The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat
The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat
复制标题
DOI：
10.1007/s00213-008-1319-0
复制
发表时间：
2009-01-01
影响因子：
3.4
通讯作者：
Reedy, Catherine
中科院分区：
文献类型：
--
作者：
Kelsey, John E.;Langelier, Nicole A.;Reedy, Catherine
考虑到腺苷A（2A）拮抗剂在帕金森病（PD）的几种动物模型中似乎是治疗性的，我们检测了咖啡因和选择性A（2A）和A（1）拮抗剂在单侧6-OHDA损伤大鼠中增强对侧前爪踩踏的程度。MFB损伤使对侧踏步减少74- 83%，而8 mg/kg的3，4-二羟基-L-苯丙氨酸（L-DOPA）使对侧踏步增加25- 26%。全身给予（15 mg/kg）或给予背侧纹状体或外部苍白球（GP（E）; 20-40 μ g）的咖啡因分别使对侧前爪踩踏增加14%、27%和26%，并增强8 mg/kg L-DOPA对踩踏的作用。选择性A（2A）拮抗剂SCH-58261（2 mg/kg）也增加了13%的步进，并增强了L-DOPA的治疗效果，而选择性A（2A）拮抗剂8-环戊基茶碱（3-7 mg/kg）和A（1）激动剂N6-环戊基腺苷（0.03-0.2 mg/kg）则无影响。这些药物似乎都没有产生运动障碍的作用，在这个经过充分验证的PD运动不能作用的动物模型中，咖啡因和选择性A（2A）拮抗剂（而不是A（1））拮抗剂）能够提供短暂和持续的治疗效果。这些数据与A（2A）拮抗剂可能对人类PD患者具有治疗作用的假设一致，并表明背侧纹状体和GP（E）是治疗作用的关键部位。
Given that adenosine A(2A) antagonists appear to be therapeutic in several animal models of Parkinson's disease (PD), we examined the extent to which caffeine and selective A(2A) and A(1) antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat.Following unilateral injections of 12 mu g 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill.The MFB lesions decreased contralateral stepping by 74-83%, and 8 mg/kg 3,4-dihydroxy-l-phenylalanine (L-DOPA) increased contralateral stepping by 25-26%. Caffeine given systemically (15 mg/kg) or into the dorsal striatum or external globus pallidus (GP(E); 20-40 mu g) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg L-DOPA on stepping. The selective A(2A) antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the selective A(2A) antagonist 8-cyclopentyltheophylline (3-7 mg/kg) and A(1) agonist N6-cyclopentyladenosine (0.03-0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects.In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A(2A), but not an A(1), antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with the hypothesis that A(2A) antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GP(E) are critical sites of therapeutic action.