title: Early L-dopa, but not pramipexole, restores basal ganglia activity in partially 6-OHDA-lesioned rats.
abstract: The most appropriate time for the initiation of dopaminergic symptomatic therapy in Parkinson's disease remains debatable. It has been suggested that early correction of basal ganglia pathophysiological abnormalities may have long-term beneficial effects. To test this hypothesis, we investigated the early and delayed actions of L-dopa and pramipexole, using a delayed-start protocol of treatment. The effects of early and delayed administration of these drugs on motor response, development of dyskinesias, neurogenesis and molecular markers in basal ganglia were studied in rats with a unilateral and partial 6-hydroxydopamine-induced nigrostriatal lesion. Ten days after lesioning, rats received treatment with: a) L-dopa methyl ester (25mg/kg with 6.25mg/kg of benserazide, i.p., twice a day); b) pramipexole (0.5mg/kg, sc, twice a day) or c) saline for 4weeks. Four weeks after treatment initiation, rats from the saline group were distributed in three groups that then received the following treatments: d) L-dopa, e) pramipexole or f) saline, for 4weeks more. Three animals in each treatment arm received 5-bromo-2-deoxyuridine injections (200mg/kg) 3days before starting treatment. When compared with delayed-start L-dopa, early-start L-dopa treatment induced a lower rotational response (p<0.01), an improvement in limb akinesia (p<0.05), a lower level of dyskinesia (p<0.01) and a normalization of lesion-induced molecular changes in basal ganglia. When compared with delayed-start pramipexole, early-start pramipexole induced a higher rotational response (p<0.01), but did not improve limb akinesia, induce dyskinesia nor normalize lesion-induced molecular changes. Neither significant modifications of striatal dopamine D1-D3 receptor heteromerization nor subventricular zone neurogenesis was found after any L-dopa or pramipexole treatments. Our data support a possible restoration of basal ganglia physiological mechanisms by early-start L-dopa therapy.
authors.affiliation: INGENIO, IRCE, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: cmarin@clinic.ub.es.
authors.forename: C
authors.initials: C
authors.lastname: Marin
authors.affiliation: INGENIO, IRCE, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Bonastre
authors.affiliation: Departament de Neuroquímica, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: G
authors.initials: G
authors.lastname: Mengod
authors.affiliation: Departament de Neuroquímica, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: R
authors.initials: R
authors.lastname: Cortés
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: A
authors.initials: A
authors.lastname: Giralt
authors.affiliation: Department of Neurology and Neuroscience Area, Clínica Universitaria and Medical School, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Obeso
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College of London, London, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects* / Q000503:physiopathology; D001545:Benserazide / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000077487:Pramipexole; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D052160:Benzothiazoles; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D007980:Levodopa; D001545:Benserazide; D000077487:Pramipexole; D016627:Oxidopamine; C035420:levodopa methyl ester
keywords: 6-Hydroxydopamine; Dyskinesias; L-dopa; Parkinson's disease; Pramipexole