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.
Frontiers in Pharmacology,
Год журнала:
2023,
Номер
14
Опубликована: Авг. 4, 2023
Therapeutics
discovery
and
development
for
Alzheimer’s
disease
(AD)
has
been
an
area
of
intense
research
to
alleviate
memory
loss
the
underlying
pathogenic
processes.
Recent
drug
approaches
have
utilized
in
silico
computational
strategies
candidate
selection
which
opened
door
repurposing
drugs
AD.
Computational
analysis
gene
expression
signatures
patients
stratified
by
APOE4
risk
allele
AD
led
FDA-approved
bumetanide
as
a
top
agent
that
reverses
transcriptomic
brain
improves
deficits
animal
models
Bumetanide
is
loop
diuretic
inhibits
kidney
Na
+
-K
-2Cl
−
cotransporter
isoform,
NKCC2,
treatment
hypertension
edema
cardiovascular,
liver,
renal
disease.
Electronic
health
record
data
revealed
exposed
lower
incidences
35%–70%.
In
brain,
proposed
antagonize
NKCC1
isoform
mediates
cellular
uptake
chloride
ions.
Blocking
neuronal
leads
decrease
intracellular
thus
promotes
GABAergic
receptor
mediated
hyperpolarization,
may
ameliorate
conditions
associated
with
GABAergic-mediated
depolarization.
expressed
neurons
all
cells
including
glia
(oligodendrocytes,
microglia,
astrocytes)
vasculature.
consideration
repurposed
AD,
this
review
evaluates
its
pharmaceutical
properties
respect
estimated
levels
across
doses
can
improve
neurologic
distinguish
between
non-NKCC1
mechanisms.
The
available
indicate
efficacy
occur
at
are
below
those
required
inhibition
transporter
implicates
mechansims
improvement
dysfunctions
deficits.
Alternatively,
peripheral
mechanisms
involve
outside
central
nervous
system
(e.g.,
epithelia
immune
system).
Clinical
improved
neurological
reviewed.
Regardless
mechanism,
model
potential
reduce
incidence
provide
support
clinical
investigation
therapeutic
agent.
Frontiers in Pharmacology,
Год журнала:
2024,
Номер
15
Опубликована: Апрель 9, 2024
Cerebrovascular
diseases
and
their
sequalae,
such
as
ischemic
stroke,
chronic
cerebral
hypoperfusion,
vascular
dementia
are
significant
contributors
to
adult
disability
cognitive
impairment
in
the
modern
world.
Astrocytes
an
integral
part
of
neurovascular
unit
CNS
play
a
pivotal
role
homeostasis,
including
ionic
p
H
balance,
neurotransmission,
blood
flow,
metabolism.
respond
insults,
inflammation,
through
unique
molecular,
morphological,
functional
changes,
collectively
known
reactive
astrogliosis.
The
function
astrocytes
has
been
subject
debate.
Initially,
were
thought
primarily
supportive
maintaining
structure
nervous
system.
However,
recent
studies
suggest
that
may
have
both
beneficial
detrimental
effects.
For
example,
can
cause
oligodendrocyte
death
demyelination.
In
this
review,
we
will
summarize
(1)
roles
ion
transporter
cascade
astrogliosis,
(2)
related
dementias,
(3)
potential
therapeutic
approaches
for
dementing
disorders
targeting
astrocytes.
Understanding
relationship
between
cascade,
cerebrovascular
reveal
mechanisms
targets
development
therapies
brain
associated
with
Frontiers in Cellular Neuroscience,
Год журнала:
2022,
Номер
16
Опубликована: Апрель 21, 2022
Increase
of
deposits
amyloid
β
peptides
in
the
extracellular
matrix
is
landmark
during
Alzheimer’s
Disease
(AD)
due
to
imbalance
production
vs.
clearance.
This
accumulation
triggers
microglial
activation.
Microglia
plays
a
dual
role
AD,
protective
by
clearing
increasing
phagocytic
response
(
CD163,
IGF-1
or
BDNF
)
and
cytotoxic
role,
releasing
free
radicals
(ROS
NO)
proinflammatory
cytokines
TNF-
α,
IL-1
β)
reactive
gliosis
activated
aggregates.
activation
correlated
with
an
increase
K
V
1.3
channels
expression,
protein
levels
current
density.
Several
studies
highlight
importance
inflammatory
inhibition
neural
progenitor
cell
proliferation
neuronal
differentiation.
However,
little
known
about
pathways
this
stem
cells
differentiation
accumulation.
In
recent
using
vitro
derived
from
mice
models,
it
has
been
demonstrated
that
blockers
inhibit
microglia-mediated
neurotoxicity
culture
reducing
expression
pro-inflammatory
α
through
NF-kB
p38MAPK
pathway.
Overall,
we
conclude
change
course
AD
development,
further
investigations
are
needed
establish
specific
pathway
validate
use
blocker
as
therapeutic
treatment
Alzheimer
patients.
Brain Sciences,
Год журнала:
2024,
Номер
14(3), С. 290 - 290
Опубликована: Март 19, 2024
Neuroinflammation
contributes
to
the
pathophysiology
of
major
depressive
disorder
(MDD)
by
inducing
neuronal
excitability
via
dysregulation
microglial
brain-derived
neurotrophic
factor
(BDNF),
Na-K-Cl
cotransporter-1
(NKCC1),
and
K-Cl
cotransporter-2
(KCC2)
due
activation
BDNF-tropomyosin
receptor
kinase
B
(TrkB)
signaling.
Allosteric
modulation
α7
nAChRs
has
not
been
investigated
on
BDNF,
KCC2,
NKCC1
during
LPS-induced
depressive-like
behavior.
Therefore,
we
examined
effects
PNU120596,
an
nAChR
positive
allosteric
modulator,
expression
in
hippocampus
prefrontal
cortex
using
Western
blot
analysis,
immunofluorescence
assay,
real-time
polymerase
chain
reaction.
The
ANA12,
a
TrkB
antagonist,
cognitive
deficit
behaviors
were
determined
Y-maze,
tail
suspension
test
(TST),
forced
swim
(FST).
Pharmacological
interactions
between
PNU120596
ANA12
also
examined.
Experiments
conducted
male
C57BL/6J
mice.
LPS
administration
(1
mg/kg)
resulted
increased
BDNF
NKCC1/KCC2
ratio
decreased
KCC2
cortex.
pretreatment
(4
attenuated
increase
reduction
these
brain
regions.
In
addition,
(0.25
or
0.50
reduced
measured
spontaneous
alternation
Y-maze
immobility
duration
TST
FST.
Coadministration
prevented
behaviors.
Overall,
behavior
likely
decreasing
targeting
Frontiers in Cellular Neuroscience,
Год журнала:
2024,
Номер
18
Опубликована: Май 17, 2024
Voltage-gated
ion
channels
are
essential
for
membrane
potential
maintenance,
homeostasis,
electrical
signal
production
and
controlling
the
Ca
2+
flow
through
membrane.
Among
all
channels,
key
regulators
of
neuronal
excitability
voltage-gated
potassium
(K
V
),
largest
family
K
+
channels.
Due
to
ROS
high
levels
in
aging
brain,
might
be
affected
by
oxidative
agents
neurodegeneration
processes.
This
review
provides
new
insight
about
channelopathies
most
studied
neurodegenerative
disorders,
such
as
Alzheimer
Disease,
Parkinson’s
Huntington
Disease
or
Spinocerebellar
Ataxia.
The
main
these
diseases
1,
2.1,
3,
4
7.
Moreover,
order
prevent
repair
development
diseases,
previous
channel
modulators
have
been
proposed
therapeutic
targets.
Frontiers in Cellular Neuroscience,
Год журнала:
2021,
Номер
15
Опубликована: Апрель 9, 2021
The
voltage-gated
proton
channel
Hv1
is
a
newly
discovered
ion
that
highly
conserved
among
species.
It
known
not
only
expressed
in
peripheral
immune
cells
but
also
one
of
the
major
channels
tissue-resident
microglia
central
nervous
systems
(CNS).
One
key
role
for
its
interaction
with
NADPH
oxidase
2
(NOX2)
to
regulate
reactive
oxygen
species
(ROS)
and
cytosolic
pH.
Emerging
data
suggest
excessive
ROS
production
increases
requires
currents
through
injured
CNS,
manipulations
ablate
expression
or
induce
loss
function
may
provide
neuroprotection
CNS
injury
models
including
stroke,
traumatic
brain
injury,
spinal
cord
injury.
Recent
demonstrating
microglial
Hv1-mediated
signaling
pathophysiology
further
supports
idea
as
mechanism
posttraumatic
neuroinflammation
neurodegeneration.
In
this
review,
we
summarize
main
findings
Hv1,
pattern,
cellular
mechanism,
aging,
animal
disease
pathology.
We
discuss
potential
therapeutic
target
Current Issues in Molecular Biology,
Год журнала:
2024,
Номер
46(2), С. 1150 - 1163
Опубликована: Янв. 29, 2024
Ion
channelopathies
result
from
impaired
ion
channel
protein
function,
due
to
mutations
affecting
transport
across
cell
membranes.
Over
40
diseases,
including
neuropathy,
pain,
migraine,
epilepsy,
and
ataxia,
are
associated
with
channelopathies,
impacting
electrically
excitable
tissues
significantly
skeletal
muscle.
Gene
transmembrane
ionic
flow
strongly
linked
muscle
disorders,
particularly
myopathies,
disrupting
excitability
contraction.
Electromyography
(EMG)
analysis
performed
on
a
patient
who
complained
of
weakness
fatigue
revealed
the
presence
primary
muscular
damage,
suggesting
an
early-stage
myopathy.
Whole
exome
sequencing
(WES)
did
not
detect
potentially
causative
variants
in
known
myopathy-associated
genes
but
novel
homozygous
deletion
P2RX6
gene
likely
function.
The
gene,
predominantly
expressed
muscle,
is
ATP-gated
receptor
belonging
purinergic
receptors
(P2RX)
family.
In
addition,
STRING
pathways
suggested
correlation
more
proteins
having
plausible
role
No
previous
studies
have
reported
implication
this
Further
needed
patients
defective
pathway,
use
vitro
functional
assays
suppressing
expression
will
be
required
validate
its
role.
Biology of Sex Differences,
Год журнала:
2024,
Номер
15(1)
Опубликована: Окт. 22, 2024
Abstract
With
the
National
Institutes
of
Health’s
mandate
to
consider
sex
as
a
biological
variable
(SABV),
there
has
been
significant
increase
studies
utilizing
both
sexes.
Historically,
we
have
known
that
and
hormones
influence
immunological
processes
now
focusing
on
interactions
between
immune,
endocrine,
nervous
systems
are
revealing
differences
pain
behavior
various
molecular
biochemical
processes.
Neuroendocrine-immune
represent
key
integrative
discipline
will
reveal
critical
in
each
field
it
pertains
novel
mechanisms
necessary
therapeutics.
Here
appraise
preclinical
clinical
literature
discuss
these
pathways
drive
cell-
sex-specific
immunity,
pain,
physiology.
