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Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.

Lundblad, Martin LU ; Vaudano, E and Cenci Nilsson, Angela LU orcid (2003) In Journal of Neurochemistry 84(6). p.1398-1410
Abstract
We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of l-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of l-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with l-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in l-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) l-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus l-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief... (More)
We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of l-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of l-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with l-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in l-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) l-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus l-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with l-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did l-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and l-DOPA nor l-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with l-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/ΔFosB-like immunoreactivity in the dopamine-denervated striatum.



These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and l-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug. (Less)
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Parkinsonian Disorders: chemically induced, Oxidopamine, Levodopa: adverse effects, Motor Activity: drug effects, Female, Enkephalins: metabolism, Enkephalins: genetics, Disease Models, Animal, Behavior, Drug Therapy, Combination, Dyskinesia, Drug-Induced: complications, Drug-Induced: drug therapy, Corpus Striatum: metabolism, Corpus Striatum: drug effects, Animal: drug effects, Parkinsonian Disorders: complications, Parkinsonian Disorders: drug therapy, Protein Precursors: genetics, Protein Precursors: metabolism, Proto-Oncogene Proteins c-fos: metabolism, Purines: pharmacology, RNA, Messenger: metabolism, Rats, Sprague-Dawley, Receptors, Purinergic P1: antagonists & inhibitors, Treatment Outcome
in
Journal of Neurochemistry
volume
84
issue
6
pages
1398 - 1410
publisher
Wiley-Blackwell
external identifiers
  • wos:000181331300018
  • pmid:12614340
  • scopus:0037345646
ISSN
1471-4159
DOI
10.1046/j.1471-4159.2003.01632.x
language
English
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yes
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094153be-a722-4c85-9e6c-bb4923376450 (old id 113026)
date added to LUP
2016-04-01 15:37:26
date last changed
2022-04-06 23:56:44
@article{094153be-a722-4c85-9e6c-bb4923376450,
  abstract     = {{We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of l-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of l-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with l-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in l-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) l-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus l-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with l-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did l-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and l-DOPA nor l-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with l-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/ΔFosB-like immunoreactivity in the dopamine-denervated striatum.<br/><br>
<br/><br>
These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and l-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.}},
  author       = {{Lundblad, Martin and Vaudano, E and Cenci Nilsson, Angela}},
  issn         = {{1471-4159}},
  keywords     = {{Parkinsonian Disorders: chemically induced; Oxidopamine; Levodopa: adverse effects; Motor Activity: drug effects; Female; Enkephalins: metabolism; Enkephalins: genetics; Disease Models; Animal; Behavior; Drug Therapy; Combination; Dyskinesia; Drug-Induced: complications; Drug-Induced: drug therapy; Corpus Striatum: metabolism; Corpus Striatum: drug effects; Animal: drug effects; Parkinsonian Disorders: complications; Parkinsonian Disorders: drug therapy; Protein Precursors: genetics; Protein Precursors: metabolism; Proto-Oncogene Proteins c-fos: metabolism; Purines: pharmacology; RNA; Messenger: metabolism; Rats; Sprague-Dawley; Receptors; Purinergic P1: antagonists & inhibitors; Treatment Outcome}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1398--1410}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Neurochemistry}},
  title        = {{Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.}},
  url          = {{https://lup.lub.lu.se/search/files/4434703/623727.pdf}},
  doi          = {{10.1046/j.1471-4159.2003.01632.x}},
  volume       = {{84}},
  year         = {{2003}},
}