56 research outputs found
Influence of SAMe on the modifications of brain poliamine levels in an animal model of depression
No full textThe mechanism(s) of the antidepressant activity of S-adenosyl-L-methionine (SAMe) have not yet been elucidated. SAMe is essential for the synthesis of polyamines, which have a key role in protein synthesis, cell proliferation, and neuronal plasticity. On the other hand, accumulating data indicate that depression is associated with a reduction in regional brain volume and that antidepressants increase neurogenesis in defined brain regions and also influence neuronal plasticity. Here we show that in a validated rat model of depression (chronic unpredictable mild stress-induced anhedonia) there is a significant reduction of putrescine, spermidine and spermine in the hippocampus, and of only putrescine in the nucleus accumbens septi. SAMe, at a fully antidepressant dose (300 mg/kg i.m., daily for 7 days), completely restores the levels of putrescine in the nucleus accumbens, and restores in part the levels of both spermidine and spermine in the hippocampus. These results may suggest (i) a role for brain polyamines in depression and in reward processes, and (ii) that the antidepressant effect of SAMe may be due, at least in part, to a normalization of putrescine levels in the nucleus accumbens septi
EFFECT OF THE D2-AUTORECEPTOR AGONIST B-HT-958 ON BOTH SPONTANEOUS AND ACTH-INDUCED STRETCHING, YAWNING AND GROOMING IN THE RAT
No full textThe D2 autoreceptor agonist B-HT 958, intraperitoneally injected into Wistar male rats in a novel environment, significantly increased stretching and yawning (SY) while inhibiting grooming. Pretreatment with the D2 antagonist sulpiride reversed these effects, antagonizing SY and restoring grooming. Similarly, when B-HT 958 was administered to rats in their home cages, it elicited SY and abolished grooming; moreover, when administered before the i.c.v. injection of adrenocorticotropin hormone, dose-dependently enhanced SY and strongly antagonized the typical syndrome of intensified grooming induced by the peptide. The possible relationship between SY and grooming and the involvement of D2 autoreceptors are discussed
Influence of UFP-101 central infusion on behavioural and cellular effects in a chronic stress model in the rat.
No full textNociceptin/orphanin FQ (N/OFQ) and its receptor (NOP)
modulate several functions in the central nervous
system. UFP-101 is a selective and high affinity NOP
receptor antagonist [1], that has been reported to elicit antidepressant-like effects in rodents. The present study
investigated the effect of UFP-101 in the chronic mild
stress (CMS) paradigm in male Wistar rats. Animals were
exposed to CMS for at least seven weeks, to induce a
condition of anhedonia (measured as reduced consumption
of a sucrose solution). UFP-101 (10 nmol/rat, i.c.v.
continuously infused by means of minipumps for 24 days)
did not influence sucrose intake in non-stressed animals,
but reinstated basal sucrose consumption in stressed
animals (+ 40% vs non treated stressed rats), beginning
from the second week of treatment. The reference drug
fluoxetine (FL, 10 mg/kg, i.p.) produced identical effects.
Similarly, in the forced swimming test (FST) performed
2, 9, 16 and 23 days after treatment, UFP-101 reverted the
effects of stress in a dose- and time-dependent manner,
reducing the time of immobility of stressed rats to the
level of non-stressed controls (−78% vs non treated
stressed rats); FL produced the same effect from day 9
onwards. Moreover, repeated co-administration of N/OFQ
(5 nmol/rat i.c.v., from day 15 to 24) completely prevented
the behavioural effects of UFP-101.
In previous animal studies the stress/depression
condition has been associated to plastic alterations
of neuronal networks, including reduced hippocampal
volume, neuronal atrophy, cell death and alterations in cell
proliferation and cell survival of newly generated neurons
in key limbic brain region implicated in depression [2],
[3]. Neurotrophic factors (NTFs) such as BDNF and
FGF-2 may be involved in the modulation of activitydependent
plasticity associated with mood pathologies.
Therefore, it was investigated whether the CMS procedure
associated with continuous central infusion of UFP-101
can affect NTFs expression, as well as proliferation and
survival of hippocampal newborn cells. After in vivo BrdU
labelling, all rats were sacrificed on day 24 and their brains
were collected for immunohistochemical analysis. Our
preliminary data confirm that CMS reduces proliferation
of neural stem cells in hippocampus. The 21-day UFP-101
treatment, which did not produce any primary effect on cell
proliferation, also did not affect the reduced proliferation
observed in stressed animals. Experiments are now in
progress to evaluate the NTFs expression levels in discrete
brain areas.
These findings support the view that blockade of NOP
receptor signaling in the brain produces antidepressantlike
effects in the CMS protocol, and indicate that the
behavioural efficacy of the NOP receptor antagonist UFP-
101 is comparable to that of classical antidepressants.
However, this effect does not appear to be mediated
by increased hippocampal stem cell proliferation. These
findings support the hypothesis that NOP receptor may
represent a candidate target for innovative antidepressant
drugs
Computer-assisted image analysis of Caveolin-1 involvement in the iternalization process of adenosine A2A-dopamine D2 Receptor heterodimers
No full textA functional aspect of horizontal molecular networks has been investigated experimentally, namely the heteromerization between adenosine A(2A) and doparnine D-2 receptors and the possible role of caveolin-1 in the cotrafficking of these molecular complexes. This study has been carried out by means of computer-assisted image analysis procedure of laser images of membrane immunoreactivity of caveolin-1, A(2A), D-1, and D-2 receptors obtained in two clones of Chinese hamster ovary cells-one transfected with A(2A) and dopamine D, receptors and the other one with A(2A) and D-2 receptors. Cells were treated for 3 h with 10 mu M D-1 receptor agonist SKF 38393,50 mu M D-2-D-3 receptor agonist quinpirole, and 200 nM A(2A) receptor agonist CGS 21680. In A(2A)-D-1-cotransfected cells, caveolin-1 was found to colocalize with both A2A and D, receptors and treatment with SKF 38393 induced internalization of caveolin-1 and D-1 receptors, with a preferential internalization of D, receptors colocalized. with caveolin-1. In A(2A)-D-2-cotransfected cells, caveolin-1 was found to colocalize with both A2A and D2 receptors and either CGS 21680 or quinpirole treatment induced internalization of caveolin-1 and A2A and D2 receptors, with a preferential internalization of A2A and D2 receptors colocalized with caveolin-1. The results suggest that A2A and D2 receptors and caveolin-1 likely interact forming a macrocomplex that internalizes upon agonist treatment. These observations are discussed in the frame of receptor oligomerization and of the possible functional role of caveolin-1 in the process of co-internalization and, hence, in controlling the permanence of receptors at the plasma membrane level (prerequisite for receptor mosaic organization and plastic adjustments) and in the control of receptor desensitization
Differential Sensitivity of A(2A) and Especially D(2) Receptor Trafficking to Cocaine Compared with Lipid Rafts in Cotransfected CHO Cell Lines. Novel Actions of Cocaine Independent of the DA Transporter
No full textThe effects of low and high concentrations of cocaine have been studied in vitro on the trafficking of plasma membrane A(2A) and D(2) immunoreactivities in previously characterized A(2A)-D(2) CHO cell lines. Receptor double immunofluorescence staining was performed with D(2) and A(2A) antibodies, planar lipid rafts immunolabeling with biotinylated cholera toxin subunit B and membrane invaginations with an anti-caveolin-1 antibody. A computer-assisted image analysis demonstrated a substantial and highly significant rise of membrane-associated D(2) immunoreactivity (IR) after 8 h of exposure to a low concentration of cocaine (150 nM). At this low concentration of cocaine, there was also an increase of membrane associated A(2A) immunoreactivity but smaller and less significant. However, this increase became considerably larger and highly significant at 150 microM at which concentration the rise of D(2) immunoreactivity had begun to disappear. It may be suggested that an allosteric action of cocaine at 150 nM on the D(2) receptors may primarily increase the insertion of D(2) monomers, homomers and also of a subpopulation of A(2A)-D(2) heteromers from the cytoplasm into the plasma membrane due to the conformational change induced by cocaine in the D(2) receptor. The planar lipid rafts and the caveolae are only affected by the higher concentrations of cocaine. It is proposed that changes in D(2) and A(2A)-D(2) trafficking induced by allosteric actions of cocaine at D(2) receptors may contribute to the alterations of D(2) signaling found in cocaine abusers
Neuropeptide S stimulates human monocyte chemotaxis via NPS receptor activation.
No full textNeuropeptide S (NPS) produces several biological actions by activating a formerly orphan GPCR, now named NPS receptor (NPSR). It has been previously demonstrated that NPS stimulates murine leukocyte chemotaxis in vitro. In the present study we investigated the ability of NPS, in comparison with the proinflammatory peptide formyl-Met-Leu-Phe (fMLP), to stimulate human monocyte chemotaxis. At a concentration of 10(-8)M fMLP significantly stimulated chemotaxis. NPS produced a concentration dependent chemotactic action over the concentration range 10(-12) to 10(-5)M. The NPSR antagonists [D-Cys((t)Bu)(5)]NPS, [(t)Bu-D-Gly(5)]NPS and SHA 68 were used to pharmacologically characterize NPS action. Monocyte chemoattractant effect of NPS, but not fMLP, was completely blocked by either peptide antagonists or SHA with the nonpeptide molecule being more potent. None of the NPSR antagonists modified per se random cell migration. Thus, the present study demonstrated that NPS is able to stimulate human monocyte chemotaxis and that this effect is entirely due to selective NPSR activation
Single center experience with the Sorin Bicarbon prosthesis. A 17-year follow-up
No full textObjective: To evaluate the long-term results of aortic valve replacement (AVR) and mitral valve replacement
(MVR) with the Sorin Bicarbon prosthesis (SBP).
Methods: Five hundred seven patients (306 men, 201 women), mean age 62 10 years (range, 21-86 years),
received an SBP between 1994 and 2000; AVR was performed in 344 (67%) and MVR in 163 (33%). The main
concomitant procedure was coronary artery grafting in 79 patients (16%). Follow-up was 99%complete; mean
follow-up was 12.7 4.0 years with a cumulative duration of follow-up of 6475 patient-years in the entire group
(4348 patient-years for AVR and 2124 patient-years for MVR).
Results: Hospital mortality was 2.7% (AVR, 2.03%; MVR, 4.3%). There were 169 late deaths (AVR, 128;
MVR, 41). Actuarial survival at 17 years is 49.7% 5.3% for AVR and 62.0% 6.1% for MVR. At the
last follow-up, 310 survivors (199 AVR, 111 MVR) are in New York Heart Association functional class I or
II. At 17 years, actuarial freedom from valve-related deaths, embolism, and bleeding is 89.8% 4.8%,
85.8% 5.4%, and 96.2% 1.2% after AVR, and 91.9% 3.9%, 96.3% 1.8%, 95.0% 2.9% after
MVR. Reoperation was required in 5 patients with AVR (thrombosis in 4 and perivalvular leak in 1). Actuarial
freedom from reoperation is 98.1% 0.8% after AVR and 100% after MVR; freedom from endocarditis is
100% after AVR and 99.2% 0.7% after MVR. No cases of intrinsic structural valve failure were observed.
Conclusions: The SBP has shown excellent results in terms of clinical improvement and freedom from
valve-related complications, even up to 17 years after AVR and MVR. It therefore seems to be a safe option
whenever a mechanical prosthesis is needed. (J Thorac Cardiovasc Surg 2014;148:2039-44
Influence of f-MLP, ACTH(1-24) and CRH on in vitro chemotaxis of monocytes from centenarians.
No full textSingle center experience with the Sorin Bicarbon prosthesis: A 17-year clinical follow-up
No full textObjectiveTo evaluate the long-term results of aortic valve replacement (AVR) and mitral valve replacement (MVR) with the Sorin Bicarbon prosthesis (SBP).MethodsFive hundred seven patients (306 men, 201 women), mean age 62 ± 10 years (range, 21-86 years), received an SBP between 1994 and 2000; AVR was performed in 344 (67%) and MVR in 163 (33%). The main concomitant procedure was coronary artery grafting in 79 patients (16%). Follow-up was 99% complete; mean follow-up was 12.7 ± 4.0 years with a cumulative duration of follow-up of 6475 patient-years in the entire group (4348 patient-years for AVR and 2124 patient-years for MVR).ResultsHospital mortality was 2.7% (AVR, 2.03%; MVR, 4.3%). There were 169 late deaths (AVR, 128; MVR, 41). Actuarial survival at 17 years is 49.7% ± 5.3% for AVR and 62.0% ± 6.1% for MVR. At the last follow-up, 310 survivors (199 AVR, 111 MVR) are in New York Heart Association functional class I or II. At 17 years, actuarial freedom from valve-related deaths, embolism, and bleeding is 89.8% ± 4.8%, 85.8% ± 5.4%, and 96.2% ± 1.2% after AVR, and 91.9% ± 3.9%, 96.3% ± 1.8%, 95.0% ± 2.9% after MVR. Reoperation was required in 5 patients with AVR (thrombosis in 4 and perivalvular leak in 1). Actuarial freedom from reoperation is 98.1% ± 0.8% after AVR and 100% after MVR; freedom from endocarditis is 100% after AVR and 99.2% ± 0.7% after MVR. No cases of intrinsic structural valve failure were observed.ConclusionsThe SBP has shown excellent results in terms of clinical improvement and freedom from valve-related complications, even up to 17 years after AVR and MVR. It therefore seems to be a safe option whenever a mechanical prosthesis is needed
Functional antagonism between nociceptin/orphanin FQ and corticotropin-releasing factor in rat anxiety-related behaviors: involvement of the serotonergic system
No full textNociceptin/orphanin FQ (N/OFQ) acts as an anxiolytic-like agent in the rat and behaves as a functional antagonist of corticotropin-releasing factor (CRF) due to its ability to oppose CRF biological actions. In response to stress, CRF triggers changes in neurotransmitter systems including serotonin (5-HT). The role of 5-HT1A receptor in anxiety has been supported by preclinical and clinical studies. The present study investigated the possible functional antagonism between N/OFQ (1nmol/rat) and CRF (0.2nmol/rat) in anxiety-related conditions in rats, using elevated plus maze and defensive burying tests, in order to confirm previous literature results. Moreover, possible changes in the serotonergic system were studied in areas rich of serotonergic neurons: frontal cortex and pons. In both tests N/OFQ showed anxiolytic-like effects while CRF displayed anxiogenic-like effects. N/OFQ before CRF treatment counteracted the anxiogenic-like effects evoked by CRF. In frontal cortex, N/OFQ significantly decreased 5-HT levels but did not modify the hydroxyindoleacetic acid (5-HIAA) ones; CRF modified neither 5-HT nor 5-HIAA content but counteracted changes induced by N/OFQ alone. In pons, N/OFQ induced no change in serotonergic activity while CRF significantly decreased 5-HT levels and increased 5-HIAA content. The two peptides' combination reinstated serotonergic parameters to controls. In frontal cortex, N/OFQ increased the 5HT1A receptor density but reduced its affinity, while CRF alone did not induce any change. In pons, CRF decreased 5HT1ABmax and KD whereas N/OFQ was ineffective. All biochemical modifications were reverted by N/OFQ plus CRF treatment. The present study confirms that N/OFQ counteracts CRF anxiogenic-like effects in the behavioral tests evaluated. These effects may involve central serotonergic mechanisms since N/OFQ plus CRF induces a reversion of serotonergic changes provoked by single peptide. Our data support the hypothesis that N/OFQ may behave as functional CRF antagonist, this action being of interest for the treatment of anxiety disorders
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