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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
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated