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: Torun Malmlöf, Kristin Feltmann, Åsa Konradsson-Geuken, Frank Schneider, Rudolf-Giesbert Alken, Torgny H Svensson, Björn Schilström
• Journal: Journal of neural transmission (Vienna, Austria : 1996) (J Neural Transm (Vienna)) Vol. 122 Issue 2 Pg. 259-72 (Feb 2015) ISSN: 1435-1463 [Electronic] Austria
• PMID: 24906468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic Agents
• Antiparkinson Agents
• Monoamine Oxidase Inhibitors
• Selegiline
• Levodopa
• Oxidopamine
• Deuterium
• Tyrosine 3-Monooxygenase
• Dopamine

Topics

• Adrenergic Agents (toxicity)
• Animals
• Antiparkinson Agents (therapeutic use)
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism, pathology)
• Deuterium
• Disease Models, Animal
• Dopamine (metabolism)
• Forelimb (physiopathology)
• Levodopa (therapeutic use)
• Male
• Microdialysis
• Monoamine Oxidase Inhibitors (therapeutic use)
• Motor Activity (drug effects)
• Oxidopamine (toxicity)
• Parkinson Disease (drug therapy, etiology, pathology)
• Rats
• Rats, Wistar
• Selegiline (therapeutic use)
• Tyrosine 3-Monooxygenase (metabolism)