Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/113026
- author
- Lundblad, Martin LU ; Vaudano, E and Cenci Nilsson, Angela LU
- organization
- publishing date
- 2003
- type
- Contribution to journal
- publication status
- published
- subject
- 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
- 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
- LU publication?
- yes
- id
- 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}}, }