title: Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by L-DOPA and an MAO-B inhibitor.
abstract: The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.
authors.affiliation: Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden, torun.malmlof@ki.se.
authors.forename: Torun
authors.initials: T
authors.lastname: Malmlöf
authors.forename: Kristin
authors.initials: K
authors.lastname: Feltmann
authors.forename: Åsa
authors.initials: Å
authors.lastname: Konradsson-Geuken
authors.forename: Frank
authors.initials: F
authors.lastname: Schneider
authors.forename: Rudolf-Giesbert
authors.initials: RG
authors.lastname: Alken
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003903:Deuterium; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005552:Forelimb / Q000503:physiopathology; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D007980:Levodopa; D016627:Oxidopamine; D003903:Deuterium; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine