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  • 1
    Language: English
    In: International Journal of Molecular Medicine, September 2011, Vol.28(3), pp.437-442
    Description: Preclinical studies have shown that the anti-glucocorticoid drug mifepristone effectively inhibits HIV replication both in vitro and in vivo. However, the drug did not demonstrate anti-HIV activity in a previous phase I/II study when administered at the daily dose of 75-225 mg. The aim of this study was to assess whether mifepristone may exert antiretroviral activity or influence immunological parameters when administered orally at daily doses of 150 or 300 mg in highly active antiretroviral therapy (HAART)-naïve HIV-infected patients. We performed an open label non-randomized phase II study that included 26 patients who underwent 28 days of once daily oral administration of 150 (12 subjects) or 300 mg (14 subjects) of mifepristone. A total of 3 patients dropped out of the study, respectively 1 in the 150 mg dose group and 2 in the 300 mg dose group. The main hemato­chemical alterations reported were hypokalemia and increase in the blood levels of cortisol, especially in those patients that received mifepristone at the dose of 300 mg/day. Although we observed a trend of reduced viral load along the study in both groups, statistical significance was not achieved for either the primary nor the secondary endpoints. In summary, mifepristone treatment was well-tolerated but it failed to significantly influence viro-immunological parameters in HAART-naïve HIV-infected patients.
    Keywords: Surgical Stapler;
    ISSN: 1107-3756
    E-ISSN: 1791244X
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  • 2
    In: Neuropsychopharmacology, 2011, Vol.37(4), p.929
    Description: Prenatal exposure to restraint stress causes long-lasting changes in neuroplasticity that likely reflect pathological modifications triggered by early-life stress. We found that the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (here named 'prenatal restraint stress mice' or 'PRS mice') developed a schizophrenia-like phenotype, characterized by a decreased expression of brain-derived neurotrophic factor and glutamic acid decarboxylase 67, an increased expression of type-1 DNA methyl transferase (DNMT1) in the frontal cortex, and a deficit in social interaction, locomotor activity, and prepulse inhibition. PRS mice also showed a marked decrease in metabotropic glutamate 2 (mGlu2) and mGlu3 receptor mRNA and protein levels in the frontal cortex, which was manifested at birth and persisted in adult life. This decrease was associated with an increased binding of DNMT1 to CpG-rich regions of mGlu2 and mGlu3 receptor promoters and an increased binding of MeCP2 to the mGlu2 receptor promoter. Systemic treatment with the selective mGlu2/3 receptor agonist LY379268 (0.5 mg/kg, i.p., twice daily for 5 days), corrected all the biochemical and behavioral abnormalities shown in PRS mice. Our data show for the first time that PRS induces a schizophrenia-like phenotype in mice, and suggest that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress.
    Keywords: Medicine ; Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology;
    ISSN: 0893-133X
    E-ISSN: 1740634X
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  • 3
    Language: English
    In: Psychopharmacology, 2011, Vol.217(3), pp.301-313
    Description: Byline: Sara Morley-Fletcher (1), Jerome Mairesse (1), Amelie Soumier (2), Mounira Banasr (2), Francesca Fagioli (3), Cecilia Gabriel (4), Elisabeth Mocaer (4), Annie Daszuta (2), Bruce McEwen (5), Ferdinando Nicoletti (1,6,7), Stefania Maccari (1) Keywords: Agomelatine; Prenatal stress; Adult neurogenesis; Ventral hippocampus; Fluoxetine; Phospho-CREB; Metabotropic glutamate receptors Abstract: Rationale and objectives The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT.sub.2c serotonin receptor antagonist. Results Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40--50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a "disease-dependent" drug. Conclusions These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders. Author Affiliation: (1) Neuroplasticity Team, UMR 8576 CNRS Structural and Functional Glycobiology Unit, University Lille North of France (USTL), 59655, Villeneuve d'Ascq, France (2) IC2N, IBDLM, UMR6216, CNRS, Marseille, France (3) Azienda Sanitaria Locale, RM.E. Unita Operativa Complessa Adolescent, Rome, Italy (4) Institut de Recherches Internationales Servier, Courbevoie, France (5) Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, USA (6) Department of Human Physiology and Pharmacology, Sapienza University, Rome, Italy (7) I.N.M. Neuromed, Pozzilli, Italy Article History: Registration Date: 24/03/2011 Received Date: 10/01/2011 Accepted Date: 23/03/2011 Online Date: 19/04/2011 Article note: S. Morley-Fletcher and J. Mairesse contributed equally to this work.
    Keywords: Agomelatine ; Prenatal stress ; Adult neurogenesis ; Ventral hippocampus ; Fluoxetine ; Phospho-CREB ; Metabotropic glutamate receptors
    ISSN: 0033-3158
    E-ISSN: 1432-2072
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  • 4
    In: Epilepsia, July 2015, Vol.56(7), pp.1141-1151
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/epi.13024/abstract Byline: Valerio D'Amore, Constanze Randow, Ferdinando Nicoletti, Richard Teke Ngomba, Gilles Luijtelaar Keywords: Glutamate; GABA ; Absence epilepsy; WAG/Rij rats; mGlu PAM Summary Objective Glutamate and [gamma]-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. Methods Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. Results Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. Significance These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA. CAPTION(S): Data S1. Surgery and EEG Recordings.
    Keywords: Glutamate ; Gaba ; Absence Epilepsy ; Wag /Rij Rats ; Mg Lu Pam
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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  • 5
    In: European Journal of Neuroscience, February 2014, Vol.39(3), pp.501-507
    Description: Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type () is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing. The ‐linked gene is characterized by an allelic variant of length, the upstream ariable umber andem epeat (‐u) region polymorphism. Two allelic variants of this gene are known, the high‐activity () and low‐activity (). We investigated the role of ‐u in cortical pain processing in a group of healthy individuals measured by the trigeminal electric pain‐related evoked potential (t) elicited by repeated painful stimulation. A group of healthy volunteers was genotyped to detect ‐u polymorphism. Electrical ts were recorded by stimulating the right supraorbital nerve with a concentric electrode. The 2 and 2 component amplitude and latency as well as the 2–2 inter‐peak amplitude were measured. The recording was divided into three blocks, each containing 10 consecutive stimuli and the 2–2 amplitude was compared between blocks. Of the 67 volunteers, 37 were and 30 were . subjects differed from subjects in terms of amplitude of the grand‐averaged and first‐block 2–2 responses (〉). The 2–2 amplitude decreased between the first and third block in subjects but not subjects. The ‐u polymorphism seemed to influence the brain response in a repeated t paradigm and suggested a role of the as a modulator of neural plasticity related to cortical pain processing. Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type () is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing.
    Keywords: Habituation ; Human ; Monoamine ; Neural Plasticity ; Pain‐Related Evoked Potential ; Sensitization
    ISSN: 0953-816X
    E-ISSN: 1460-9568
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  • 6
    Language: English
    In: European Child & Adolescent Psychiatry, 2017, Vol.26(12), pp.1433-1441
    Description: This study aims at determining serum levels of tryptophan and other metabolites of the kynurenine pathway in children with attention deficit hyperactivity disorder (ADHD) compared to healthy controls. Such metabolites interact with glutamate receptors in the central nervous system, potentially modulating mechanisms that are pivotal in ADHD and thus potentially representing peripheral biomarkers of the disorder. We measured serum levels of tryptophan and some metabolites of the kynurenine pathway in 102 children with ADHD and 62 healthy controls by liquid chromatography–tandem mass spectrometry (LC–MS/MS). As compared to healthy controls, children with ADHD showed a reduction in serum levels of anthranilic acid (−60%), kynurenic acid (−11.2%), and xanthurenic acid (−12.5%). In contrast, serum levels of tryptophan (+11.0%) and kynurenine (+48.6%) were significantly enhanced, and levels of quinolinic acid were unchanged in children with ADHD. In a logistic regression model, the presence of ADHD was predicted by low anthranilic acid and high tryptophan levels. These findings support the involvement of the kynurenine pathway in the pathophysiology of ADHD and suggest that anthranilic acid and tryptophan levels should be investigated as potential peripheral biomarker for ADHD.
    Keywords: ADHD ; Biomarker ; Kynurenines ; Children ; Neurobiology
    ISSN: 1018-8827
    E-ISSN: 1435-165X
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  • 7
    In: Journal of Neurochemistry, June 2013, Vol.125(5), pp.649-656
    Description: The αδ subunit of voltage‐sensitive calcium channels (s) is the molecular target of pregabalin and gabapentin, two drugs marked for the treatment of focal epilepsy, neuropathic pain, and anxiety disorders. Expression of the αδ subunit is up‐regulated in the dorsal horns of the spinal cord in models of neuropathic pain, suggesting that plastic changes in the αδ subunit are associated with pathological states. Here, we examined the expression of the αδ‐1 subunit in the amygdala, hippocampus, and frontal cortex in the trimethyltiazoline () mouse model of innate anxiety. is a volatile molecule present in the feces of the rodent predator, red fox. Mice that show a high defensive behavior during exposure developed anxiety‐like behavior in the following 72 h, as shown by the light–dark test. Anxiety was associated with an increased expression of the αδ‐1 subunit of s in the amygdaloid complex at all times following exposure (4, 24, and 72 h). No changes in the αδ‐1 protein levels were seen in the hippocampus and frontal cortex of mice exposed to . Pregabalin (30 mg/kg, i.p.) reduced anxiety‐like behavior in ‐exposed mice, but not in control mice. These data offer the first demonstration that the αδ‐1 subunit of s undergoes plastic changes in a model of innate anxiety, and supports the use of pregabalin as a disease‐dependent drug in the treatment of anxiety disorders. Changes in αδ subunit expression in anxiety modelThe αδ subunit is the molecular target for pregabalin, which is used in humans for the treatment of anxiety disorders. We found that αδ subunit was up‐regulated in the amygdala in a mouse model of innate anxiety where pregabalin was proved to be effective. These findings suggest that pregabalin acts as ‘disease‐dependent’ drug in the treatment of anxiety.
    Keywords: Αδ‐1 Subunit ; Amygdala ; Innate Anxiety ; Tmt ; Voltage‐Sensitive Calcium Channels
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 8
    Language: English
    In: Psychiatry Research, 30 June 2015, Vol.227(2-3), pp.171-178
    Description: Electroconvulsive therapy (ECT) is effective in treatment-resistant depression (TRD). It may act through intracellular process modulation, but its exact mechanism is still unknown. Animal research supports a neurotrophic effect for ECT. We aimed to investigate the association between changes in serum brain-derived neurotrophic factor (sBDNF) levels and clinical improvement following ECT in patients with TRD. Twenty-one patients with TRD (2 men, 19 women; mean age, 63.5 years; S.D., 11.9) were assessed through the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impressions scale, Severity (CGIs) before and after a complete ECT cycle. At the same time-points, patients underwent blood withdrawal for measuring sBDNF levels. ECT significantly reduced HDRS, BPRS, and CGIS scores, but not sBDNF levels. No significant correlation was found between sBDNF changes, and each of HDRS, BPRS, and CGIs score changes. sBDNF levels in TRD patients were low both at baseline and post-ECT. Our results do not support that improvements in TRD following ECT are mediated through increases in sBDNF levels.
    Keywords: Electroconvulsive Therapy (Ect) ; Brain-Derived Neurotrophic Factor (Bdnf), Serum Levels ; Treatment-Resistant Depression ; Major Depression ; Bipolar Depression ; Medicine
    ISSN: 0165-1781
    E-ISSN: 1872-7123
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  • 9
    In: Epilepsia, August 2010, Vol.51(8), pp.1511-1521
    Description: Genetically epileptic WAG/Rij rats develop spontaneous absence‐like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type‐1 cannabinoid (CB) receptors. Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of “presymptomatic” 2‐month old and “symptomatic” 8‐month‐old WAG/Rij rats relative to age‐matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB receptor affects absence seizures. We recorded spontaneous spike‐wave discharges (SWDs) in 8‐month old WAG/Rij rats systemically injected with the potent CB receptor agonist, (+)WIN55,212‐2 (3–12 mg/kg, s.c.), given alone or combined with the CB receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). Data showed a reduction of CB receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB receptor protein levels in ventral basal thalamic nuclei of 8‐month‐old WAG/Rij rats, as compared with age‐matched ACI control rats. In vivo, (+)WIN55,212‐2 caused a dose‐dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB receptor agonists. Both effects were reversed or attenuated when (+)WIN55,212‐2 was combined with AM251. These data indicate that the development of absence seizures is associated with plastic modifications of CB receptors within the thalamic‐cortical‐thalamic network, and raise the interesting possibility that CB receptors are targeted by novel antiabsence drugs.
    Keywords: Absence Epilepsy ; Endocannabinoid System ; Rtn
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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  • 10
    In: Epilepsia, November 2017, Vol.58(11), pp.1993-2001
    Description: Summary Objectives Thrombospondins, which are known to interact with the [alpha]2[delta] subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). Methods We measured the transcripts of thrombospondin-1 and [alpha]2[delta] subunit, and protein levels of [alpha]2[delta], Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium. Results Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. Significance These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs.
    Keywords: Thrombospondins ; Absence Epilepsy ; Α 2 Δ Subunit ; Wag /Rij Rats ; Genetic Variants
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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