Redefining Roles: A Paradigm Shift in Tryptophan–Kynurenine Metabolism for Innovative Clinical Applications
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(23), С. 12767 - 12767
Опубликована: Ноя. 27, 2024
The
tryptophan-kynurenine
(KYN)
pathway
has
long
been
recognized
for
its
essential
role
in
generating
metabolites
that
influence
various
physiological
processes.
Traditionally,
these
have
categorized
into
distinct,
often
opposing
groups,
such
as
pro-oxidant
versus
antioxidant,
excitotoxic/neurotoxic
neuroprotective.
This
dichotomous
framework
shaped
much
of
the
research
on
conditions
like
neurodegenerative
and
neuropsychiatric
disorders,
well
cancer,
where
metabolic
imbalances
are
a
key
feature.
effects
significantly
influenced
by
factors,
including
concentration
particular
cellular
milieu
which
they
generated.
A
molecule
acts
neuroprotective
at
low
concentrations
may
exhibit
neurotoxic
elevated
levels.
oxidative
equilibrium
surrounding
environment
can
alter
function
KYN
from
an
antioxidant
to
pro-oxidant.
narrative
review
offers
comprehensive
examination
analysis
contemporary
understanding
metabolites,
emphasizing
their
multifaceted
biological
functions
relevance
numerous
pathological
underscores
pressing
necessity
paradigm
shift
comprehension
metabolism.
Understanding
context-dependent
roles
is
vital
novel
therapies
Alzheimer's
disease,
multiple
sclerosis,
cancer.
Comprehensive
modulation,
balancing
inflammatory
signals
enzyme
regulation,
promising
avenues
targeted,
effective
treatments.
Язык: Английский
UPF 648, a Selective KMO Inhibitor, Attenuates Psychomotor and Cognitive Impairment in Chronic Kidney Disease
ACS Chemical Neuroscience,
Год журнала:
2025,
Номер
16(5), С. 908 - 919
Опубликована: Фев. 17, 2025
Kynurenine-3-monooxygenase
(KMO),
a
key
enzyme
in
the
kynurenine
pathway
(KP)
of
tryptophan
metabolism,
converts
into
neurotoxic
intermediate
quinolinic
acid
(QA).
QA,
an
N-methyl-d-aspartate
(NMDA)
receptor
agonist,
increases
glutamate
release
and
inhibits
its
reuptake,
resulting
excitotoxic
cell
death
hippocampus
striatum.
Plasma
metabolomics
study
exhibited
KP
metabolites
as
most
altered
patients
with
chronic
kidney
disease
(CKD).
Recently,
QA
was
linked
to
kidney-brain
axis
one
major
neurotoxins
responsible
for
cognitive
impairment
advanced
CKD
stages.
Various
preclinical
models
are
being
tested
explore
different
intermediates
that
can
be
targeted
ameliorate
central
nervous
system
(CNS)
complications
CKD.
In
this
study,
adenine-induced
model
developed
C57BL/6
mice,
where
UPF
648,
selective
KMO
inhibitor,
administered
observe
changes
hippocampus.
Treatment
648
did
not
alter
function
or
morphology
inhibition
led
decreased
plasma
levels
reduced
pro-inflammatory
cytokine
interleukin-1-β
(IL-1β).
treatment
ameliorated
characteristic
symptoms
motor
dysfunction,
anxiety,
depression,
hippocampus-dependent
memory.
Important
markers
neuronal
survival
plasticity
through
brain-derived
neurotrophic
factor
(BDNF)-tropomyosin
kinase
B
(TRKB)-cAMP-responsive
element
binding
protein
1
(CREB1)
were
upregulated
after
inhibition.
conclusion,
exciting
target
attenuate
neuropsychiatric
burden
stages
Язык: Английский
Metabolic Syndrome and Schizophrenia: Adding a Piece to the Interplay Between the Kynurenine Pathway and Inflammation
Metabolites,
Год журнала:
2025,
Номер
15(3), С. 176 - 176
Опубликована: Март 5, 2025
The
biology
of
schizophrenia
is
highly
complex
and
multifaceted.
Numerous
efforts
have
been
made
over
the
years
to
disentangle
heterogeneity
disease,
gradually
leading
a
more
detailed
understanding
its
underlying
pathogenic
mechanisms.
Two
cardinal
elements
in
pathophysiology
are
neuroinflammation
alterations
neurotransmission.
kynurenine
(KYN)
pathway
(KP)
particular
importance
because
it
inducted
by
systemic
low-grade
inflammation
peripheral
tissues,
producing
metabolites
that
neuroactive
(i.e.,
modulating
glutamatergic
cholinergic
neurotransmission),
neuroprotective,
or
neurotoxic.
Consequently,
KP
at
crossroads
between
two
primary
systems
involved
pathogenesis
schizophrenia.
It
bridges
central
nervous
system
(CNS)
periphery,
as
can
cross
blood–brain
barrier
modulate
neuronal
activity.
Metabolic
syndrome
plays
crucial
role
this
context,
frequently
co-occurs
with
schizophrenia,
contributing
sub-inflammatory
state
able
activate
KP.
This
narrative
review
provides
valuable
insights
into
these
interactions,
offering
framework
for
developing
targeted
therapeutic
interventions
precision
psychiatry
approaches
disorder.
Язык: Английский
Physiological and pathophysiological effects of L-tryptophan’s metabolites on the brain and immunity – a challenge for drug development
Pharmacia,
Год журнала:
2025,
Номер
72, С. 1 - 7
Опубликована: Март 19, 2025
The
dysregulation
of
the
kynurenine
branch
from
tryptophan
(TRP)
metabolism
can
cause
an
imbalance
between
neuroprotective
kynurenic
acid
and
neurotoxic
metabolites
in
some
psychiatric
neurodegenerative
disorders.
Therefore,
modulation
TRP
may
contribute
to
novel
therapeutic
strategies
for
several
neuropsychiatric
diseases.
Targeting
L-TRP-kynurenine
pathway
enzymes,
particularly
involving
indoleamine
2,3-dioxygenase-1,
2,3-dioxygenase,
3-monooxygenase,
aminotransferase
II,
is
a
promising
approach.
future
development
potent
selective
inhibitors
these
enzymes
with
good
safety
profile
would
be
potential
new
avenue
treatment
many
essential
amino
L-Tryptophan,
together
its
metabolites,
plays
key
role
diverse
physiological
pathophysiological
processes
brain,
especially
disorders
autoimmunity.
Also,
vital
biochemical
precursor
functional
neuroactive
molecules,
including
serotonin
melatonin,
which
are
great
importance
memory
learning,
emotional
regulation,
circadian
cycle,
hunger,
pain,
etc.
This
article
aims
underscore
links
tryptophan’s
certain
diseases
central
nervous
system.
Язык: Английский
Kynurenine amplifies tetrahydrocannabinol-induced sensorimotor impairment and classic “tetrad” effects in mice
Progress in Neuro-Psychopharmacology and Biological Psychiatry,
Год журнала:
2025,
Номер
unknown, С. 111342 - 111342
Опубликована: Март 1, 2025
Язык: Английский
Kynurenine Pathway in Epilepsy: Unraveling Its Role in Glutamate Excitotoxicity, GABAergic Dysregulation, Neuroinflammation, and Mitochondrial Dysfunction
Neurotoxicity Research,
Год журнала:
2025,
Номер
43(2)
Опубликована: Март 28, 2025
Язык: Английский
Navigating Neurodegeneration: Integrating Biomarkers, Neuroinflammation, and Imaging in Parkinson’s, Alzheimer’s, and Motor Neuron Disorders
Biomedicines,
Год журнала:
2025,
Номер
13(5), С. 1045 - 1045
Опубликована: Апрель 25, 2025
Neurodegenerative
diseases
represent
a
daunting
global
challenge,
affecting
millions
worldwide
and
imposing
significant
clinical
socioeconomic
burdens
[...]
Язык: Английский
Seventy-Five Years of Interactions: The Department of Physiology and Pharmacology at Karolinska Institutet andPharmacological Reviews
Pharmacological Reviews,
Год журнала:
2024,
Номер
76(6), С. 972 - 977
Опубликована: Окт. 16, 2024
This
special
issue
emerged
from
an
informal
discussion
at
editorial
board
meeting
during
2023,
where
the
75th
anniversaries
of
Pharmacological
Reviews
and
Department
Physiology
Pharmacology
Karolinska
Institutet,
Stockholm,
Sweden
were
coincidentally
discussed.
The
idea
for
Язык: Английский
The genetic landscape of kynurenine predicts neurovascular pathology and disrupted white matter integrity in patients with mood disorders
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 12, 2024
Abstract
Low-grade
systemic
inflammation
is
linked
to
cardiometabolic
diseases
and
increased
cardiovascular
risk.
Patients
with
mood
disorders,
such
as
Major
Depressive
Disorder
(MDD)
Bipolar
(BD),
also
show
elevated
risk
inflammatory
markers,
suggesting
shared
biological
pathways
between
conditions.
The
kynurenine
(KYN)
pathway,
activated
by
cytokines
involved
in
neurotransmitter
systems
mood,
provides
a
promising
area
explore
inflammatory-related
genetic
overlaps
these
increasing
interest
the
SH2B3
rs3184504
SNP.
Imaging
markers
like
white
matter
hyperintensities
(WMHs)
(WM)
microstructure
alterations
are
associated
disorders.
This
study
aimed
investigate
load
link
KYN
levels,
polygenic
score
(PRS)
its
effect
on
(WMHs),
outcomes
of
presumed
vascular
suffering,
WM
sample
95
MDD
80
BD
patients.
Higher
PRS
for
was
circulating
levels
KYN/TRP
ratio.
predicted
presence
WMHs.
T
variant
higher
number
ratio
were
not
WMHs,
while
positively
correlated
axial
(AD)
mean
diffusivity
(MD),
nominal
significance
radial
(RD).
findings
support
contribution
integrity
indicates
potential
predisposition
dysregulation,
may
modulate
this
Язык: Английский