title: Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?
abstract: In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia.
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: C
authors.initials: C
authors.lastname: Laloux
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: F
authors.initials: F
authors.lastname: Gouel
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: C
authors.initials: C
authors.lastname: Lachaud
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: K
authors.initials: K
authors.lastname: Timmerman
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: B
authors.initials: B
authors.lastname: Do Van
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Jonneaux
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: M
authors.initials: M
authors.lastname: Petrault
authors.affiliation: Institut Pasteur de Lille, EA4483-IMPECS, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, Lille, France.
authors.forename: G
authors.initials: G
authors.lastname: Garcon
authors.affiliation: Service de biochimie, dosage des catécholamines, et biologie moléculaire, CHRU de Lille, France.
authors.forename: N
authors.initials: N
authors.lastname: Rouaix
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France; Université de Lille, CHU de Lille, INSERM UMRS_1171, Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Moreau
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: R
authors.initials: R
authors.lastname: Bordet
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, UK; Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Duce
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Devedjian
authors.affiliation: Département de Pharmacologie médicale, INSERM UMRS-1171, Université Lille Nord de France, CHRU de Lille, Faculté de médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille cedex, France; Université de Lille, CHU de Lille, INSERM UMRS_1171, Service de Pharmacologie Clinique et service de Neurologie LICEND COEN Center Lille, France. Electronic address: david.devos@chru-lille.fr.
authors.forename: D
authors.initials: D
authors.lastname: Devos
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000008:administration & dosage* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D057967:Infusions, Intraventricular; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D004298:Dopamine
keywords: Dopamine; Parkinson's disease; Treatment–disease modifying effect; l-dopa related motor complications