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Deuterium substitut...
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Malmlof, TorunKarolinska Institutet
(author)
Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias
- Article/chapterEnglish2010
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LIBRIS-ID:oai:lup.lub.lu.se:e125986f-a82b-42ca-bf71-b3cc2c25b496
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https://lup.lub.lu.se/record/1695295URI
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https://doi.org/10.1016/j.expneurol.2010.07.018DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:121325119URI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
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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.
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Rylander, DaniellaLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups(Swepub:lu)med-drr
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Alken, Rudolf-Giesbert
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Schneider, Frank
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Svensson, Torgny H.Karolinska Institutet
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Cenci Nilsson, AngelaLund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups(Swepub:lu)mphy-ace
(author)
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Schilstrom, BjornKarolinska Institutet
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Cenci, MA
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Karolinska InstitutetBasala gangliernas patofysiologi
(creator_code:org_t)
Related titles
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In:Experimental Neurology: Elsevier BV225:2, s. 408-4150014-48861090-2430
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