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Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target.
[cowden syndrome]
The
mammalian
target
of
rapamycin
(
mTOR
)
signaling
pathway
regulates
cell
growth
,
differentiation
,
proliferation
,
and
metabolism
.
Loss
-of-function
mutations
in
upstream
regulators
of
mTOR
have
been
highly
associated
with
dysplasias
,
epilepsy
,
and
neurodevelopmental
disorders
.
These
include
tuberous
sclerosis
,
which
is
due
to
mutations
in
TSC
1
or
TSC
2
genes
;
mutations
in
phosphatase
and
tensin
homolog
(
PTEN
)
as
in
Cowden
syndrome
,
polyhydramnios
,
megalencephaly
,
symptomatic
epilepsy
syndrome
(
PMSE
)
due
to
mutations
in
the
STE
20
-
related
kinase
adaptor
alpha
(
STRADalpha
)
;
and
neurofibromatosis
type
1
attributed
to
neurofibromin
1
mutations
.
Inhibition
of
the
mTOR
pathway
with
rapamycin
may
prevent
epilepsy
and
improve
the
underlying
pathology
in
mouse
models
with
disrupted
mTOR
signaling
,
due
to
PTEN
or
TSC
mutations
.
However
the
timing
and
duration
of
its
administration
appear
critical
in
defining
the
seizure
and
pathology-related
outcomes
.
Rapamycin
application
in
human
cortical
slices
from
patients
with
cortical
dysplasias
reduces
the
4
-
aminopyridine-induced
oscillations
.
In
the
multiple
-hit
model
of
infantile
spasms
,
pulse
high
-dose
rapamycin
administration
can
reduce
the
cortical
overactivation
of
the
mTOR
pathway
,
suppresses
spasms
,
and
has
disease-modifying
effects
by
partially
improving
cognitive
deficits
.
In
post-
status
epilepticus
models
of
temporal
lobe
epilepsy
,
rapamycin
may
ameliorate
the
development
of
epilepsy
-related
pathology
and
reduce
the
expression
of
spontaneous
seizures
,
but
its
effects
depend
on
the
timing
and
duration
of
administration
,
and
possibly
the
model
used
.
The
observed
recurrence
of
seizures
and
epilepsy
-related
pathology
after
rapamycin
discontinuation
suggests
the
need
for
continuous
administration
to
maintain
the
benefit
.
However
,
the
use
of
pulse
administration
protocols
may
be
useful
in
certain
age-
specific
epilepsy
syndromes
,
like
infantile
spasms
,
whereas
repetitive-pulse
rapamycin
protocols
may
suffice
to
sustain
a
long
-term
benefit
in
genetic
disorders
of
the
mTOR
pathway
.
In
summary
,
mTOR
dysregulation
has
been
implicated
in
several
genetic
and
acquired
forms
of
epileptogenesis
.
The
use
of
mTOR
inhibitors
can
reverse
some
of
these
epileptogenic
processes
,
although
their
effects
depend
upon
the
timing
and
dose
of
administration
as
well
as
the
model
used
.
Diseases
Validation
Diseases presenting
"acquired forms of epileptogenesis. the use"
symptom
cowden syndrome
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