Abstract
Kv1.3
channels
in
microglia
are
pivotal
regulating
neuroinflammation.
The
antipsychotic
chlorpromazine
(CPZ)
demonstrates
anti-inflammatory
effects
by
decreasing
activity
mPFC
microglia.
However,
the
precise
mechanism
of
CPZ’s
effect
remains
unclear,
given
that
CPZ
is
known
to
inhibit
dopamine
receptors
and
contains
various
cell
types
with
receptors.
In
this
study,
we
investigate
how
inhibits
using
human
channel-expressing
Xenopus
laevis
oocytes.
directly
channel
currents
a
concentration-dependent
manner.
CPZ-mediated
inhibition
not
voltage-dependent,
accelerates
inactivation
without
significantly
affecting
its
activation.
Our
findings
suggest
blocks
involving
other
ion
or
receptors,
including
thereby
contributing
understanding
neuroinflammation-suppressing
mechanism.
Epilepsy
is
a
chronic
neurological
disorder
marked
by
recurrent
seizures,
significantly
impacting
individuals
worldwide.
Current
treatments
are
often
ineffective
for
third
of
patients
and
can
cause
severe
side
effects,
necessitating
new
therapeutic
approaches.
Glial
cells,
particularly
astrocytes,
microglia,
oligodendrocytes,
emerging
as
crucial
targets
in
epilepsy
management.
Astrocytes
regulate
neuronal
homeostasis,
excitability,
synaptic
plasticity,
playing
key
roles
maintaining
the
blood-brain
barrier
(BBB)
mediating
neuroinflammatory
responses.
Dysregulated
astrocyte
functions,
such
reactive
astrogliosis,
lead
to
abnormal
activity
seizure
generation.
They
release
gliotransmitters,
cytokines,
chemokines
that
may
exacerbate
or
mitigate
seizures.
Microglia,
innate
immune
cells
CNS,
contribute
neuroinflammation,
glutamate
excitotoxicity,
balance
between
excitatory
inhibitory
neurotransmission,
underscoring
their
dual
role
promotion
protection.
Meanwhile,
primarily
involved
myelination,
also
modulate
axonal
excitability
neuron-glia
network
underlying
pathogenesis.
Understanding
dynamic
interactions
glial
with
neurons
provides
promising
avenues
novel
therapies.
Targeting
these
improved
control
better
clinical
outcomes,
offering
hope
refractory
epilepsy.
Neurobiology of Disease,
Год журнала:
2025,
Номер
206, С. 106833 - 106833
Опубликована: Фев. 6, 2025
Microglial
canonical
transient
receptor
potential
channel
1
(TRPC1)
has
been
proposed
to
influence
neuroinflammation
after
cerebral
ischemia
and
reperfusion
injury
(CIRI),
however,
the
underlying
mechanism
remains
poorly
understood.
This
study
demonstrates
that
TRPC1
is
modified
by
small
ubiquitin-related
modifier
(SUMO)ylation.
Our
findings
suggest
a
notable
increase
in
microglial
SUMOylation
within
both
middle
artery
occlusion
(MCAO/R)
model
vitro
oxygen-glucose
deprivation/regeneration
model.
Mice
with
loss
of
microglia
exhibited
improved
stroke
outcomes
including
reduced
behavior
deficits,
infarct
volume,
blood
brain
barrier
damage
as
well
neuronal
apoptosis.
Mechanistically,
exacerbated
neutrophil
infiltration
into
peri-infarct
area.
Additionally,
SUMOylated
activates
Nod-like
protein
(NLRP)
3
signaling
pathway
stimulates
multiple
CC-chemokine
ligands
C-X-C
motif
ligand
chemokines
MCAO/R.
facilitates
interaction
between
β-arrestin2
(ARRB2),
negative
regulator
NLRP3
inflammasome,
which
disrupts
NLPR3/ARRB2
complex
activation
NLPR3
pathway.
Furthermore,
ARRB2
directly
binds
residues
46
61
N
terminus,
enhanced
SUMOylation.
Collectively,
our
demonstrate
previously
unidentified
regulates
leukocyte
stroke,
suggesting
inhibition
may
provide
therapeutic
benefits
for
CIRI.
Frontiers in Neurology,
Год журнала:
2025,
Номер
16
Опубликована: Апрель 15, 2025
Background
Post-traumatic
epilepsy
(PTE)
is
a
common
complication
following
traumatic
brain
injury
(TBI).
Early
PTE
refers
to
the
appearance
of
seizure
symptoms
within
7
days
injury.
The
glucose-to-potassium
ratio
(GPR)
has
emerged
as
potential
biomarker
for
predicting
risk.
This
study
aimed
evaluate
association
between
GPR
and
risk
PTE,
assess
predictive
value
through
various
analyses.
Methods
A
total
2,049
TBI
patients
were
included
in
analysis,
with
evaluated
both
continuous
categorical
variable.
Logistic
regression,
trend
tests,
Kaplan-Meier
(KM)
curve
analyses
performed
relationship
PTE.
Subgroup
conducted
explore
effect
modifiers,
restricted
cubic
spline
(RCS)
used
examine
non-linear
associations.
Adjustments
made
demographic,
clinical,
biochemical
factors.
Results
demonstrated
significant
risk,
turning
point
at
=
2.835.
Patients
>
2.835
exhibited
higher
epilepsy,
indicated
by
KM
analysis
(
P
<
0.0001).
regression
revealed
that
was
an
independent
predictor
unadjusted
adjusted
models.
In
fully
model,
remained
significantly
associated
early
(OR:
1.499,
95%
CI:
1.188–1.891,
0.001).
identified
gender,
hypertension,
diabetes
modifiers.
Trend
tests
dose-response
quartiles
highest
quartile
showing
partially
models
0.017).
Conclusions
robust
levels
strongly
increased
epilepsy.
variations
across
subgroups
underscore
clinical
utility
stratification
personalized
management
patients.
Abstract
Kv1.3
channels
in
microglia
are
pivotal
regulating
neuroinflammation.
The
antipsychotic
chlorpromazine
(CPZ)
demonstrates
anti-inflammatory
effects
by
decreasing
activity
mPFC
microglia.
However,
the
precise
mechanism
of
CPZ’s
effect
remains
unclear,
given
that
CPZ
is
known
to
inhibit
dopamine
receptors
and
contains
various
cell
types
with
receptors.
In
this
study,
we
investigate
how
inhibits
using
human
channel-expressing
Xenopus
laevis
oocytes.
directly
channel
currents
a
concentration-dependent
manner.
CPZ-mediated
inhibition
not
voltage-dependent,
accelerates
inactivation
without
significantly
affecting
its
activation.
Our
findings
suggest
blocks
involving
other
ion
or
receptors,
including
thereby
contributing
understanding
neuroinflammation-suppressing
mechanism.
