Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.
Brain Res. 2010 Apr 6;1323:184-91. doi: 10.1016/j.brainres.2010.01.080. Epub 2010 Feb 4.
The effect of chronic treatment with the selective adenosine A(2A) receptor agonist CGS 21680 on N-Methyl-d-Aspartate (NMDA) receptor function and expression has been studied in the striatum and cortex of R6/2 mice, a genetic mouse model of Huntington's disease (HD). Starting from 8weeks of age, R6/2 and wild type (WT) mice were treated daily with CGS 21680 (0.5mg/kg i.p.) for 3weeks and the expression levels of NMDA receptor subunits were then evaluated. In addition, to study CGS 21680-induced changes in NMDA receptor function, NMDA-induced toxicity in corticostriatal slices from both R6/2 and WT mice was investigated. We found that CGS 21680 increased NR2A subunit expression and the NR2A/NR2B ratio in the cortex of R6/2 mice, having no effect in WT mice. In the striatum, CGS 21680 reduced NR1 expression in both R6/2 and WT mice while the effect on NR2A and NR2/NR2B expression was genotype-dependent, reducing and increasing their expression in WT and R6/2 mice, respectively. On the contrary, NMDA-induced toxicity in corticostriatal slices was not modified by the treatment in WT or HD mice. These results demonstrate that in vivo activation of A(2A) receptors modulates the subunit composition of NMDA receptors in the brain of HD mice.
慢性给予选择性腺苷 A（2A）受体激动剂 CGS 21680 对 N-甲基-D-天冬氨酸（NMDA）受体功能和表达的影响已在亨廷顿病（HD）的遗传小鼠模型 R6/2 小鼠的纹状体和皮质中进行了研究。从 8 周龄开始，R6/2 和野生型（WT）小鼠每天用 CGS 21680（0.5mg/kg 腹腔注射）治疗 3 周，然后评估 NMDA 受体亚基的表达水平。此外，为了研究 CGS 21680 诱导的 NMDA 受体功能变化，研究了来自 R6/2 和 WT 小鼠的皮质纹状体切片中 NMDA 诱导的毒性。我们发现 CGS 21680 增加了 R6/2 小鼠皮质中 NR2A 亚基的表达和 NR2A/NR2B 比值，而对 WT 小鼠没有影响。在纹状体中，CGS 21680 降低了 WT 和 R6/2 小鼠中 NR1 的表达，而对 NR2A 和 NR2/NR2B 表达的影响则依赖于基因型，分别降低和增加 WT 和 R6/2 小鼠的表达。相反，NMDA 诱导的 WT 或 HD 小鼠皮质纹状体切片中的毒性未被治疗所改变。这些结果表明，体内激活 A（2A）受体可调节 HD 小鼠大脑中 NMDA 受体的亚基组成。
