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Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Malmlof, Torun; Rylander, Daniella LU ; Alken, Rudolf-Giesbert; Schneider, Frank; Svensson, Torgny H.; Cenci Nilsson, Angela LU and Schilstrom, Bjorn (2010) In Experimental Neurology 225(2). p.408-415
Abstract
Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the... (More)
Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (p<0.05), whereas the equipotent dose of D3-L-DOPA produced an anti-akinetic effect similar to L-DOPA. Dyskinesias developed to the same degree in the groups treated with equivalent doses of D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA induced fewer dyskinesias than L-DOPA (p<0.05). In conclusion, our study provides evidence for improved potency and reduced side-effects of L-DOPA by deuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms. (C) 2010 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Pharmacokinetics, Enzyme, Rat, Behavior, 6-OHDA, Dyskinesia, Parkinson's disease, L-DOPA, Deuterium, Isotope
in
Experimental Neurology
volume
225
issue
2
pages
408 - 415
publisher
Academic Press
external identifiers
  • wos:000282191500021
  • scopus:77956427251
ISSN
0014-4886
DOI
10.1016/j.expneurol.2010.07.018
language
English
LU publication?
yes
id
e125986f-a82b-42ca-bf71-b3cc2c25b496 (old id 1695295)
date added to LUP
2010-10-26 14:00:12
date last changed
2018-05-29 10:05:33
@article{e125986f-a82b-42ca-bf71-b3cc2c25b496,
  abstract     = {Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (p&lt;0.05), whereas the equipotent dose of D3-L-DOPA produced an anti-akinetic effect similar to L-DOPA. Dyskinesias developed to the same degree in the groups treated with equivalent doses of D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA induced fewer dyskinesias than L-DOPA (p&lt;0.05). In conclusion, our study provides evidence for improved potency and reduced side-effects of L-DOPA by deuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms. (C) 2010 Elsevier Inc. All rights reserved.},
  author       = {Malmlof, Torun and Rylander, Daniella and Alken, Rudolf-Giesbert and Schneider, Frank and Svensson, Torgny H. and Cenci Nilsson, Angela and Schilstrom, Bjorn},
  issn         = {0014-4886},
  keyword      = {Pharmacokinetics,Enzyme,Rat,Behavior,6-OHDA,Dyskinesia,Parkinson's disease,L-DOPA,Deuterium,Isotope},
  language     = {eng},
  number       = {2},
  pages        = {408--415},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2010.07.018},
  volume       = {225},
  year         = {2010},
}