25 results on '"Etienne C. Hirsch"'
Search Results
2. Seven Solutions for Neuroprotection in Parkinson's Disease
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David Devos, Etienne C. Hirsch, Richard K. Wyse, Université de Lille, Inserm, CHU Lille, Lille Neurosciences & Cognition (LilNCog) - U 1172, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute [ICM], Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), European Project: 633190,H2020,H2020-PHC-2014-two-stage,FAIR-PARK-II(2015), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Drug ,Parkinson's disease ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,media_common.quotation_subject ,preclinical studies ,drug development ,s disease ,clinical trial ,Parkinson' modifying effect ,disease‐ neuroprotection ,Substantia nigra ,Disease ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Tissue Distribution ,media_common ,business.industry ,Mechanism (biology) ,Parkinson Disease ,medicine.disease ,3. Good health ,Substantia Nigra ,Clinical trial ,Neuroprotective Agents ,030104 developmental biology ,Neurology ,Drug development ,alpha-Synuclein ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive, and we outline approaches to help generate successful development of neuroprotective drugs for PD: (1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement, (2) combine treatments that target multiple pathways, (3) establish earliest interventions and develop better prodromal biomarkers, (4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials, (5) customize drug with better brain biodistribution, (6) prioritize repurposed drugs as a first line approach, and (7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value. © 2020 International Parkinson and Movement Disorder Society 36;2
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- 2020
3. NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients
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Manuela eMellone, Jennifer eStanic, Ledia F Hernandez, Elena eIglesias, Elisa eZianni, Annalisa eLonghi, Annick ePrigent, Barbara ePicconi, Paolo eCalabresi, Etienne C Hirsch, Jose A Obeso, Monica eDi Luca, and Fabrizio eGardoni
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Patients ,Striatum ,Parkinson’s disease ,NMDA receptor ,Levodopa-induced dyskinesias ,6-OHDA rat model ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson’s disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at i. characterizing NMDA receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs and in dyskinetic PD patients, and ii. validating the potential therapeutic effect of a cell-permeable peptide interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein PSD-95 leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
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- 2015
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4. Long-term outcome in neuroZika
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Quentin Lobjois, Pascale Poullain, Etienne C. Hirsch, Guillaume Thiery, Françoise Lazarini, Fatiha Najioullah, Jean-Louis Fergé, Emmanuel Roze, Sébastien Breurec, Anne-Charlotte Savidan, Benoit Tressières, Annie Lannuzel, Eavan McGovern, Aissatou Signate, André Cabié, Ruddy Valentino, Yoann Madec, Pierre-Marie Lledo, Benoît Rozé, Raymond Césaire, Cécile Herrmann, Hirsch, Etienne, Service de Neurologie [CHU Pointe à Pitre], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU de la Martinique [Fort de France], Centre d'investigation clinique Antilles-Guyane (CIC - Antilles Guyane), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de la Martinique [Fort de France]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur de la Guadeloupe, Réseau International des Instituts Pasteur (RIIP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Perception et Mémoire - Perception and Memory, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université des Antilles (UA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de la Martinique [Fort de France]-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Institut Pasteur [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Perception et Mémoire / Perception and Memory, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,West Indies ,medicine.medical_treatment ,Guillain-Barre Syndrome ,[SCCO]Cognitive science ,03 medical and health sciences ,0302 clinical medicine ,Modified Rankin Scale ,Interquartile range ,Epidemiology ,medicine ,Humans ,Encephalitis, Viral ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,030212 general & internal medicine ,Child ,Encephalomyelitis ,Stroke ,Aged ,Mechanical ventilation ,Guillain-Barre syndrome ,Zika Virus Infection ,business.industry ,[SCCO.NEUR]Cognitive science/Neuroscience ,Infant ,Odds ratio ,Middle Aged ,Prognosis ,medicine.disease ,Respiration, Artificial ,Cranial Nerve Diseases ,3. Good health ,Hospitalization ,Treatment Outcome ,Child, Preschool ,RNA, Viral ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Encephalitis - Abstract
ObjectiveTo characterize the full spectrum, relative frequency, and prognosis of the neurologic manifestations in Zika virus (ZIKV) postnatal infection.MethodsWe conducted an observational study in consecutive ZIKV-infected patients presenting with neurologic manifestations during the French West Indies 2016 outbreak.ResultsEighty-seven patients, including 6 children, were enrolled. Ninety-five percent of all cases required hospitalization. Guillain-Barré syndrome was the most frequent manifestation (46.0%) followed by encephalitis or encephalomyelitis (20.7%), isolated single or multiple cranial nerve palsies (9.2%), other peripheral manifestations (6.9%), and stroke (1.1%). Fourteen patients (16.1%), including one child, developed a mixed disorder involving both the central and peripheral nervous system. Mechanical ventilation was required in 21 cases, all of whom had ZIKV RNA in at least one biological fluid. Two adult patients died due to neuroZika. Clinical follow-up (median 14 months; interquartile range, 13–17 months) was available for 76 patients. Residual disability (modified Rankin Scale score ≥2) was identified in 19 (25.0%) patients; in 6 cases (7.9%), disability was severe (modified Rankin Scale score ≥4). Among patients with ZIKV RNA detected in one biological fluid, the risk of residual disability or death was higher (odds ratio 9.19; confidence interval 1.12–75.22; p = 0.039).ConclusionsNeuroZika spectrum represents a heterogeneous group of clinical neurologic manifestations. During an outbreak, clinicians should consider neuroZika in patients presenting with cranial nerve palsies and a mixed neurologic disorder. Long-term sequelae are frequent in NeuroZika. ZIKV reverse-transcription PCR status at admission can inform prognosis and should therefore be taken into consideration in the management of hospitalized patients.
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- 2019
5. Glutaredoxin 1 downregulation in the substantia nigra leads to dopaminergic degeneration in mice
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Bernard L. Schneider, Etienne C. Hirsch, Reddy Peera Kommaddi, Ajit Ray, Aditi Verma, Deepti Bapat, Vijayalakshmi Ravindranath, Latha Diwakar, Indian Institute of Science [Bangalore] (IISc Bangalore), Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hirsch, Etienne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,mouse model ,Dopamine ,translocation ,Down-Regulation ,Substantia nigra ,24 tyrosine hydroxylase 25 ,Striatum ,thioltransferase ,03 medical and health sciences ,Mice ,0302 clinical medicine ,glutaredoxin 1 ,tyrosine hydroxylase ,shRNA ,medicine ,oxidative stress ,Animals ,Humans ,glutathione ,Glutaredoxins ,dysfunction ,dopaminergic neurons ,Tyrosine hydroxylase ,Chemistry ,Pars compacta ,[SCCO.NEUR]Cognitive science/Neuroscience ,Dopaminergic ,Neurodegeneration ,[SCCO.NEUR] Cognitive science/Neuroscience ,neurodegeneration ,mitochondrial complex-i ,medicine.disease ,cell-death ,Cell biology ,Ventral tegmental area ,Substantia Nigra ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,nervous system ,parkinsons-disease ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
International audience; Background: Parkinson's disease (PD) is characterized by a severe loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Perturbation of protein thiol redox homeostasis has been shown to play a role in the dysregulation of cell death and cell survival signaling pathways in these neurons. Glutaredoxin 1 (Grx1) is a thiol/disulfide oxidoreductase that catalyzes the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis.Objectives: We evaluated if the downregulation of Grx1 could lead to dopaminergic degeneration and PD-relevant motor deficits in mice.Methods: Grx1 was downregulated unilaterally through viral vector-mediated transduction of short hairpin RNA against Grx1 into the SNpc. Behavioral assessment was performed through rotarod and elevated body swing test. Stereological analysis of tyrosine hydroxylase-positive and Nissl-positive neurons was carried out to evaluate neurodegeneration.Results: Downregulation of Grx1 resulted in contralateral bias of elevated body swing and reduced latency to fall off, accelerating rotarod. This was accompanied by a loss of tyrosine hydroxylase-positive neurons in the SNpc and their DA projections in the striatum. Furthermore, there was a loss Nissl-positive neurons in the SNpc, indicating cell death. This was selective to the SNpc neurons because DA neurons in the ventral tegmental area were unaffected akin to that seen in human PD. Furthermore, Grx1 mRNA expression was substantially decreased in the SNpc from PD patients.Conclusions: Our study indicates that Grx1 is critical for the survival of SNpc DA neurons and that it is downregulated in human PD. © 2020 International Parkinson and Movement Disorder Society.
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- 2020
6. Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson’s disease
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Suresh P, Ravindranath, Gnanabharathi B, Etienne C. Hirsch, and Aditi Verma
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Parkinson's disease ,Pars compacta ,MPTP ,Dopaminergic ,Substantia nigra ,Biology ,medicine.disease ,Pathogenesis ,chemistry.chemical_compound ,chemistry ,Downregulation and upregulation ,nervous system ,Cancer research ,medicine ,Synaptic vesicle recycling - Abstract
We performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and Parkinson’s disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as, LMX1B, FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1, and GRB10 were downregulated in human PD and overexpression of LMX1B rescued MPP+ induced death in SH-SY5Y neurons. Downregulation of gene ensemble involved in development and differentiation of dopaminergic neurons indicate their critical involvement in pathogenesis and progression of human PD.
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- 2020
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7. Ten Unsolved Questions About Neuroinflammation in Parkinson's Disease
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Etienne C. Hirsch, David G. Standaert, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Alabama at Birmingham [ Birmingham] (UAB), Hirsch, Etienne, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,medicine.medical_specialty ,Postmortem studies ,Parkinson's disease ,Disease ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,α-synuclein ,microglial cells ,Epidemiology ,medicine ,Humans ,Lymphocytes ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neuroinflammation ,business.industry ,Neurodegeneration ,neurodegeneration ,Parkinson Disease ,medicine.disease ,Acquired immune system ,3. Good health ,030104 developmental biology ,Neurology ,alpha-Synuclein ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Parkinson's disease is a progressive and debilitating disorder that has so far eluded attempts to develop disease-modifying treatment. Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson's disease. Postmortem studies and experimental analyses suggest the involvement of both innate and adaptive immunity in the degenerative process. There is also some circumstantial evidence for effects of immune therapies on the disease. In the present article, we review 10 unanswered questions related to neuroinflammatory processes in Parkinson's disease with the goal of stimulating research in the field and accelerating the clinical development of neuroprotective therapies based on anti-inflammatory strategies. © 2020 International Parkinson and Movement Disorder Society.
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- 2020
8. Parkinson's disease: A target for therapies?
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Etienne C. Hirsch
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Oncology ,medicine.medical_specialty ,Parkinson's disease ,Neurology ,business.industry ,Internal medicine ,Medicine ,Neurology (clinical) ,business ,medicine.disease - Published
- 2021
9. S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization
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Aakash Patel, Hala Guedouari, Elzbieta Janda, Karine Reybier, Istvan Gacsalyi, Vishalgiri Goswami, Jean A. Boutin, Adeline Giganti, Mathias Antoine, Monivan Chhour, Marie-Claude Viaud-Massuard, Hervé Da Costa, Marc Bertrand, Pierre Ducrot, Jérôme Paysant, Patrick P. Michel, Gilles Ferry, Thierry Le Diguarher, Daniel A. Kane, Françoise Nepveu, Frédéric Bouillaud, Karen Brebner, Gérald Guillaumet, Etienne C. Hirsch, Philippe Dupuis, Johann Stojko, Institut de Recherches SERVIER (IRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Università degli Studi 'Magna Graecia' di Catanzaro [Catanzaro, Italie] (UMG), Egis Pharmaceuticals, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), St. Francis Xavier University (StFX), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Eurofins-Cerep, Technologie Servier, GICC UMR 7292 CNRS, IMT (Innovation moléculaire et thérapeutique) (IMT), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Oxygen Healthcare Pvt Ltd, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), GICC EA 7501, IMT (Innovation moléculaire et thérapeutique) (IMT), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Hirsch, Etienne, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), and Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Male ,Rats Wistar ,Pyridines ,[SDV]Life Sciences [q-bio] ,Quinone Reductases / antagonists & inhibitors ,Reductase ,Cell Membrane / drug effects ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pyrrolizidine Alkaloids / pharmacology ,In vivo ,Cell Line, Tumor ,NAD(P)H Dehydrogenase (Quinone) ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Quinone Reductases ,Rats, Wistar ,NAD(P)H Dehydrogenase (Quinone) / metabolism ,Pyrrolizidine Alkaloids ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Chemistry ,Cell Membrane ,Autophagy ,Neurodegeneration ,Reactive Oxygen Species / metabolism ,Hep G2 Cells ,Cell Membrane / metabolism ,medicine.disease ,Quinone ,Cell Line / Tumor ,Rats ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Enzyme ,Biochemistry ,Molecular Medicine ,NAD+ kinase ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Pyridines / pharmacology - Abstract
International audience; Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC50 = 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.
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- 2019
10. NEUROPROTECTION OF DOPAMINE NEURONS BY XENON AGAINST LOW-LEVEL EXCITOTOXIC INSULTS IS NOT REPRODUCED BY OTHER NOBLE GASES
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Juan Fernando Ramirez-Gil, Géraldine Farjot, Jérémie Lavaur, Aude Milet, Etienne C. Hirsch, Déborah Le Nogue, Ira Katz, Marc Lemaire, Patrick P. Michel, Hirsch, Etienne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Air Liquide Santé International [Jouy-en-Josas, France] (Campus Innovation Paris), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Xenon ,Pyridines ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Excitotoxicity ,Carboxylic Acids ,medicine.disease_cause ,Helium ,Dopamine neurons ,0302 clinical medicine ,Mesencephalon ,Cells, Cultured ,Neurodegeneration ,Glutamate receptor ,Noble gas ,Noble gases ,Parkinson disease ,[SDV] Life Sciences [q-bio] ,Psychiatry and Mental health ,Neuroprotective Agents ,Neurology ,NMDA receptor ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.drug ,circulatory and respiratory physiology ,chemistry.chemical_element ,Neon ,Neurology and Preclinical Neurological Studies - Original Article ,Neuroprotection ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Dopamine ,Memantine ,medicine ,Animals ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Rats, Wistar ,Biological Psychiatry ,Dopaminergic Neurons ,Krypton ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.disease ,Embryo, Mammalian ,Rats ,030104 developmental biology ,chemistry ,Biophysics ,Neurology (clinical) ,Excitatory Amino Acid Antagonists ,030217 neurology & neurosurgery - Abstract
Using midbrain cultures, we previously demonstrated that the noble gas xenon is robustly protective for dopamine (DA) neurons exposed to l-trans-pyrrolidine-2,4-dicarboxylate (PDC), an inhibitor of glutamate uptake used to generate sustained, low-level excitotoxic insults. DA cell rescue was observed in conditions where the control atmosphere for cell culture was substituted with a gas mix, comprising the same amount of oxygen (20%) and carbon dioxide (5%) but 75% of xenon instead of nitrogen. In the present study, we first aimed to determine whether DA cell rescue against PDC remains detectable when concentrations of xenon are progressively reduced in the cell culture atmosphere. Besides, we also sought to compare the effect of xenon to that of other noble gases, including helium, neon and krypton. Our results show that the protective effect of xenon for DA neurons was concentration-dependent with an IC50 estimated at about 44%. We also established that none of the other noble gases tested in this study protected DA neurons from PDC-mediated insults. Xenon’s effectiveness was most probably due to its unique capacity to block NMDA glutamate receptors. Besides, mathematical modeling of gas diffusion in the culture medium revealed that the concentration reached by xenon at the cell layer level is the highest of all noble gases when neurodegeneration is underway. Altogether, our data suggest that xenon may be of potential therapeutic value in Parkinson disease, a chronic neurodegenerative condition where DA neurons appear vulnerable to slow excitotoxicity.
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- 2019
11. Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Techniques, Side Effects, and Postoperative Imaging
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Andres M. Lozano, Peter A. Silburn, Clement Hamani, Wesley Thevathasan, Joachim K. Krauss, William D. Hutchison, Edgar Garcia-Rill, Peter Brown, Bastiaan R. Bloem, Laurent Goetz, Mesbah Alam, Michael S. Okun, Etienne C. Hirsch, Anand I. Rughani, Terry Coyne, Tipu Z. Aziz, Kelly D. Foote, Elena Moro, Paolo Mazzone, Ludvic Zrinzo, Erlick A. C. Pereira, and Stephan Chabardes
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0301 basic medicine ,medicine.medical_specialty ,Deep brain stimulation ,Deep Brain Stimulation ,medicine.medical_treatment ,Disease ,Article ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Physical medicine and rehabilitation ,Neuroimaging ,Pedunculopontine Tegmental Nucleus ,medicine ,Humans ,Electrode placement ,Pedunculopontine nucleus ,Postoperative Care ,Surgical approach ,business.industry ,Parkinson Disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Subthalamic nucleus ,030104 developmental biology ,Surgery ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 168033.pdf (Publisher’s version ) (Open Access) The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS.
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- 2016
12. Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity
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Layal, Maatouk, Chenju, Yi, Maria-Angeles, Carrillo-de Sauvage, Anne-Claire, Compagnion, Stéphane, Hunot, Pascal, Ezan, Etienne C, Hirsch, Annette, Koulakoff, Frank W, Pfrieger, François, Tronche, Luc, Leybaert, Christian, Giaume, and Sheela, Vyas
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Male ,Mice ,Astrocytes ,Dopaminergic Neurons ,Animals ,Humans ,Parkinson Disease ,Connexins ,Article - Abstract
The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson’s disease (PD) is not well characterized. In this study, using GRCx30CreERT2 mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GRCx30CreERT2 mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated transcripts ICAM-1, TNF-α and Il-1β as well as TNF-α protein levels were significantly elevated after MPTP neurotoxicity compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+ . The increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTP-injected GRCx30CreERT2 mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both DN loss and microglial activation; in wild-type mice there was partial but significant survival effect. In the SN of post-mortem PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine neurodegeneration in PD pathology.
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- 2017
13. The Oxygen Paradox, the French Paradox, and age-related diseases
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Jean Mariani, Christian J. Pike, David Warburton, Adam J. Lundquist, Mathias Mericskay, Josiane Cillard, Joanna M. S. Davies, Rachael Cayce, Jean Rosenbaum, David Huang, Etienne C. Hirsch, Steven Burstein, Andrew Fishmann, Fatima Mechta-Grigoriou, Jean Cadet, Laura C.D. Pomatto, Bertrand Friguet, Enrique Cadenas, Henry Jay Forman, Onnik Agbulut, Delphine Sauce, Giselle M. Petzinger, Anne-Laure Bulteau, Michael W. Jakowec, Zhenlin Li, Matthew R. Halliday, Amélie Rébillard, Florian Sennlaub, Kelvin J.A. Davies, Pierre Cillard, Christian Neri, Anne Negre Salvayre, Caleb E. Finch, Nicolaus A. Jakowec, David Liao, Jacqueline Capeau, Patrick Y. Sun, Robert A. Kloner, Fulvio Ursini, Christina Economides, Frédéric Derbré, Pinchas Cohen, Mustapha Rouis, Ellsworth Grant, Matilde Maiorino, Isabelle Limon, University of Southern California (USC), Université de Rennes 1 - Faculté des sciences pharmaceutiques et biologiques (UR1 Pharmacie), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Sherbrooke (UdeS), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Huntington Medical Research Institute, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondation de France, Université Pierre et Marie Curie, Ligue Contre le Cancer, National Parkinson Foundation, Children's Hospital Los Angeles, Assistance Publique - Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale, American Foundation for Aging Research, Centre National de la Recherche Scientifique, U01HL122681, National Heart, Lung, and Blood Institute, R01AG034430, National Institute on Aging, DGE-1418060, National Science Foundation, Pasadena Guild, Don Roberto Gonzalez and Family Foundation, the webb foundation, ES023864, National Institute of Environmental Health Sciences, The Garland Foundation, Université Toulouse III - Paul Sabatier, Conseil Régional de Bretagne, DOD-PC160353U, U.S. Department of Defense, Agence Nationale de la Recherche, Université de Rennes - Faculté des sciences pharmaceutiques et biologiques (UR Pharmacie), Université de Rennes (UR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-École normale supérieure - Rennes (ENS Rennes)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Jonchère, Laurent, École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Sherbrooke [Sherbrooke], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), SIGNALISATION ET PHYSIOPATHOLOGIE CARDIOVASCULAIRE (UMRS1180, LabEx LERMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP]
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0301 basic medicine ,Male ,Aging ,French Paradox ,Psychoanalysis ,[SDV]Life Sciences [q-bio] ,Early death ,Review Article ,80 and over ,French paradox ,Aged, 80 and over ,Low dose ,Middle Aged ,Oxygen Paradox ,Adaptation, Physiological ,3. Good health ,[SDV] Life Sciences [q-bio] ,High-Protein ,Diet, High-Protein ,Female ,France ,Free Radicals ,Physiological ,Hypercholesterolemia ,and over ,Adaptive Homeostasis ,Age-related diseases ,Ageing ,Healthspan ,Oxidative stress ,Proteostasis ,Aged ,Geriatric Assessment ,Humans ,Oxidative Stress ,Oxygen ,Risk Assessment ,Geriatrics and Gerontology ,03 medical and health sciences ,Age related ,Adaptation ,proteostasis ,Geriatrics gerontology ,Biological phenomenon ,Biological signal transduction ,Human physiology ,Diet ,Good Health and Well Being ,030104 developmental biology ,Generic health relevance - Abstract
International audience; A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and paté) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428-1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance, "healthspan," "lifespan," and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as "Adaptive Homeostasis" (Davies Mol Asp Med 49:1-7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573-2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself.
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- 2017
14. Dysfunction of mitochondrial Lon protease and identification of oxidized protein in mouse brain following exposure to MPTP: Implications for Parkinson disease
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Christian S. Lobsiger, Etienne C. Hirsch, Anne Laure Bulteau, Jean-Michel Camadro, Natalia P. Mena, Annick Prigent, Irene Lee, Françoise Auchère, HAL-UPMC, Gestionnaire, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, MNP : Maladies neurologiques et maladies psychiatriques - Comprendre les modifications du métabolisme du fer dans la maladie de Parkinson pour combattre la mort neuronale - - Parklron2009 - ANR-09-MNPS-0019 - MNP - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidad de Chile, Millennium Institute of Cell Dynamics and Biotechnology [Santiago], Mitochondries, métaux et stress oxydatif, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Case Western Reserve University [Cleveland], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-09-MNPS-0019,Parklron,Comprendre les modifications du métabolisme du fer dans la maladie de Parkinson pour combattre la mort neuronale(2009), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mitochondries, Métaux et stress oxydatif, and Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Proteomics ,0301 basic medicine ,Protease La ,Parkinson's disease ,Respiratory chain ,Mitochondrion ,Biology ,Protein oxidation ,medicine.disease_cause ,Biochemistry ,Aconitase ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mesencephalon ,Physiology (medical) ,medicine ,Animals ,Humans ,Ketoglutarate Dehydrogenase Complex ,protein oxidation ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Aconitate Hydratase ,Cell Death ,Dopaminergic Neurons ,MPTP ,Lon protease ,Parkinson Disease ,Molecular biology ,3. Good health ,Mice, Inbred C57BL ,mitochondria ,Disease Models, Animal ,030104 developmental biology ,Electron Transport Chain Complex Proteins ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Mitochondrial matrix ,Oxidative stress ,Unfolded Protein Response ,Unfolded protein response ,bacteria ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Reactive Oxygen Species ,Oxidation-Reduction ,030217 neurology & neurosurgery - Abstract
International audience; Compelling evidence suggests that mitochondrial dysfunction leading to reactive oxygen species (ROS) production and protein oxidation could represent a critical event in the pathogenesis of Parkinson's disease (PD). Pioneering studies have shown that the mitochondrial matrix contains the Lon protease, which degrades oxidized, dysfunctional, and misfolded protein. Using the PD animal model of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxication in mice, we showed that Lon protease expression increased in the ventral mesencephalon of intoxicated animals, concomitantly with the appearance of oxidized proteins and dopaminergic cell loss. In addition, we report that Lon is inactivated by ROS. Moreover, proteomic experiments provide evidence of carbonylation in α-ketoglutarate dehydrogenase (KGDH), aconitase or subunits of respiratory chain complexes.Lon protease inactivation upon MPTP treatment in mice raises the possibility that Lon protease dysfunction is an early event in the pathogenesis of PD.
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- 2017
15. Hepcidin attenuates amyloid beta-induced inflamatory and pro-oxidant responses in astrocytes and microglia
- Author
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Marco T. Núñez, Christian Gonzalez-Billault, Pamela J. Urrutia, and Etienne C. Hirsch
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0301 basic medicine ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Amyloid beta ,Primary Cell Culture ,Inflammation ,medicine.disease_cause ,Biochemistry ,Hippocampus ,Antioxidants ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Hepcidins ,Hepcidin ,hemic and lymphatic diseases ,medicine ,Animals ,Senile plaques ,Injections, Intraventricular ,Neurons ,Amyloid beta-Peptides ,biology ,Microglia ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Neurotoxicity ,nutritional and metabolic diseases ,medicine.disease ,Peptide Fragments ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Astrocytes ,Culture Media, Conditioned ,Immunology ,biology.protein ,medicine.symptom ,030217 neurology & neurosurgery ,Oxidative stress ,Astrocyte - Abstract
Alzheimer's disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal death. Aggregated amyloid-β (Aβ) induces inflammation and oxidative stress, which have pivotal roles in the pathogenesis of AD. Hepcidin is a key regulator of systemic iron homeostasis. Recently, an anti-inflammatory response to hepcidin was reported in macrophages. Under the hypothesis that hepcidin mediates anti-inflammatory response in the brain, in this study, we evaluated the putative anti-inflammatory role of hepcidin on Aβ-activated astrocytes and microglia. Primary culture of astrocytes and microglia were treated with Aβ, with or without hepcidin, and cytokine levels were then evaluated. In addition, the toxicity of Aβ-treated astrocyte- or microglia-conditioned media was tested on neurons, evaluating cellular death and oxidative stress generation. Finally, mice were injected in the right lateral ventricle with Aβ, with or without hepcidin, and hippocampus glial activation and oxidative stress were evaluated. Pre-treatment with hepcidin reduced the expression and secretion of TNF-α and IL-6 in astrocytes and microglia treated with Aβ. Hepcidin also reduced neurotoxicity and oxidative damage triggered by conditioned media obtained from astrocytes and microglia treated with Aβ. Stereotaxic intracerebral injection of hepcidin reduced glial activation and oxidative damage triggered by Aβ injection in mice. Overall, these results are consistent with the hypothesis that in astrocytes and microglia hepcidin down-regulates the inflammatory and pro-oxidant processes induced by Aβ, thus protecting neighboring neurons. This is a newly described property of hepcidin in the central nervous system, which may be relevant for the development of strategies to prevent the neurodegenerative process associated with AD.
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- 2017
16. Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes
- Author
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Stéphane Hunot, Guillaume Lornet, Christophe Combadière, Yann Monnet, Vincent R. Parillaud, Anne-Laure Privat, Etienne C. Hirsch, Camille Baudesson de Chanville, Andrei T. Haddad, Vanessa Brochard, Amaury Jean-Marie Bekaert, Christian S. Lobsiger, BMC, BMC, BLANC - Relations Neuro-Immunes pendant la Dégénérescence Neuronale dans la Maladie de Parkinson: Rôle des Chimiokines - - ParKemoS2010 - ANR-10-BLAN-1418 - BLANC - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), ANR-10-BLAN-1418,ParKemoS,Relations Neuro-Immunes pendant la Dégénérescence Neuronale dans la Maladie de Parkinson: Rôle des Chimiokines(2010), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
- Subjects
0301 basic medicine ,Lipopolysaccharides ,CCR2 ,Chemokine ,Time Factors ,animal diseases ,[SDV]Life Sciences [q-bio] ,Dopaminergic neurons ,Monocytes ,Receptors, Interleukin-8A ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Neuroinflammation ,Cell Movement ,CX3CR1 ,Chemokine CCL2 ,CD11b Antigen ,General Neuroscience ,MPTP ,Microfilament Proteins ,CCL2-CCR2 ,Substantia Nigra ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Neurology ,CX3CL1-CX3CR1 ,MPTP Poisoning ,Microglia ,Chemokines ,Infiltration (medical) ,Tyrosine 3-Monooxygenase ,Receptors, CCR2 ,Immunology ,Mice, Transgenic ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine ,Animals ,Monocyte ,Research ,Calcium-Binding Proteins ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Gene Expression Regulation ,nervous system ,Astrocytes ,Cancer research ,biology.protein ,Parkinson’s disease ,030217 neurology & neurosurgery - Abstract
Background Evidence from mice suggests that brain infiltrating immune cells contribute to neurodegeneration, and we previously identified a deleterious lymphocyte infiltration in Parkinson’s disease mice. However, this remains controversial for monocytes, due to artifact-prone techniques used to distinguish them from microglia. Our aim was to reassess this open question, by taking advantage of the recent recognition that chemokine receptors CCR2 and CX3CR1 can differentiate between inflammatory monocytes and microglia, enabling to test whether CCR2+ monocytes infiltrate the brain during dopaminergic (DA) neurodegeneration and whether they contribute to neuronal death. This revealed unexpected insights into possible regulation of monocyte-attracting CCL2 induction. Methods We used acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice and assessed monocyte infiltration by combining laser microdissection-guided chemokine RNA profiling of the substantia nigra (SN) with immunohistochemistry and CCR2-GFP reporter mice. To determine contribution to neuronal loss, we used CCR2-deletion and CCL2-overexpression, to reduce and increase CCR2+ monocyte infiltration, and CX3CR1-deletion to assess a potential implication in CCL2 regulation. Results Nigral chemokine profiling revealed early CCL2/7/12-CCR2 axis induction, suggesting monocyte infiltration in MPTP mice. CCL2 protein showed early peak induction in nigral astrocytes, while CCR2-GFP mice revealed early but limited nigral monocyte infiltration. However, blocking infiltration by CCR2 deletion did not influence DA neuronal loss. In contrast, transgenic astrocytic CCL2 over-induction increased CCR2+ monocyte infiltration and DA neuronal loss in MPTP mice. Surprisingly, CCL2 over-induction was also detected in MPTP intoxicated CX3CR1-deleted mice, which are known to present increased DA neuronal loss. Importantly, CX3CR1/CCL2 double-deletion suggested that increased neurotoxicity was driven by astrocytic CCL2 over-induction. Conclusions We show that CCR2+ monocytes infiltrate the affected CNS, but at the level observed in acute MPTP mice, this does not contribute to DA neuronal loss. In contrast, the underlying astrocytic CCL2 induction seemed to be tightly controled, as already moderate CCL2 over-induction led to increased neurotoxicity in MPTP mice, likely due to the increased CCR2+ monocyte infiltration. Importantly, we found evidence suggesting that during DA neurodegeneration, this control was mediated by microglial CX3CR1 signaling, which protects against such neurotoxic CCL2 over-induction by astrocytes, thus hinting at an endogenous mechanism to limit neurotoxic effects of the CCL2-CCR2 axis. Electronic supplementary material The online version of this article (doi:10.1186/s12974-017-0830-9) contains supplementary material, which is available to authorized users.
- Published
- 2017
17. Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology
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Laurent Goetz, Stephan Chabardes, Edgar Garcia-Rill, Peter A. Silburn, Andres M. Lozano, Ludvic Zrinzo, Elena Moro, William D. Hutchison, Paolo Mazzone, Joachim K. Krauss, Wesley Thevathasan, Tipu Z. Aziz, Erlick A. C. Pereira, Kelly D. Foote, Anand I. Rughani, Terry Coyne, Michael S. Okun, Etienne C. Hirsch, Clement Hamani, Mesbah Alam, Peter Brown, and Bastiaan R. Bloem
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0301 basic medicine ,Movement disorders ,Deep brain stimulation ,medicine.medical_treatment ,Deep Brain Stimulation ,Article ,Progressive supranuclear palsy ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,Terminology as Topic ,Basal ganglia ,medicine ,Pedunculopontine Tegmental Nucleus ,Humans ,Pedunculopontine nucleus ,Parkinson Disease ,medicine.disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Subthalamic nucleus ,030104 developmental biology ,Surgery ,Neurology (clinical) ,medicine.symptom ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 168032.pdf (Publisher’s version ) (Open Access) Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.
- Published
- 2016
18. Understanding Dopaminergic Cell Death Pathways in Parkinson Disease
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Etienne C. Hirsch, Stéphane Hunot, and Patrick P. Michel
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0301 basic medicine ,Programmed cell death ,Dopamine ,Substantia nigra ,Disease ,Biology ,Midbrain ,03 medical and health sciences ,0302 clinical medicine ,Dopaminergic Cell ,medicine ,Animals ,Humans ,Cell Death ,General Neuroscience ,Endoplasmic reticulum ,Dopaminergic Neurons ,Autophagy ,Parkinson Disease ,3. Good health ,Mitochondria ,Substantia Nigra ,030104 developmental biology ,nervous system ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder, the etiology of which remains largely unknown. Progressive impairment of voluntary motor control, which represents the primary clinical feature of the disease, is caused by a loss of midbrain substantia nigra dopamine (DA) neurons. We present, here, a synthetic overview of cell autonomous mechanisms that are likely to participate in DA cell death in both sporadic and inherited forms of the disease. In particular, we describe how damage to vulnerable DA neurons may arise from cellular disturbances produced by protein misfolding and aggregation, disruption of autophagic catabolism, endoplasmic reticulum (ER) stress, mitochondrial dysfunction or loss of calcium homeostasis. Where pertinent, we show how these mechanisms may mutually cooperate to promote neuronal death.
- Published
- 2016
19. Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson's disease
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Chantal François, Etienne C. Hirsch, Stewart D. Clark, Manale Bensaid, Patrick P. Michel, HAL-UPMC, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Male ,Parkinson's disease ,Dopamine ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Substantia nigra ,6-OHDA ,Biology ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Developmental Neuroscience ,medicine ,Pedunculopontine Tegmental Nucleus ,Animals ,Cholinergic neuron ,Oxidopamine ,Cholinergic ,Pedunculopontine nucleus ,MPTP ,Dopaminergic Neurons ,Dopaminergic ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Parkinson Disease ,Cholinergic Neurons ,Rats ,Macaca fascicularis ,030104 developmental biology ,Neurology ,chemistry ,nervous system ,Diphtheria toxin-urotensin II ,Neuroscience ,030217 neurology & neurosurgery ,Mptp ,medicine.drug - Abstract
International audience; Pedunculopontine nucleus (PPN) cholinergic neurons, which exert excitatory nicotinic control over substantia nigra dopaminergic neurons, degenerate in Parkinson's disease (PD). This finding and other studies showing that nicotine, the preferential agonist of nicotinic acetylcholine receptors, is neuroprotective in experimental models of PD suggest that a deficit in PPN excitatory cholinergic inputs might contribute to the death of nigral dopaminergic neurons in PD. To explore this possibility, we used lesion paradigms of dopaminergic and/or cholinergic systems in rats and monkeys. Consistent with our hypothesis, we observed that stereotaxic lesioning of PPN cholinergic neurons with diphtheria toxin coupled to urotensin II resulted in a significant loss of nigral dopaminergic neurons in rats and induced morphological changes in these neurons in macaques. Unexpectedly, a lesion of dopaminergic neurons induced by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) in rats, or by repeated systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in macaques, led to a 29% and 7% loss of PPN cholinergic neurons, respectively. Lastly, when the PPN cholinergic lesion was performed in rats in which the dopaminergic lesion induced by 6-OHDA was in progress, loss of cholinergic neurons was more drastic than when each neurotransmitter system was lesioned separately. Thus, our results suggest that strong PPN cholinergic and dopaminergic interactions may be an important mechanism in the pathophysiology of PD.
- Published
- 2016
20. Dyskinesia in Parkinson’s disease: a clinical complication and an open scientific question
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Manolo Carta and Etienne C. Hirsch
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Dyskinesia, Drug-Induced ,medicine.medical_specialty ,Parkinson's disease ,Neurology ,business.industry ,MEDLINE ,Parkinson Disease ,medicine.disease ,Antiparkinson Agents ,Levodopa ,Psychiatry and Mental health ,Dyskinesia ,medicine ,Animals ,Humans ,Neurology (clinical) ,medicine.symptom ,Biological psychiatry ,Complication ,Psychiatry ,business ,Biological Psychiatry ,Introductory Journal Article - Published
- 2018
21. Effect of melatonin on sleep disorders in a monkey model of Parkinson's disease
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Hayat Belaid, Chantal François, Joëlle Adrien, Carine Karachi, and Etienne C. Hirsch
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Male ,Sleep Wake Disorders ,Levodopa ,Parkinson's disease ,Polysomnography ,Melatonin ,Antiparkinson Agents ,chemistry.chemical_compound ,medicine ,Animals ,medicine.diagnostic_test ,MPTP ,Central Nervous System Depressants ,Parkinson Disease ,General Medicine ,medicine.disease ,Sleep in non-human animals ,Sleep time ,nervous system diseases ,Disease Models, Animal ,Macaca fascicularis ,chemistry ,Anesthesia ,Psychology ,medicine.drug - Abstract
Objectives To evaluate and compare the effects of melatonin and levodopa (L-dopa) on sleep disorders in a monkey model of Parkinson's disease. Materials and methods The daytime and nighttime sleep patterns of four macaques that were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were recorded using polysomnography in four conditions: at baseline, during the parkinsonian condition; after administration of L-dopa, and after administration of a combination of melatonin with L-dopa. Results It was confirmed that MPTP intoxication induces sleep disorders, with sleep episodes during daytime and sleep fragmentation at nighttime. L-dopa treatment significantly reduced the awake time during the night and tended to improve all other sleep parameters, albeit not significantly. In comparison to the parkinsonian condition, combined treatment with melatonin and L-dopa significantly increased total sleep time and sleep efficiency, and reduced the time spent awake during the night in all animals. A significant decrease in sleep latencies was also observed in three out of four animals. Compared with L-dopa alone, combined treatment with melatonin and L-dopa significantly improved all these sleep parameters in two animals. On the other hand, combined treatment had no effect on sleep architecture and daytime sleep. Conclusion These data demonstrated, for the first time, objective improvement on sleep parameters of melatonin treatment in MPTP-intoxicated monkeys, showing that melatonin treatment has a real therapeutic potential to treat sleep disturbances in people with Parkinson's disease.
- Published
- 2015
22. The sleep-modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine
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Erwann Rousseau, Etienne C. Hirsch, Clélia Florence, Patrick P. Michel, Sabah Hamadat, and Serge Guerreiro
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Agonist ,medicine.medical_specialty ,Nicotine ,medicine.drug_class ,Neuropeptide ,Biology ,Neuroprotection ,Calcium in biology ,Dopamine ,Mesencephalon ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Receptor ,Cells, Cultured ,Pharmacology ,Orexins ,Dose-Response Relationship, Drug ,Ryanodine receptor ,Dopaminergic Neurons ,Neuropeptides ,Intracellular Signaling Peptides and Proteins ,Orexin ,Rats ,Endocrinology ,Neuroprotective Agents ,nervous system ,Nerve Degeneration ,Molecular Medicine ,Drug Therapy, Combination ,Sleep ,medicine.drug - Abstract
To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-protein-coupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype, N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala(11), d-Leu(15)]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of α-bungarotoxin-sensitive (presumably α7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder.
- Published
- 2015
23. Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease
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Annekathrin Sturn, Carmen Noelker, René Roscher, Lixia Lu, Günter U. Höglinger, Etienne C. Hirsch, Hartmann Andreas, Franca Vulinovic, Matthias Höllerhage, Daniel Alvarez-Fischer, Wolfgang H. Oertel, Administateur, HAL Sorbonne Université, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of neurology, Philipps Universität Marburg = Philipps University of Marburg, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of translational neurodegeneration, German Center for Neurodegenerative Diseases, Institute of Neurogenetics, Universität zu Lübeck = University of Lübeck [Lübeck], Actelion Pharmaceuticals Ltd, Department of psychiatry, Lubeck University Hospital, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Philipps Universität Marburg, and Universität zu Lübeck [Lübeck]
- Subjects
Male ,Parkinson's disease ,Mitochondrial Diseases ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Cell Count ,Gaucher disease ,Pharmacology ,metabolism [Histocompatibility Antigens] ,chemistry.chemical_compound ,metabolism [Inositol] ,Mice ,0302 clinical medicine ,prevention & control [Parkinsonian Disorders] ,Mesencephalon ,pathology [Brain] ,Histocompatibility Antigens ,Miglustat ,Mitochondrial respiratory chain complex I ,pharmacology [1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine] ,analogs & derivatives [Inositol] ,Cells, Cultured ,Neurons ,0303 health sciences ,metabolism [Mesencephalon] ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,therapeutic use [1-Deoxynojirimycin] ,MPTP ,Brain ,etiology [Mitochondrial Diseases] ,α-Syn ,3. Good health ,Mitochondria ,metabolism [L-Lactate Dehydrogenase] ,Neurology ,Biochemistry ,prevention & control [Gaucher Disease] ,metabolism [Neurons] ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Toxicity ,therapeutic use [Glycoside Hydrolase Inhibitors] ,drug effects [Brain] ,medicine.drug ,Glucocerebrosidase ,1-Deoxynojirimycin ,Tyrosine 3-Monooxygenase ,etiology [Gaucher Disease] ,Glucocerebroside ,conduritol epoxide ,03 medical and health sciences ,Parkinsonian Disorders ,complications [Parkinsonian Disorders] ,medicine ,Animals ,drug effects [Neurons] ,Glycoside Hydrolase Inhibitors ,ddc:610 ,030304 developmental biology ,Alpha-synuclein ,L-Lactate Dehydrogenase ,drug therapy [Gaucher Disease] ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,analogs & derivatives [1-Deoxynojirimycin] ,medicine.disease ,Embryo, Mammalian ,metabolism [Tyrosine 3-Monooxygenase] ,Mice, Inbred C57BL ,Disease Models, Animal ,chemistry ,metabolism [Brain] ,Dopamine cell death ,miglustat ,Neurology (clinical) ,030217 neurology & neurosurgery ,Inositol ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57Bl/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP+ (1-methyl-4-phenylpyridinium) or alpha-synuclein (α-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP-induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both α-Syn and MPP+ induced toxicity in vitro. However, only CBE-induced enhancement of MPP+ toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat. Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity.
- Published
- 2015
24. The global fight against dementia
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Michel Goldman, Yves Joanette, and Etienne C. Hirsch
- Subjects
medicine.medical_specialty ,Aging ,media_common.quotation_subject ,International Cooperation ,Age Factors ,Cognition ,General Medicine ,Disease ,medicine.disease ,Global Health ,Prognosis ,Interinstitutional Relations ,Risk Factors ,Reading (process) ,mental disorders ,medicine ,Dementia ,Humans ,Cooperative Behavior ,Psychology ,Psychiatry ,media_common - Abstract
Very few of those reading this editorial will have had no contact with the devastating consequences of dementia. Dementia, caused by a variety of neurodegenerative conditions, including Alzheimer’s disease, occurs in 35% of individuals over 80 years of age ([ 1 ][1]). The disease ravages cognitive
- Published
- 2014
25. Comment protéger les neurones en pratique dans la maladie de Parkinson ? Voie unique ou mécanisme spécifique ?
- Author
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Etienne C. Hirsch
- Subjects
Neurology ,Philosophy ,Neurology (clinical) ,Molecular biology - Abstract
La maladie de Parkinson est une pathologie neurodegenerative dont l’etiologie est inconnue dans la majorite des cas mais qui est multifactorielle. La maladie provoque principalement une destruction progressive des neurones dopaminergiques de la substance noire a l’origine d’alterations des mouvements volontaires. Les mecanismes a l’origine de la mort de ces neurones sont multiples et impliquent aussi bien des mecanismes intrinseques aux neurones en degenerescence (mecanismes de mort autonome) que d’autres cellules (mecanismes non autonomes). Les mecanismes autonomes de mort neuronale impliques aussi bien dans les formes hereditaires que sporadiques de la maladie impliquent une alteration du repliement des proteines et une agregation des proteines qui pourraient etre transmises par un mecanisme de type prion, une dysfonction des mecanismes autophagiques, un stress du reticulum endoplasmique, une alteration du fonctionnement des mitochondries et une deregulation de l’homeostasie calcique. Si certaines de ces alterations sont les consequences les unes des autres certaines de ces voies de degenerescence sont independantes. Les consequences en termes de strategies therapeutiques sont particulierement importantes et implique l’utilisation d’agents therapeutiques agissant ces diverses cibles. Les mecanismes non autonomes de mort neuronale participent aussi a la cascade des evenements qui contribuent a la progression de la neurodegenerescence dans la maladie de Parkinson. A cet egard nous avons montre que la mort neuronale est associee a une activation microgliale et a une infiltration de lymphocytes T de type CD4 et CD8. Toutefois, seuls les CD4 jouent un role deletere qui implique la voie Fas et Fas ligand.
- Published
- 2017
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