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1. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Author

Nancy J. Newman, Patrick Yu-Wai-Man, Valerio Carelli, Valerie Biousse, Mark L. Moster, Catherine Vignal-Clermont, Robert C. Sergott, Thomas Klopstock, Alfredo A. Sadun, Jean-François Girmens, Chiara La Morgia, Adam A. DeBusk, Neringa Jurkute, Claudia Priglinger, Rustum Karanjia, Constant Josse, Julie Salzmann, François Montestruc, Michel Roux, Magali Taiel, and José-Alain Sahel

Subjects
Leber hereditary optic neuropathy, ND4, gene therapy, natural history, visual acuity, Neurology. Diseases of the nervous system, RC346-429
Abstract

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Published
2021
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2. Heart rate lowering treatment leads to a reduction in vulnerable plaque features in atherosclerotic rabbits.

Author

Raf H M van Hoof, Evelien Hermeling, Judith C Sluimer, Julie Salzmann, Arnold P G Hoeks, Jérôme Roussel, Mat J A P Daemen, Harry Struijker-Boudier, Joachim E Wildberger, Sylvia Heeneman, and M Eline Kooi

Subjects
Medicine, Science
Abstract

To investigate the effect of a heart rate (HR) lowering agent (Ivabradine) on features of atherosclerotic plaque vulnerability with magnetic resonance imaging (MRI), ultrasound imaging, and histology.Atherosclerosis was induced in the abdominal aorta of 19 rabbits. Nine rabbits were treated with Ivabradine (17 mg/kg/day) during the entire study period. At week 14, imaging was performed. Plaque size was quantified on contrast-enhanced T1-weighted MR images. Microvascular flow, density, and permeability was studied with dynamic contrast-enhanced MRI. Plaque biomechanics was studied by measuring the aortic distension with ultrasound. After, animals were sacrificed and histology was performed. HR was reduced by 16% (p = 0.026) in Ivabradine-treated animals. No differences in absolute and relative vessel wall beat-to-beat distension were found, but due to the reduction in HR, the frequency of the biomechanical load on the plaque was reduced. Plaque size (MR and histology) was similar between groups. Although microvessel density (histology) was similar between groups, AUC and Ktrans, indicative for plaque microvasculature flow, density, and permeability, were decreased by 24% (p = 0.029) and 32% (p = 0.037), respectively. Macrophage content (relative RAM11 positive area) was reduced by 44% (p

Published
2017
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3. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation

Author

Valerio, Carelli, Nancy J, Newman, Patrick, Yu-Wai-Man, Valerie, Biousse, Mark L, Moster, Prem S, Subramanian, Catherine, Vignal-Clermont, An-Guor, Wang, Sean P, Donahue, Bart P, Leroy, Robert C, Sergott, Thomas, Klopstock, Alfredo A, Sadun, Gema, Rebolleda Fernández, Bart K, Chwalisz, Rudrani, Banik, Jean François, Girmens, Chiara, La Morgia, Adam A, DeBusk, Neringa, Jurkute, Claudia, Priglinger, Rustum, Karanjia, Constant, Josse, Julie, Salzmann, François, Montestruc, Michel, Roux, Magali, Taiel, José-Alain, Sahel, Rod, Forooza, Carelli, Valerio, Newman, Nancy J, Yu-Wai-Man, Patrick, Biousse, Valerie, Moster, Mark L, Subramanian, Prem S, Vignal-Clermont, Catherine, Wang, An-Guor, Donahue, Sean P, Leroy, Bart P, Sergott, Robert C, Klopstock, Thoma, Sadun, Alfredo A, Rebolleda Fernández, Gema, Chwalisz, Bart K, Banik, Rudrani, Girmens, Jean Françoi, La Morgia, Chiara, DeBusk, Adam A, Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, Françoi, Roux, Michel, Taiel, Magali, Sahel, José-Alain, Carelli, Valerio [0000-0003-4923-6404], and Apollo - University of Cambridge Repository

Subjects
MT-ND4, Ophthalmology, LHON, Gene therapy, Visual acuity, Medicine and Health Sciences, Natural history, Leber hereditary optic neuropathy
Abstract

Introduction: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. Methods: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. Results: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P

Published
2023

4. Heart rate lowering treatment leads to a reduction in vulnerable plaque features in atherosclerotic rabbits

Author

Mat J.A.P. Daemen, M. Eline Kooi, Evelien Hermeling, Judith C. Sluimer, Julie Salzmann, Arnold P.G. Hoeks, Joachim E. Wildberger, Harry A.J. Struijker-Boudier, Raf H. M. van Hoof, Jérôme Roussel, Sylvia Heeneman, Amsterdam Cardiovascular Sciences, Pathology, ACS - Heart failure & arrhythmias, ACS - Atherosclerosis & ischemic syndromes, Promovendi CD, Beeldvorming, Pathologie, RS: CARIM - R3.06 - The vulnerable plaque: makers and markers, Biomedische Technologie, Farmacologie en Toxicologie, RS: CARIM - R2.03 - ECM + Wnt signaling, MUMC+: DA Beeldvorming (5), RS: CARIM - R3.11 - Imaging, RS: SHE - R1 - Research (OvO), MUMC+: DA BV Klinisch Fysicus (9), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, and RS: NUTRIM - R1 - Metabolic Syndrome

Subjects
Male, lcsh:Medicine, Blood Pressure, 030204 cardiovascular system & hematology, Distension, medicine.disease_cause, Vascular Medicine, 030218 nuclear medicine & medical imaging, Diagnostic Radiology, CONTRAST-ENHANCED MRI, White Blood Cells, 0302 clinical medicine, Heart Rate, Animal Cells, Ultrasound Imaging, Medicine and Health Sciences, Ivabradine, lcsh:Science, Aorta, Mammals, Multidisciplinary, medicine.diagnostic_test, Neovascularization, Pathologic, Radiology and Imaging, Abdominal aorta, Ultrasound, Animal Models, CORONARY ATHEROSCLEROSIS, Magnetic Resonance Imaging, Plaque, Atherosclerotic, Biomechanical Phenomena, Experimental Organism Systems, CARDIOVASCULAR-DISEASE, Vertebrates, Cardiology, CAROTID ATHEROSCLEROSIS, Rabbits, Anatomy, Cellular Types, NONINVASIVE ASSESSMENT, ARTERIAL STIFFNESS, medicine.drug, Research Article, medicine.medical_specialty, Histology, DCE-MRI, Imaging Techniques, Immune Cells, Immunology, Research and Analysis Methods, 03 medical and health sciences, Necrosis, RISK-FACTOR, Diagnostic Medicine, medicine.artery, Internal medicine, Heart rate, medicine, INTRAPLAQUE HEMORRHAGE, Animals, Blood Cells, business.industry, Macrophages, lcsh:R, Organisms, Biology and Life Sciences, Magnetic resonance imaging, Cell Biology, Benzazepines, Atherosclerosis, Vulnerable plaque, BRADYCARDIAC AGENT, Microvessels, Amniotes, Cardiovascular Anatomy, Blood Vessels, lcsh:Q, business
Abstract

OBJECTIVE To investigate the effect of a heart rate (HR) lowering agent (Ivabradine) on features of atherosclerotic plaque vulnerability with magnetic resonance imaging (MRI), ultrasound imaging, and histology. APPROACH AND RESULTS Atherosclerosis was induced in the abdominal aorta of 19 rabbits. Nine rabbits were treated with Ivabradine (17 mg/kg/day) during the entire study period. At week 14, imaging was performed. Plaque size was quantified on contrast-enhanced T1-weighted MR images. Microvascular flow, density, and permeability was studied with dynamic contrast-enhanced MRI. Plaque biomechanics was studied by measuring the aortic distension with ultrasound. After, animals were sacrificed and histology was performed. HR was reduced by 16% (p = 0.026) in Ivabradine-treated animals. No differences in absolute and relative vessel wall beat-to-beat distension were found, but due to the reduction in HR, the frequency of the biomechanical load on the plaque was reduced. Plaque size (MR and histology) was similar between groups. Although microvessel density (histology) was similar between groups, AUC and Ktrans, indicative for plaque microvasculature flow, density, and permeability, were decreased by 24% (p = 0.029) and 32% (p = 0.037), respectively. Macrophage content (relative RAM11 positive area) was reduced by 44% (p

Published
2016

5. Rnd family genes are differentially regulated by 3,4-methylenedioxymethamphetamine and cocaine acute treatment in mice brain

Author

Alexandre David, Cynthia Marie-Claire, Cindie Courtin, Florence Noble, Corinne Canestrelli, Julie Salzmann, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique ( NAVVEC (UM 81) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Diderot - Paris 7 (UPD7), and Marie-Claire, Cynthia

Subjects
Male, rho GTP-Binding Proteins, MESH : RNA, Messenger, MESH : Cocaine, Time Factors, MESH: Dopamine Uptake Inhibitors, MESH : Brain Chemistry, Hippocampus, Striatum, Pharmacology, Mice, 0302 clinical medicine, Cocaine, Dopamine Uptake Inhibitors, MESH: Up-Regulation, MESH: Animals, MESH: Brain Chemistry, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Prefrontal cortex, MESH : Up-Regulation, MESH: Extracellular Signal-Regulated MAP Kinases, MESH: Adrenergic Uptake Inhibitors, MESH : Adrenergic Uptake Inhibitors, 0303 health sciences, MESH : Gene Expression Regulation, Adrenergic Uptake Inhibitors, General Neuroscience, Brain, MDMA, MESH : Extracellular Signal-Regulated MAP Kinases, MESH: Cocaine-Related Disorders, MESH: Gene Expression Regulation, Up-Regulation, 3. Good health, medicine.anatomical_structure, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Enzyme Inhibitors, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine.symptom, MESH : Time Factors, medicine.drug, MESH : Male, N-Methyl-3,4-methylenedioxyamphetamine, Central nervous system, Biology, MESH : Cocaine-Related Disorders, MESH: Brain, Cocaine-Related Disorders, 03 medical and health sciences, MESH: Cocaine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : Mice, MESH : rho GTP-Binding Proteins, medicine, Animals, RNA, Messenger, MESH : N-Methyl-3,4-methylenedioxyamphetamine, MESH: Mice, Molecular Biology, MESH: RNA, Messenger, 030304 developmental biology, Brain Chemistry, MESH : Enzyme Inhibitors, Rnd3, MESH: Time Factors, MESH: rho GTP-Binding Proteins, Actin cytoskeleton, MESH: Male, MESH : Brain, Gene Expression Regulation, Mechanism of action, MESH: N-Methyl-3,4-methylenedioxyamphetamine, MESH : Animals, Neurology (clinical), MESH : Dopamine Uptake Inhibitors, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Drugs of abuse induce alterations in cytoskeletal and cytoskeleton associated genes in several brain areas. We have previously shown that acute MDMA regulates the mRNA level of Rnd3, a Rho GTPase involved in actin cytoskeleton regulation, in mice striatum. In this study we investigated the effects of single administration of cocaine, another psychostimulant with a slightly different mechanism of action, on the mRNA levels of the three members of the Rnd genes family (Rnd1, Rnd2 and Rnd3). Mice were treated with either MDMA (9 mg/kg) or cocaine (20 mg/jg) and brain samples (i.e. hippocampus, striatum and prefrontal cortex) were processed for quantitative real-time PCR assay 1, 2, 4 and 6 h after the injections. The expression level of Rnd2 was differentially affected depending on the drug, brain area and time point after injection. Interestingly the two drugs up-regulate Rnd3 gene expression in the three structures tested with some differences in the timing. The effects of MDMA on Rnd3 appear earlier in the hippocampus as compared to cocaine, while it is the opposite in the prefrontal cortex. However, in the dorsal striatum, the two drugs induce an early and significant up-regulation of Rnd3 expression that is longer-lasting in the case of MDMA. In the case of cocaine contrarily to what was observed with MDMA, this modulation could not be blocked with the ERK activation inhibitor SL327 suggesting that the two drugs lead to the same effect on Rnd3 by two distinct pathways.

Published
2007
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6. Effets aigus et à long terme de l’ecstasy

Author

Cynthia Marie-Claire, Florence Noble, and Julie Salzmann

Subjects
Drug, Hallucinogen, business.industry, media_common.quotation_subject, Ecstasy, Neurotoxicity, MDMA, General Medicine, Pharmacology, medicine.disease, Serotonergic, Euphoriant, Serotonin Agents, Medicine, business, media_common, medicine.drug
Abstract

Side effects in the short term Recreational use of Ecstasy (3,4-methylenedioxymethamphetamine or MDMA), a synthetic drug, has considerably increased over the last decade. Since its appearance it is associated with the rave culture, but its use has spread to other social settings. The drug produces euphoria and empathy, but can lead to side effects, notably acute, potentially lethal, toxicity (malignant hyperthermia and/or hepatitis). Neurotoxicity in the long-term Moreover, MDMA has been shown to induce long-term deleterious effects and provoke neurotoxic affecting the serotoninergic system. However, the psychopathological consequences of such neurotoxicity are still controversial, particularly since many ecstasy consumers are multi-drug users. A complex pharmacological profile The mechanism of action of MDMA involves various neurobiological systems (serotonin, dopamine, noradrenalin), that may all interact.

Published
2004
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7. Importance of ERK activation in behavioral and biochemical effects induced by MDMA in mice

Author

Stéphanie Le Guen, Bernard P. Roques, Julie Salzmann, Cynthia Marie-Claire, and Florence Noble

Subjects
Pharmacology, MAPK/ERK pathway, 0303 health sciences, Chemistry, MDMA, Nucleus accumbens, Conditioned place preference, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Neuroplasticity, Gene expression, medicine, Protein kinase A, Neuroscience, Immediate early gene, psychological phenomena and processes, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract

Little is known about the cellular effects induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), although changes in gene expression have been observed following treatments with other psychostimulants. Thus, the aim of this study was to investigate in mice, the relationships between the ras-dependent protein kinase ERK and MDMA-induced reinforcement using the conditioned place preference (CPP) and locomotor activity measurements. This was completed using real-time quantitative PCR method by a study of immediate early-genes (IEGs) transcription known to be involved in neuronal plasticity. A significant CPP was observed after repeated MDMA treatment in CD-1 mice at a dose of 9 mg kg-1 i.p. but not at 3 and 6 mg kg-1. This rewarding effect was abolished by the selective inhibitor of ERK activation, SL327 (50 mg kg-1; i.p.). Similar results were obtained on MDMA-induced locomotor activity, clearly suggesting a role of ERK pathway in these behavioral responses. Following acute i.p. injection, MDMA induced a strong c-fos transcription in brain structures, such as caudate putamen, nucleus accumbens and hippocampus, whereas egr-1 and egr-3 transcripts were only increased in the caudate putamen. MDMA-induced IEGs transcription was selectively suppressed by SL327 in the caudate putamen, suggesting a role for other signaling pathways in regulation of IEGs transcription in the other brain structures. In agreement with these results, MDMA-induced c-fos protein expression was blocked by SL327 in the caudate putamen. This study confirms and extends to mice the reported role of ERK pathway in the development of addiction-like properties of MDMA. This could facilitate studies about the molecular mechanism of this process by using mutant mice.

Published
2003
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8. Analysis of transcriptional responses in the mouse dorsal striatum following acute 3,4-methylenedioxymethamphetamine (ecstasy): identification of extracellular signal-regulated kinase-controlled genes

Author

Cynthia Marie-Claire, Corinne Canestrelli, Florence Noble, Julie Salzmann, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Diderot - Paris 7 (UPD7), Consortium National de Recherche en Génomique (CNRG) 4999, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique ( NAVVEC (UM 81) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Marie-Claire, Cynthia, Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MAPK/ERK pathway, Male, MESH: Signal Transduction, MESH : RNA, Messenger, MESH: Cytoskeletal Proteins, MESH: Neurons, MESH: Hallucinogens, Mice, 0302 clinical medicine, Gene expression, MESH: Up-Regulation, MESH : Trans-Activation (Genetics), MESH : Neuronal Plasticity, MESH: Animals, MESH: Nerve Tissue Proteins, MESH: Neuronal Plasticity, Extracellular Signal-Regulated MAP Kinases, MESH : Nerve Tissue Proteins, MESH : Up-Regulation, MESH: Extracellular Signal-Regulated MAP Kinases, Oligonucleotide Array Sequence Analysis, Neurons, 0303 health sciences, Neuronal Plasticity, Kinase, General Neuroscience, MESH: Gene Expression Regulation, Enzymologic, MESH : Extracellular Signal-Regulated MAP Kinases, Cell biology, Up-Regulation, MESH : Oligonucleotide Array Sequence Analysis, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Signal transduction, Intracellular, psychological phenomena and processes, Signal Transduction, Transcriptional Activation, MESH: Enzyme Activation, MESH : Neostriatum, MESH : Male, N-Methyl-3,4-methylenedioxyamphetamine, Nerve Tissue Proteins, Biology, MESH : Neurons, Article, Gene Expression Regulation, Enzymologic, MESH : Gene Expression Regulation, Enzymologic, 03 medical and health sciences, MESH: Gene Expression Profiling, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH : Mice, mental disorders, Extracellular, Animals, RNA, Messenger, MESH : N-Methyl-3,4-methylenedioxyamphetamine, Transcription factor, MESH: Mice, Protein kinase C, 030304 developmental biology, MESH: RNA, Messenger, MESH : Signal Transduction, MESH : Gene Expression Profiling, Gene Expression Profiling, MESH : Cytoskeletal Proteins, MESH : Hallucinogens, Molecular biology, MESH: Male, Enzyme Activation, Neostriatum, Cytoskeletal Proteins, MESH: Neostriatum, MESH: Trans-Activation (Genetics), MESH: Oligonucleotide Array Sequence Analysis, Hallucinogens, MESH: N-Methyl-3,4-methylenedioxyamphetamine, MESH : Animals, MESH : Enzyme Activation, 030217 neurology & neurosurgery
Abstract

International audience; 3,4-Methylenedioxymethamphetamine (ecstasy), a widely used recreational drug with psychoactive properties, induces both serotonin and dopamine release in the brain. However, little is known about its intracellular effects. We previously showed that 3,4-methylenedioxymethamphetamine rewarding effects in mice were dependent upon extracellular signal-regulated kinase activation and that dorsal striatum was a critical region for mediating extracellular signal-regulated kinase-dependent Egr1 3,4-methylenedioxymethamphetamine-induced transcription. Here, we extend these findings by showing that 3,4-methylenedioxymethamphetamine is indeed able to activate extracellular signal-regulated kinase within this structure. To identify genes regulated by acute 3,4-methylenedioxymethamphetamine in the mice dorsal striatum, and selectively controlled by this kinase, we performed microarray experiments by using a selective inhibitor of extracellular signal-regulated kinase activation, SL327. Of the approximately 24,000 genes from the microarray, 27 showed altered expression after exposure to 3,4-methylenedioxymethamphetamine, and among these, 59% were partially or totally inhibited by SL327 pretreatment. Our results showed that the genes regulated by 3,4-methylenedioxymethamphetamine encode proteins that belong to transcription factors family, signaling pathways (phosphatases, cytoskeleton regulation), and synaptic functions. These early changes, and especially those controlled by extracellular signal-regulated kinase activation might play significant roles in the expression of many of the behaviors that occur following 3,4-methylenedioxymethamphetamine taking.

Published
2006
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