5 research outputs found
Cytokines in the nervous system with emphasis on interleukin-1 receptor-mediated activity
Interleukin-1 (IL-1) is one of the most important pro-inflammatory
cytokines and plays a pivotal role in the neuroinflammation associated
with certain forms of neurodegeneration, such as epilepsy, cerebral
ischemia, trauma, and Alzheimer's disease (AD). Also, it was suggested
that IL-1 is involved in physiological processes, namely modulation of
sleep, glucose and lipid metabolism, and neuroendocrine regulation, as
well as modulation of learning and memory. The objectives of the present
work were to study the role of the IL- 1 system in the pathogenesis of
neurodegenerative disorders such as epilepsy and cerebral ischemia, as
well as the influence of central IL-1 signalling on brain morphology,
expression of AD-related proteins, and inflammatory markers, and on
different aspects of behaviour, activation of
hypothalamo-pituitary-adrenal (HPA)-axis, and brain monoamines.
It is well known that hypothermia protects against neurodegeneration
induced by excitotoxic brain damage, while hyperthermia has an
aggravating effect. In Paper I and II, experimental excitotoxicity was
induced by peripheral administration of the glutamate analogue kainic
acid (KA) in rats, a well known model for human temporal lobe epilepsy,
which leads to epileptic seizures, temperature changes, and specific
brain damage characterized by neuronal cell death and glial activation,
as well as induction of inflammatory cytokines. The aims were to study
the mechanisms underlying KA-induced core temperature changes, i.e.
initial hypothermia followed by a longer hyperthermic effect, with regard
to the subtypes of glutamate receptors and the involvement of IL-1, as
well as interleukin-6 (IL6) and IL-1 receptor antagonist (IL-1ra). We
found that KA-induced changes in core temperature are not dependent upon
NMDAreceptors activation and are unlikely to be a result of increased
motor activity since dizocilpine, a non-competitive antagonist of
NMDA-receptors, blocked KA-induced behavioural, but not temperature
changes (Paper I). The levels of IL-1beta, IL-6 and IL-1ra in the
hypothalamus did not seem to correlate with KA-induced changes in core
temperature, except for the increase in IL-1beta in the hypothalamus, at
2 h after KA-injection. The ratios between IL-1beta and IL-1ra or IL-6
were increased at the time points when the core temperatures were
modified, suggesting that imbalances between cytokine levels may
contribute to KA-induced core temperature changes (Paper II).
The role of IL- 1 receptor-mediated activity in the brain, upon focal
cerebral ischemia and under normal conditions, was investigated in a
previously developed transgenic mouse strain with central blockade of
IL-1 signalling, due to the brain-directed overexpression of human
soluble IL-1ra (Tg hsIL-1ra) (Paper III-V). A model of permanent focal
cerebral ischemia was established in the Tg hsIL-1ra mice and analysis of
neurological scores, lesion size, and inflammatory markers showed similar
results in Tg hsIL-1ra (heterozygotic) and wild type mice, indicating
that the brain-directed blockade of IL-1 signalling was not
neuroprotective in this model of permanent focal cerebral ischemia in
mice (Paper III).
Analysis of the phenotype of the Tg hsIL-ra mice indicated that there
were no significant compensatory changes of IL-1beta, IL-6, or tumour
necrosis factor-alpha (TNF-alpha) in the brain. However, the marked
reduction in area density and brain volume in the Tg hsIL-1ra
(homozygotic) mice indicates that IL-1 signalling in the brain affects
CNS development. Furthermore, the expression of amyloid precursor protein
(APP) was lower in heterozygotic, but not homozygotic male Tg hsIL-1ra
mice (Paper IV). In addition, we observed modulation of different aspects
of behaviour, and of the expression of dopamine (DA), serotonin (5-HT)
and their metabolites in the brain of Tg hsIL-1ra mice, but no effect on
the activation of the HPA-axis, reflected in the serum levels of
corticosterone (Paper V). Studies on the behavioural phenotype revealed
higher locomotor activity, decreased habituation for locomotion, and
lower anxiety levels in the Tg hsIL-1ra mice. The levels of DA, 5-HT, and
their metabolites were decreased in certain brain regions of the Tg
hsIL-1ra mice.
IL-1 signalling in the brain seems to have important roles, both in the
basic functionality of the CNS, but also in the pathogenesis of
excitototoxic neurodegeneration, suggesting that the manipulation of IL-1
system can have promising therapeutic implications
Effects of chronic overexpression of interleukin-1 receptor antagonist in a model of permanent focal cerebral ischemia in mouse
Interleukin-1 receptor antagonist (IL-1ra) has been shown previously to have neuroprotective effects in animal models of stroke. The effects of chronic overexpression of human soluble IL-1ra (hsIL-1ra) were studied in a mouse model of permanent focal cerebral ischemia. A transgenic mouse strain (Tg hsIL-1ra+/-) has been developed using the promoter for glial fibrillary acidic protein (GFAP) to limit the overexpression to the CNS. Analysis of the neurological scores, infarct volume and edema formation revealed no differences between Tg hsIL-1ra+/- and wild-type (WT) mice. The cerebral ischemia resulted in pronounced astrocyte proliferation and microglial activation, as well as induction of inflammatory markers in both Tg hsIL-1ra+/- and WT mice, with no major differences between the two genotypes. Interestingly, hsIL-1ra expression in astrocytes was reduced in infarcted areas as compared to non-ischemic regions and sham-operated controls. In conclusion, transgenic overexpression of hsIL1-ra was not neuroprotective in this cerebral ischemia model, possibly due to insufficient levels for protection against the extensive lesion, or an up-regulation of compensatory inflammatory signals due to the lifetime blockade of IL-1 receptors