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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 (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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@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},
  keyword      = {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          = {http://dx.doi.org/10.1046/j.1471-4159.2003.01632.x},
  volume       = {84},
  year         = {2003},
}