Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, 12 Smętna Street, Kraków, Poland.
Neurotox Res. 2012 Aug;22(2):150-7. doi: 10.1007/s12640-012-9316-9. Epub 2012 Mar 10.
It has been shown that a decreased vesicular monoamine transporter (VMAT2) function and the disruption of dopamine (DA) storage is an early contributor to oxidative damage of dopamine neurons in Parkinson's disease (PD). In our previous study, we demonstrated that adenosine A(2A) receptor antagonists suppressed oxidative stress in 6-hydroxydopamine-treated rats suggesting that this effect may account for neuroprotective properties of drugs. In the present study, rats were injected with reserpine (10 mg/kg sc) and 18 h later the effect of the adenosine A(2A) receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on extracellular DA, glutamate and hydroxyl radical formation was studied in the rat striatum using in vivo microdialysis. By disrupting VMAT2 function, reserpine depleted DA stores, and increased glutamate and hydroxyl radical levels in the rat striatum. CSC (1 mg/kg) but not ZM 241385 (3 mg/kg) increased extracellular DA level and production of hydroxyl radical in reserpinised rats. Both antagonists decreased the reserpine-induced increase in extracellular glutamate. L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration. CSC but not ZM 241385 given jointly with L-DOPA increased the effect of L-DOPA on extracellular DA and augmented the reserpine-induced hydroxyl radical production. CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA. It seems that by decreasing the MAO-dependent DA metabolism rate, CSC raised cytosolic DA and by DA autoxidation, it induced hydroxyl radical overproduction. Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD.
已经表明，囊泡单胺转运体 (VMAT2) 功能下降和多巴胺 (DA) 储存中断是帕金森病 (PD) 中多巴胺神经元氧化损伤的早期原因。在我们之前的研究中，我们证明了腺苷 A(2A) 受体拮抗剂抑制了 6-羟多巴胺处理的大鼠的氧化应激，这表明这种作用可能是药物神经保护特性的原因。在本研究中，大鼠注射利血平 (10 mg/kg sc)，18 小时后，研究了腺苷 A(2A) 受体拮抗剂 8-(3-氯代肉桂酰基)咖啡碱 (CSC) 和 4-(2-[7-氨基-2-(2-呋喃基)[1,2,4]三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚 (ZM 241385) 对大鼠纹状体细胞外 DA、谷氨酸和羟基自由基形成的影响，采用体内微透析法。通过破坏 VMAT2 功能，利血平耗尽 DA 储存，并增加大鼠纹状体中的谷氨酸和羟基自由基水平。CSC(1 mg/kg)但不是 ZM 241385(3 mg/kg)增加了利血平化大鼠细胞外 DA 水平和羟基自由基的产生。两种拮抗剂均降低了利血平引起的细胞外谷氨酸的增加。L-3,4-二羟基苯丙氨酸 (L-DOPA)(25 mg/kg)显著增强细胞外 DA，对利血平引起的羟基自由基生成无影响，并降低细胞外谷氨酸浓度。CSC 但不是 ZM 241385 与 L-DOPA 一起给药增加了 L-DOPA 对细胞外 DA 的作用，并增强了利血平引起的羟基自由基生成。CSC 和 ZM 241385 不影响细胞外谷氨酸水平，L-DOPA 降低了细胞外谷氨酸水平。似乎通过降低 MAO 依赖性 DA 代谢率，CSC 提高了细胞溶质 DA，并通过 DA 自动氧化，诱导了羟基自由基的过度产生。因此，具有 MAO-B 抑制剂特性的甲基黄嘌呤 A(2A) 受体拮抗剂，如 CSC，可能会导致由于早期 PD 中 DA 储存机制功能障碍而导致的氧化应激风险。
