Journal
BRAIN RESEARCH
Volume 953, Issue 1-2, Pages 119-125Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0006-8993(02)03277-8
Keywords
KW-6002; (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione; Parkinson's disease; adenosine A(2A) receptor antagonist; distribution; gene expression
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A novel adenosine A,,, receptor selective antagonist, KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1Hpurine-2,6-dione], possesses antiparkinsonian activities in rodent and primate models. In the present study, we investigated the distribution of [C-14]KW-6002 in forebrain after oral administration at pharmacologically effective doses. Also, we monitored the effects of the compound on preproenkephalin (PPE) and preprotachykinin (PPT) gene expression in rat striatum. The highest level of radioactivity was observed in the striatum after oral administration of [C-14]KW-6002; 30 min after 0.1 and 0.3 mg/kg, the density values in the striatum were 2.45 and 2.43 times higher than those in a reference region (frontal cortex), respectively. At the dose of 3 mg/kg, p.o., the ratio was only 1.58 and the compound was distributed more extensively in the brain. The distribution pattern and intensity of radioactivity were maintained even 90 min after the administration of [C-14]KW-6002. Oral administration of KW-6002 (0.3 and 3 mg/kg/day) to rats for 14 days reversed the increased gene expression of PPE in striatum that had been depleted of dopamine by prior treatment with 6-hydroxydopamine (6-OHDA). On the other hand, KW-6002 did not alter the decreased gene expression of PPT in 6-OHDA-treated rats. These results are the first to show directly that orally administered KW-6002 is distributed selectively to the striatum and that it modulates the activity of striatopallidal enkephalin-containing neurons but not striatonigral substance P-containing neurons. (C) 2002 Elsevier Science B.V. All rights reserved.
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