
several
compounds
are
active
at
micromolar
levels
in
suppressing
the
expression
of
GFAP
.
Treatment
of
mice
for
3
weeks
with
one
of
these
drugs
,
clomipramine
,
causes
nearly
50
%
reduction
in
the
levels
of
GFAP
protein
in
brain
.
Diseases
Validation
Diseases presenting
"changes in gfap promoter"
symptom
alexander disease
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