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

作者：Malmlof Torun^*; Feltmann Kristin; Konradsson Geuken Asa; Schneider Frank; Alken Rudolf Gie**ert; Svensson Torgny H; Schilstrom Bjorn

来源：Journal of Neural Transmission, 2015, 122(2): 259-272.

DOI：10.1007/s00702-014-1247-6

• Parkinson's disease
• L-DOPA
• Selegiline
• Deuterium
• Dopamine
• Metabolism

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.

• 出版日期2015-2