Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 Street, 31-343, Kraków, Poland.
Neurotox Res. 2013 Jul;24(1):29-40. doi: 10.1007/s12640-012-9372-1. Epub 2013 Jan 8.
The study shows effects of the nonselective adenosine A1/A2A receptor antagonist caffeine and the selective A2A receptor antagonist KW6002 on LPS-induced changes in the extracellular levels of dopamine (DA), glutamate, adenosine, hydroxyl radical, and A2A receptor density in the rat striatum. Intrastriatal LPS (10 μg) injection decreased extracellular level of DA and increased the level of adenosine, glutamate, and hydroxyl radical on the ipsilateral side 24 h after LPS administration. Caffeine (10 and 20 mg/kg i.p.) and KW6002 (1.5 and 3 mg/kg i.p.) given once daily for 6 days and on the 7th day 2 h before and 4 h after LPS injection reversed the LPS-induced changes in extracellular levels of DA, adenosine, glutamate, and hydroxyl radical production. Moreover, LPS-induced decrease in the striatal A2A receptor density was increased by caffeine and KW6002. In order to show the late LPS effect on oxidative damage of DA neurons, the contents of DA, DOPAC, HVA, and hydroxyl radical were determined 72 h after LPS (10 μg) administration into both striata. LPS decreased striatal and substantia nigra content of DA, DOPAC, and HVA while increased striatal but not nigral content of hydroxyl radical. Caffeine (20 mg/kg) and KW60002 (3 mg/kg) given once daily for 6 days and on the 7th day 2 h before and 4 h after intrastriatal injection of LPS normalized the content of DA and its metabolites in both brain regions as well as decreased LPS-induced increase in the striatal level of hydroxyl radical. In conclusion, our data demonstrated antioxidant effects of caffeine and KW6002 in the inflammatory model of PD.
这项研究表明，非选择性腺苷 A1/A2A 受体拮抗剂咖啡因和选择性 A2A 受体拮抗剂 KW6002 对 LPS 诱导的大鼠纹状体细胞外多巴胺（DA）、谷氨酸、腺苷、羟自由基和 A2A 受体密度变化的影响。纹状体内注射 LPS（10μg）后 24 小时，可降低细胞外 DA 水平，增加 LPS 处理后同侧纹状体腺苷、谷氨酸和羟自由基的水平。连续 6 天每天腹腔注射咖啡因（10 和 20mg/kg）和 KW6002（1.5 和 3mg/kg），并在 LPS 注射前 2 小时和后 4 小时给予一次，可逆转 LPS 诱导的细胞外 DA、腺苷、谷氨酸和羟自由基产生的变化。此外，咖啡因和 KW6002 增加了 LPS 诱导的纹状体 A2A 受体密度降低。为了显示 LPS 对 DA 神经元氧化损伤的晚期影响，在 LPS（10μg）注射到双侧纹状体后 72 小时测定 DA、DOPAC、HVA 和羟自由基的含量。LPS 降低了纹状体和黑质中 DA、DOPAC 和 HVA 的含量，而增加了纹状体中但不增加黑质中羟自由基的含量。连续 6 天每天腹腔注射咖啡因（20mg/kg）和 KW6002（3mg/kg），并在 LPS 注射前 2 小时和后 4 小时给予一次，可使两个脑区的 DA 及其代谢物含量正常化，并降低 LPS 诱导的纹状体羟自由基水平升高。总之，我们的数据表明咖啡因和 KW6002 在 PD 的炎症模型中具有抗氧化作用。
