1,721,038 research outputs found
Stress, Hormones, and Metabolism
No full textFrom an evolutionary perspective, the stress response system has evolved to ensure the survival of the organism and therefore of the species. Triggering the stress response system leads to several hormone-mediated metabolic alterations, aimed at exploiting energy resources and adaptive behavioral strategies to cope with real or perceived threats. In the modern highly stressed society, the majority of the stressors we face chronically are psychological. The consequent activation of the stress response system mobilizes energy resources that are not expended in the short term, but rather compromise the energetic balance of the organism for long intervals. Stress and obesity are widespread conditions that mutually interplay, as they share at the basis an intricated network of pathways that regulate the physical, behavioral, and cognitive spheres of the organism. The type of stressor, along with substantial differences in genetic, environmental, and developmental factors, are important determinants for the vulnerability to hormones-related negative consequences on metabolism, and therefore the different susceptibility to develop obesity and eventually metabolic diseases associated with an obese state, like metabolic syndrome and type 2 diabetes. The main purpose of this article is to discuss the cardinal stress-activated pathways that, combined with an impaired energy balance, result in fat mass accumulation, especially visceral, and in the onset of a chronic low-grade inflammation. These features contribute to the development of insulin resistance, and therefore to the incidence of common metabolic dysregulations which in turn represent important risk factors for other widespread and severe pathologies, such as cardiovascular diseases and tumors
Sex- and age-specific differences in core body temperature of C57Bl/6 mice
No full textGender-specific differences in longevity are reported across species and are mediated by mechanisms not entirely understood. In C57Bl/6 mice, commonly used in aging research, males typically outlive females. Since in these animals modest but prolonged reduction of core body (Tc) increased life span, we hypothesized that differential Tc may contribute to sex-specific longevity. Here, we compared the circadian profiles of Tc and locomotor activity (LMA) of male and female C57Bl/6 mice. Since Tc and LMA normally change with age, measurements were carried out in young (3 months) as well as in old (24 months) mice. In young females, Tc was influenced by estrous but was overall higher than in males. This difference was larger in old animals after age eliminated the variations associated with estrous. Although temperature homeostasis is regulated centrally by the sexually dimorphic hypothalamic preoptic area, these differences were uniquely dependent on the gonads. In fact, bilateral gonadectomy abolished the effects of estrous and increased resting Tc in males eliminating all sex-specific differences in Tc and LMA. These effects were only partially mimicked by hormonal replacement as Tc was affected by progesterone and to a lesser extent by estrogen but not by testosterone. Thus, gonadal-dependent modulation of Tc may be one of the physiological parameters contributing to gender-specific differences in longevity
Editorial: Cytokines as players of neuronal plasticity and sensitivity to environment in healthy and pathological brain
Full text linkN
Chronic antidepressant treatments resulted in altered expression of genes involved in inflammation in the rat hypothalamus
No full textTo gain insight into the possible immune targets of antidepressant, we evaluated the expression of several inflammatory mediators in the hypothalamus of rats chronically (28 days) treated with the serotonin selective reuptake inhibitor fluoxetine (5mg/kg, i.p.) or the tricyclic compound imipramine (15 mg/kg, i.p.). We focused our attention on the hypothalamus as it plays a key role in determining many of the somatic symptoms experienced by depressed patients. This brain region, critical also for expression of motivated behaviours, participates in the control of the hypothalamic-pituitary-adrenal axis activity and in stress response as well as coordinates physiological functions such as sleep and food intake that have been found altered in a high percentage of depressed patients. Notably, hypothalamus is a key structure for brain cytokine expression and function as it integrates signals from the neuro, immune, endocrine systems. By means of quantitative Real Time PCR experiments we demonstrated that a chronic treatment with either fluoxetine or imipramine resulted in a reduction of IL-6 and IFN-γ mRNAs and increased IL-4 mRNA expression in the rat hypothalamus. Moreover, we demonstrated that hypothalamic expression of members of IL-18 system was differentially affected by chronic antidepressant treatments. Chronically administered fluoxetine decreased IL-8 and CX3CL1 hypothalamic expression, while a chronic treatment with imipramine decreased p11 mRNA. Our data suggest that a shift in the balance of the inflammation toward an anti-inflammatory state in the hypothalamus may represent a common mechanism of action of both the chronic treatments with fluoxetine and imipramine
P.2.a.012 Co-administration of fluoxetine with acetylsalicylic acid, but not flurbiprofen or celecoxib, for one week shows an antidepressant-like effect
No full textIncreasing evidence is now demonstrating the involvement of the immune system and in particular of their effectors, cytokines, in the development and progression of depression. In particular, it is worth underlying how pro-inflammatory cytokines appear to be increased in blood or brain of patients with major depression (MD) and that pharmacological use of pro-inflammatory cytokines (i.e. interferon alpha) may induce MD. These data suggest a role for inflammation in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy in the treatment of MD. However, some studies reported contradictory results and suggest that adverse effects may contraindicate the use of anti-inflammatory agents in the treatment of depression. Nevertheless, non-steroidal anti-inflammatory drugs (NSAIDs) can have different mechanisms of action also depending on the dose. This is true for the therapeutic effects as well as for the unwanted side effects.
On this basis, the present study aimed at evaluating the behavioural effect of the co-administration of fluoxetine (FLX, 5 mg/kg i.p.) with different NSAIDs in the chronic escape model of depression (CED). The CED model of depression possesses face, construct and pharmacological validity and is based on the induction, and maintenance, of an escape deficit upon exposing rats to unavoidable stressors. We previously demonstrated that, in this model, the stress-induced impaired behaviour can be resolved by one week of treatment with the co-administration of FLX (5 mg/kg/i.p.) plus acetylsalicylic acid (ASA, 45 mg/kg i.p.) but not FLX alone [1]. Here we evaluated the effect of the co-administration of FLX and flurbiprofen (FLB, an inhibitor of Cox-1 and Cox-2, 5 mg/kg, p.o.) or celecoxib (CLX, a selective COX2 inhibitor, 5 mg/kg, p.o.) in the CED model after 7 days of treatment. The co-administration FLX plus ASA (45mg/kg i.p.) was used as a positive control. Morever we tested the behavioral effect of different doses (45, 22.5 and 11.25 mg/Kg i.p.) of ASA as potentiating agent of the effect of fluoxetine.
Our study shows that only the co-administration of ASA with FLX reverted the stress-induced condition of escape deficit after 7 days of treatment. Moreover, the amplitude of the antidepressant-like effect was dose dependent. The percentage of the antidepressant response was about 90%, 60% and 40% for animals receiving FLX (5 mg/kg/i.p.) plus ASA at the dose of 45, 22.5 or 11.25 mg/Kg i.p. respectively. Both flurbiprofen and celecoxib, when administered together with FLX for 7 days, failed to induce an antidepressant-like effects in the CED model. Higher dose of FLB (50 mg/Kg p.o.) and CLX (20 mg/Kg p.o.) were also tested, but they were associated to high mortality rate (80% and 25% respectively).
These data demonstrated that neither all NSAIDs, nor all doses, may be useful in the treatment of depression while adverse effects can be potentiated or induced by the co-administration with antidepressants. Unraveling the cellular and molecular mechanisms behind the dissimilar behavioral response elicited by different anti-inflammatory drugs can contribute to understand the role of inflammation in the etiopathogensis of MD and to improve patient care.
[1] Brunello, N., Alboni, S., Capone, G., Benatti, C., Blom, J.M., Tascedda, F., Kriwin, P., Mendlewicz, J., 2006 Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 21:227-31
Interleukin 18 in the CNS
Full text linkAbstract Interleukin (IL)-18 is a cytokine isolated as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, the localization of the IL-18 receptor complex in neurons and the neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease.</p
Metabolic characterization of SH-SY5Y cells and effects of interferon-alpha exposure
No full textThe human neuroblastoma SH-SY5Y cell line is a third successive subclone of the SK-N-SH line, originally established from a bone marrow biopsy of a neuroblastoma patient. These cells possess many characteristics of neurons, and they represent one of the most-used models for studying cellular events and mechanisms involved in neurotoxicity and neurodegeneration or even in neuroprotection. Interferons are cytokines endowed with a pleiotropic spectrum of biological properties, including immunomodulation, antiviral and proinflammatory activity. Interferon (IFN)-α is a type I IFN that may have broad-ranging actions in the brain, affecting neuronal differentiation, survival and synaptic plasticity. We previously demonstrated that a 72 hours exposure to IFN-α induces early apoptosis in SH-SY5Y cells. This prompted us to investigate the metabolic profile of the SH-SY5Y cells using HR-MAS NMR Spectroscopy after a 72 hours exposure to IFN-α to explore the metabolic changes that characterize these cells. Moreover, since a metabolic characterization of this extensively used cell clone is still lacking, we analyzed the metabolic profile of the SH-SY5Y in standard growth conditions. Results show some interesting changes in metabolites, such as choline containing compounds, creatine and glutamate. Our goal will be to relate the metabolic changes to IFN-α exposure
Neither all anti-inflammatory drugs nor all doses are effective in accelerating the antidepressant-like effect of fluoxetine in an animal model of depression
No full textIntroduction: Non-steroidal anti-inflammatory drugs (NSAIDs) have been studied as possible adjunctive therapy in the treatment of depression. However, administering NSAIDs to increase the effectiveness of antidepressant has yielded inconsistent results. Methods: We evaluated the effect of the co-administration of fluoxetine (5 mg/kg) and flurbiprofen (5 mg/kg) or fluoxetine (5 mg/kg) and celecoxib (5 mg/kg) in the chronic escape deficit (CED) model of depression after 7 days of treatment. The co-administration of fluoxetine plus acetylsalicylic acid (ASA, 45 mg/kg i.p.) was used as a positive control. Moreover, we tested the behavioral effect of different doses (45, 22.5, and 11.25 mg/Kg i.p.) of ASA as potentiating agent of the effect of fluoxetine in the same paradigm. Results: Our study showed that only the co-administration of ASA with fluoxetine was able to revert the stress-induced condition of escape deficit after 7 days of treatment, and that the amplitude of the antidepressant-like effect of ASA was dose dependent. In the same experimental conditions, celecoxib with fluoxetine only partially resolved the stress-induced impaired behavior while flurbiprofen/fluoxetine cotreatment was ineffective. Limitations: Our study is still exploratory, more doses, longer treatment regimens, and different behavioral outcomes must be investigated to draw a clear conclusion. Conclusion: Our results further stress the importance of the type and dose when NSAIDs are associated with antidepressants to ameliorate a clinical response
Regulation of CREB function in rat frontal cortex after combined treatment with Fluoxetine and Olanzapine
No full textStatement of the Study: Generally, drugs used in the treatment of depression
exert their therapeutic effect after 4/6 weeks and only in 60–65% of patients. The
search for an adequate and faster treatment of major depression is one of the main
challenges in neuropsychopharmacology. Recently, a clinical study of treatmentresistant
depressed patients without a psychotic component, showed that after
only one week of treatment, Fluoxetine (a selective serotonin reuptake inhibitor
antidepressant) and Olanzapine (an atypical antipsychotic agent) produced a
higher level of improvement than either monotherapy alone (Shelton et al., American
Journal of Psychiatry 158(1), 131–134, 2001). Furthermore, preclinical data,
using microdialysis, indicated that the combination of Olanzapine and Fluoxetine
resulted in an increase in the extracellular levels of dopamine and norepinephrine
in the rat prefrontal cortex, an effect that was significantly bigger than after treatment
with either drug alone (Zhang et al., Neuropsychopharmacology 23(3),250–
262, 2000). However, it is not yet completely understood which intracellular
signaling pathway could be involved in the fast response (seen in clinical trials)
to Fluoxetine plus Olanzapine co-treatment.
Methods: Since antidepressant and antipsychotic drugs affect the cyclic
adenosine monophosphate (cAMP) pathway, including the expression of the
cAMP response element binding protein (CREB), the levels of CREB mRNA
and CREB nuclear protein, total and phosphorylated, were studied in the frontal
cortex of rats using RNase protection assay and Western Blotting analysis
respectively. Four experimental groups were used: rats were treated for one,
five or ten days with either saline, Fluoxetine (ip 10 mg/Kg), Olanzapine (sc
1 mg/Kg) or combined Fluoxetine plus Olanzapine (10 mg/Kg and 1 mg/Kg).
Summary of Results: Our results show that the level of phosphorylated
CREB Ser133 was significantly increased in the frontal cortex of rats receiving
the combined treatment regimen (Fluoxetine plus Olanzapine) for five days. No
effect was observed in acutely and ten day treated rats.
Conclusion: This specific effect on CREB phosphorylation levels after five
days of combined treatment with Fluoxetine plus Olanzapine might represent
one of the mechanisms underlying the faster response to this therapy recently
observed in several clinical trials
Interferon-alpha exposure increases the expression of enzymes of the kynurenine pathway and induces apoptosis in a model of human neurons
No full textMajor depression (MD) is associated with a profound unbalance
between the nervous-, the endocrine- and the immune- systems.
This suggests the possibility that molecules that regulate the
homeostasis of these systems may contribute to the development
of MD. For instance, some cytokines, important neuro-endocrineimmuno
modulators, have been proposed to have a role in MD
as supported by the observation that activation of immune system
with therapeutically used cytokines may induce MD.
IFN-a is an innate immune cytokine with potent antiviral and
anti-proliferative properties that is used to treat viral infections,
such as hepatitis C, and certain cancers. Despite therapeutic
efficacy in these illnesses, it has been observed that IFN-a exposure
may be associated with important side effects including
neuropsychological and behavioural changes that overlap with
MD.
Although IFN-a- induced effects on the brain make IFN-alpha a
model to study the influence of pro-inflammatory cytokines in the
CNS and behavior, the molecular mechanisms underlying these
effects are far from being fully understood.
It has been proposed that cytokines may contribute to the
etiology of MD by inducing indolamine 2,3-dioxygenase (IDO)
expression. IDO catalyzes the initial rate-limiting step in tryptophan
(TPR) degradation along the kynurenine pathway (KP).
Kynurenine, the initial product of TPR degradation, is further
catalysed into neurotoxic end-products through steps catalyzed by
kynurenine 3-monooxygenase (KMO) and kynureninase (Kynu).
However, Kynurenine can also be catabolised by kynurenine
aminotransferase (KAT), into kynurenic acid, a potentially neuroprotective
agent. A role for a disturbance in the KP in the
neuroprotective–neurodegenerative balance in the brain of patients
with MD, has been proposed in the neurodegeneration hypothesis
of depression.
This prompted us to investigate the effects of IFN-a on the
expression of the IDO, KMO, Kynu and KAT mRNAs in an in
vitro model of human neurons: SH-SY5Y (human neuroblastoma)
cells. We also evaluated the IFN-a-induced effect on cell viability and number in these cells. Finally, because cell number results
from the balance between cell proliferation and cell elimination,
we measured cell proliferation and apoptosis in SH-SY5Y cells
after IFN-a exposure. The same experiments were performed in
differentiated SH-SY5Y cells with retinoic acid (RA) and Brain-
Derived Neurotrophic Factor (BDNF).
Our studies show that IFN-a exposure increased the expression
of all the kynurenergic enzymes investigated (with an unbalance
of the KP toward the synthesis of neurotoxic end-products) and in
more particularly strongly induced the expression of IDO mRNA
(more than 900-fold) in SH-SY5Y cells. We also demonstrated
that IFN-a reduced in a dose- (2, 20, 50 and 100 ng/ml) and time-
(24, 48 and 72 hrs) dependent manner the cell number and induces
apoptosis in SH-SY5Y cells. Similar results were obtained in SHSY5Y
RA/BDNF differentiated cells.
Together our results clearly enlighten the cytotoxic effects of
IFN-a in this in vitro model of human neurons. Moreover, our
findings provide further information on the molecular pathways
involved in cytokine-induced effects in the brain and add a piece
to the puzzle of what and how these factors or pathways may
contribute to the pathogenesis of MD
- …
