Publications (36)191.43 Total impact
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Article: Aging of the dopaminergic system and motor behavior in mice intoxicated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
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ABSTRACT: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.Journal of Neurochemistry 06/2012; 122(5):1032-46. · 4.06 Impact Factor -
Article: Effects of Spironolactone Alone and in Addition to a Beta-blocker on Myocardial Histological and Electrical Remodeling in Chronic Severe Failing Rat Hearts.
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ABSTRACT: : Aldosterone antagonists (AAs) have beneficial effects on ventricular histological and electrical remodeling and improve noradrenaline uptake. Adding an AA to a beta-blocker (BB) further improves cardiac mortality in heart failure patients. We investigated if adjunction of a BB modifies beneficial effects of spironolactone on different parameters of the ventricular remodeling. : A severe myocardial infarction (MI) was produced in rats. Three months after surgery, left ventricular (LV) function was assessed by echocardiography. Fifty-five rats with heart failure were then randomized in 5 groups: sham, MI, and MI treated for 4 weeks with spironolactone (10 mg·kg·d), atenolol (1 mg·kg·d), or both. Holter transducers were implanted to record 24-hour ventricular electrical parameters, mean cycle length (RR) and SD of RR. Before killing, invasive left ventricular end diastolic pressure (LVEDP) was recorded. LV samples were used for histological analysis and catecholamine assay. : Rats with MI had significantly increased LVEDP (32 ± 3 vs. 14 ± 1 mm Hg), LV, collagen content (5.8% ± 1.4% vs. 3.6% ± 0.7%), ventricular premature complexes (2.5 10 ± 10 vs. 30 ± 13), and decreased meanRR (164 ± 2 vs. 169 ± 1 milliseconds) and SDRR (3.9 ± 0.2 vs. 5.4 ± 0.2 milliseconds) compared with sham. At nonhypotensive doses, spironolactone and atenolol similarly improved LVEDP. Compared with MI, although spironolactone significantly decreased ventricular premature complexes, LV collagen and noradrenaline contents, and improved meanRR and SDRR, atenolol had effects only on meanRR and SDRR. Addition of atenolol to spironolactone further improved spironolactone effects on all these parameters. : AA improved, independently of the cardiac function, histological and electrical remodeling after MI. A BB added to an AA did not blunt these beneficial effects; furthermore, it improved these effects related to spironolactone.Journal of cardiovascular pharmacology 06/2012; 60(3):315-21. · 2.83 Impact Factor -
Article: Decreased osteoclastogenesis in serotonin-deficient mice.
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ABSTRACT: Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH(1)), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling.We therefore decided to investigate in detail bone remodeling in growing and mature TPH(1) knockout mice (TPH(1)(-/-)). Bone resorption in TPH(1)(-/-) mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH(1)(-/-) mice is cell-autonomous. Cultures from TPH(1)(-/-) in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH(1) and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis.Proceedings of the National Academy of Sciences 02/2012; 109(7):2567-72. · 9.68 Impact Factor -
Article: Neuritogenesis: the prion protein controls β1 integrin signaling activity.
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ABSTRACT: Cytoskeleton modifications are required for neuronal stem cells to acquire neuronal polarization. Little is known, however, about mechanisms that orchestrate cytoskeleton remodeling along neuritogenesis. Here, we show that the silencing of the cellular prion protein (PrP(C)) impairs the initial sprouting of neurites upon induction of differentiation of the 1C11 neuroectodermal cell line, indicating that PrP(C) is necessary to neuritogenesis. Such PrP(C) function relies on its capacity to negatively regulate the clustering, activation, and signaling activity of β1 integrins at the plasma membrane. β1 Integrin aggregation caused by PrP(C) depletion triggers overactivation of the RhoA-Rho kinase-LIMK-cofilin pathway, which, in turn, alters the turnover of focal adhesions, increases the stability of actin microfilaments, and in fine impairs neurite formation. Inhibition of Rho kinases is sufficient to compensate for the lack of PrP(C) and to restore neurite sprouting. We also observe an increased secretion of fibronectin in the surrounding milieu of PrP(C)-depleted 1C11 cells, which likely self-sustains β1 integrin signaling overactivation and contributes to neuritogenesis defect. Our overall data reveal that PrP(C) contributes to the acquisition of neuronal polarization by modulating β1 integrin activity, cell interaction with fibronectin, and cytoskeleton dynamics.The FASEB Journal 02/2012; 26(2):678-90. · 5.71 Impact Factor -
Article: Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension.
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.Blood 12/2011; 119(7):1772-80. · 9.90 Impact Factor -
Article: Ineffective erythropoiesis with reduced red blood cell survival in serotonin-deficient mice.
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ABSTRACT: Serotonin (5-HT) has long been recognized as a neurotransmitter in the central nervous system, where it modulates a variety of behavioral functions. Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), and the recent discovery of a dual system for 5-HT synthesis in the brain (TPH2) and periphery (TPH1) has renewed interest in studying the potential functions played by 5-HT in nonnervous tissues. Moreover, characterization of the TPH1 knockout mouse model (TPH1(-/-)) led to the identification of unsuspected roles for peripheral 5-HT, revealing the importance of this monoamine in regulating key physiological functions outside the brain. Here, we present in vivo data showing that mice deficient in peripheral 5-HT display morphological and cellular features of ineffective erythropoiesis. The central event occurs in the bone marrow where the absence of 5-HT hampers progression of erythroid precursors expressing 5-HT(2A) and 5-HT(2B) receptors toward terminal differentiation. In addition, red blood cells from 5-HT-deficient mice are more sensitive to macrophage phagocytosis and have a shortened in vivo half-life. The combination of these two defects causes TPH1(-/-) animals to develop a phenotype of macrocytic anemia. Direct evidence for a 5-HT effect on erythroid precursors is provided by supplementation of the culture medium with 5-HT that increases the proliferative capacity of both 5-HT-deficient and normal cells. Our thorough analysis of TPH1(-/-) mice provides a unique model of morphological and functional aberrations of erythropoiesis and identifies 5-HT as a key factor for red blood cell production and survival.Proceedings of the National Academy of Sciences 08/2011; 108(32):13141-6. · 9.68 Impact Factor -
Article: How to obtain DNA from injection drug users?
Clinical Chemistry and Laboratory Medicine 06/2011; 49(8):1391-2. · 2.15 Impact Factor -
Article: Deconstructing antiobesity compound action: requirement of serotonin 5-HT2B receptors for dexfenfluramine anorectic effects.
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ABSTRACT: The now-banned anorectic molecule, dexfenfluramine, promotes serotonin release through a serotonin transporter-dependent mechanism, and it has been widely prescribed for the treatment of obesity. Previous studies have identified that 5-HT(2B) receptors have important roles in dexfenfluramine side effects, that is, pulmonary hypertension, plasma serotonin level regulation, and valvulopathy. We thus investigated a putative contribution of 5-HT(2B) receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10 mg/kg) observed in wild-type mice (1-4 h) was eliminated in mice lacking 5-HT(2B) receptors (5-HT(2B)(-/-)). These findings were further validated by the lack of hypophagic response to dexfenfluramine in wild-type mice treated with RS127445, a highly selective and potent antagonist (pKi=8.22 ± 0.24). Using microdialysis, we observed that in 5-HT(2B)(-/-) awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1 h) was strongly reduced (fourfold) compared with wild type. Moreover, using hypothalamic synaptosomes, we established the serotonergic neuron autonomous properties of this effect: a strong serotonin release was observed upon dexfenfluramine stimulation of synaptosome preparation from wild type but not from mice lacking active 5-HT(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT(2B) receptors is a limiting step in the serotonin transporter dependent-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 36(2):423-33. · 6.99 Impact Factor -
Article: Chronic systemic treatment with a high-dose proteasome inhibitor in mice produces akinesia unrelated to nigrostriatal degeneration.
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ABSTRACT: Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD.Neurobiology of aging 12/2009; 32(11):2100-2. · 5.94 Impact Factor -
Article: Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice.
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ABSTRACT: The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT(2B) receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT(2B) receptors to the reinforcing properties of MDMA.We show here that 5-HT(2B) (-/-) mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT(2B) receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT(2B) receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT(2B) receptor-independent behavioral effects.These results underpin the importance of 5-HT(2B) receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.PLoS ONE 01/2009; 4(11):e7952. · 4.09 Impact Factor -
Article: Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation.
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ABSTRACT: Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years. 5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)--the 5-HT/MAO catabolite--in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity. This is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health.PLoS ONE 01/2009; 4(11):e7959. · 4.09 Impact Factor -
Dataset: ARTICLE IN PRESS Chronic systemic treatment with a high-dose proteasome inhibitor in mice produces akinesia unrelated to nigrostriatal degeneration
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ABSTRACT: Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD. -
Article: Chronic systemic treatment with a high-dose proteasome inhibitor in mice produces akinesia unrelated to nigrostriatal degeneration.
[show abstract] [hide abstract]
ABSTRACT: Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD.Neurobiology of aging. 01/2009; -
Article: Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease.
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ABSTRACT: Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.Journal of Clinical Investigation 01/2009; 119(1):182-92. · 15.39 Impact Factor -
Article: Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy.
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ABSTRACT: By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin 5-HT(2B) receptors did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT(2B) receptors (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT(2B) receptor solely in cardiomyocytes, like global 5-HT(2B) receptor-null mice, are resistant to isoproterenol-induced cardiac hypertrophy and dysfunction, as well as to isoproterenol-induced increases in cytokine plasma-levels. These data reveal a key role of noncardiomyocytes in isoproterenol-induced hypertrophy in vivo. Interestingly, we show that primary cultures of angiotensinogen null adult cardiac fibroblasts are releasing cytokines on stimulation with either angiotensin II or serotonin, but not in response to isoproterenol stimulation, demonstrating a critical role of angiotensinogen in adrenergic-dependent cytokine production. We then show a functional interdependence between AT(1)Rs and 5-HT(2B) receptors in fibroblasts by revealing a transinhibition mechanism that may involve heterodimeric receptor complexes. Both serotonin- and angiotensin II-dependent cytokine production occur via a Src/heparin-binding epidermal growth factor-dependent transactivation of epidermal growth factor receptors in cardiac fibroblasts, supporting a common signaling pathway. Finally, we demonstrate that 5-HT(2B) receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and norepinephrine plasma levels. Collectively, these results reveal for the first time that interactions between AT(1) and 5-HT(2B) receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT(2B) receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure.Circulation Research 12/2008; 104(1):113-23. · 9.49 Impact Factor -
Article: Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro.
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ABSTRACT: The "club drug" 3,4-methylenedioxymethamphetamine (MDMA; also known as ecstasy) binds preferentially to and reverses the activity of the serotonin transporter, causing release of serotonin [5-hydroxytryptamine (5-HT)] stores from nerve terminals. Subsequent activation of postsynaptic 5-HT receptors by released 5-HT has been shown to be critical for the unique psychostimulatory effects of MDMA. In contrast, the effects of direct activation of presynaptic and/or postsynaptic receptors by MDMA have received far less attention, despite the agonist actions of the drug itself at 5-HT(2) receptors, in particular the 5-HT(2B) receptor. Here we show that acute pharmacological inhibition or genetic ablation of the 5-HT(2B) receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area. Furthermore, the 5-HT(2B) receptor dependence of MDMA-stimulated release of endogenous 5-HT from superfused midbrain synaptosomes suggests that 5-HT(2B) receptors act, unlike any other 5-HT receptor, presynaptically to affect MDMA-stimulated 5-HT release. Thus, our findings reveal a novel regulatory component in the actions of MDMA and represent the first demonstration that 5-HT(2B) receptors play an important role in the brain, i.e., modulation of 5-HT release. As such, 5-HT(2B) receptor antagonists may serve as promising therapeutic drugs for MDMA abuse.Journal of Neuroscience 04/2008; 28(11):2933-40. · 7.11 Impact Factor -
Article: Genetic heterogeneity versus molecular analysis of prion susceptibility in neuroblasma N2a sublines.
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ABSTRACT: The neuroblastoma-derived cell line N2a is permissive to certain prion strains but resistant sublines unable to accumulate the pathological proteinase-K resistant form of the prion protein can be isolated. We compared for gene expression and phenotypes different N2a sublines that were susceptible or resistant to the 22L prion strain. Karyotypes and comparative genomic hybridization arrays revealed chromosomal imbalances but did not demonstrate a characteristic profile of genomic alterations linked to prion susceptibility. Likewise, we showed that this phenotype was not dependent on the binding of PrPres, the expression of the prion protein gene, or on its primary sequence. We completed this analysis by looking using real-time quantitative PCR at the expression of a set of genes encoding proteins linked to prion biology. None of the candidates could account by itself for the infection phenotype, nevertheless sublines had distinct transcriptional profiles. Taken together, our results do not support a role for specific genomic abnormalities and possible candidate proteins in N2a prion susceptibility. They also reveal genetic heterogeneity among the sublines and serve as a guidance for further investigation into the molecular mechanisms of prion infection.Archives of Virology 02/2008; 153(9):1693-702. · 2.11 Impact Factor -
Article: Modified receptor internalization upon coexpression of 5-HT1B receptor and 5-HT2B receptors.
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ABSTRACT: Serotonin 5-HT(2B) receptors are often coexpressed with 5-HT(1B) receptors, and cross-talk between the two receptors has been reported in various cell types. However, many mechanistic details underlying 5-HT(1B) and 5-HT(2B) receptor cross-talk have not been elucidated. We hypothesized that 5-HT(2B) and 5-HT(1B) receptors each affect the others' signaling by modulating the others' trafficking. We thus examined the agonist stimulated internalization kinetics of fluorescent protein-tagged 5-HT(2B) and 5-HT(1B) receptors when expressed alone and upon coexpression in LMTK(-) murine fibroblasts. Time-lapse confocal microscopy and whole-cell radioligand binding analyses revealed that, when expressed alone, 5-HT(2B) and 5-HT(1B) receptors displayed distinct half-lives. Upon coexpression, serotonin-induced internalization of 5-HT(2B) receptors was accelerated 5-fold and was insensitive to a 5-HT(2B) receptor antagonist. In this context, 5-HT(2B) receptors did internalize in response to a 5-HT(1B) receptor agonist. In contrast, co-expression did not render 5-HT(1B) receptor internalization sensitive to a 5-HT(2B) receptor agonist. The altered internalization kinetics of both receptors upon coexpression was probably not due to direct interaction because only low levels of colocalization were observed. Antibody knockdown experiments revealed that internalization of 5-HT(1B) receptors (expressed alone) was entirely clathrin-independent and Caveolin1-dependent, whereas that of 5-HT(2B) receptors (expressed alone) was Caveolin1-independent and clathrin-dependent. Upon coexpression, serotonin-induced 5-HT(2B) receptor internalization became partially Caveolin1-dependent, and serotonin-induced 5-HT(1B) receptor internalization became entirely Caveolin1-independent in a protein kinase Cepsilon-dependent fashion. In conclusion, these data demonstrate that coexpression of 5-HT(1B) and 5-HT(2B) receptors influences the internalization pathways and kinetics of both receptors.Molecular Pharmacology 07/2007; 71(6):1463-74. · 4.88 Impact Factor -
Article: Activation of peroxisome proliferator-activated receptor-alpha by fenofibrate prevents myocardial dysfunction during endotoxemia in rats.
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ABSTRACT: To investigate the effects of fenofibrate, an activator of peroxisome proliferator-activated receptor-alpha, on cardiac function in a rat endotoxemia model. Prospective, randomized, controlled study. University research laboratory. Three-month-old male Wistar rats. Animals were fed with standard diet containing no drug or fenofibrate (0.2%) for 14 days. They were then injected intravenously with either 5 mg/kg lipopolysaccharide (LPS and fenofibrate + LPS groups) or saline (control and fenofibrate groups). In the LPS group, body weight loss, metabolic acidosis, and thrombocytopenia confirmed presence of systemic endotoxemia. LPS administration resulted in an early peak in plasma tumor necrosis factor-alpha, decreased cardiac contractility (isolated and perfused heart), reduced myofilament Ca2+ sensitivity (Triton-skinned cardiac fibers), and increased left ventricular nitric oxide (NO) end-oxidation products (NO(x) and NO2), without evidence of myocardial oxidative stress (thiobarbituric acid-reactive substances and antioxidant enzyme activities). Fenofibrate pretreatment (fenofibrate + LPS group) did not alter signs of endotoxemia but prevented reductions in both cardiac contractility and myofilament Ca2+ sensitivity. The peak of plasma tumor necrosis factor-alpha was attenuated, whereas myocardial NO(x) and NO2 remained similar to the LPS group. Oxidative stress was suggested from moderate increase in cardiac thiobarbituric acid-reactive substances and reduced glutathione peroxidase activity. Fenofibrate, an activator of peroxisome proliferator-activated receptor-alpha, may prevent endotoxemia-induced cardiac dysfunction and reduction in myofilament Ca2+ sensitivity. Our data also suggest a mediating role for early peak plasma tumor necrosis factor-alpha, but not for myocardial NO production or oxidative stress.Critical Care Medicine 04/2007; 35(3):856-63. · 6.33 Impact Factor -
Article: Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene.
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ABSTRACT: Wilson disease (WD) is an autosomal recessive disorder of copper biliary excretion caused by an impaired function of ATP7B, a metal-transporting P-type ATPase encoded by WD gene. It results in copper accumulation, mostly in liver and brain tissues. Mutation analysis was carried out on 11 WD French unrelated patients presenting a predominant neurological form of this illness. SSCP and dHPLC analysis followed by sequencing of the 21 exons and their flanking introns were performed. Thirteen different mutations in a total of 17, and, among them, 10 novel variants were evidenced. Two deletions (c.654_655delCC and c.1745_1746delTA), 4 missense mutations (p.F763Y, p.G843R, p.D918A and p.L979Q), 1 nonsense mutation (p.Q1200X), 1 splice site mutation (c.1947-1G>C) and 2 intronic silent substitutions (c.2448-25G>T and c.3412+13T>A) were detected. These data extend the mutational spectrum of the disease, already known to be a very heterogeneous genetic disorder. As compared to hepatic manifestations, the phenotypes associated to these mutations confirm that neurological presentations associated with other mutations than p.H1069Q are also often late in their onset. Most of these neurological forms probably correspond to an attenuated impairment of copper metabolism, as compared to hepatic forms of the disease, mostly diagnosed earlier.Journal of Trace Elements in Medicine and Biology 01/2007; 21(1):37-42. · 1.68 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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Hôpital Charles Foix – Groupe Hospitaliere "La Pitié Salpêtrière - Charles Foix"
Ivry-sur-Seine, Ile-de-France, France
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2008–2011
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Assistance Publique – Hôpitaux de Paris
Paris, Ile-de-France, France -
Université Pierre et Marie Curie Paris 6
Paris, Ile-de-France, France -
Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France
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2010
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INSERM, GIP CYCERON
Caen, Basse-Normandie, France
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2007
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French National Centre for Scientific Research
Lyon, Rhone-Alpes, France
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