Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
Braz J Med Biol Res. 2010 Nov;43(11):1047-53. doi: 10.1590/s0100-879x2010007500111. Epub 2010 Oct 14.
7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson's disease.
7-硝基吲唑（7-NI）在体内抑制神经元型一氧化氮合酶，并减少帕金森病大鼠模型中 l-DOPA 诱导的运动障碍。本研究的目的是确定 7-NI 的抗运动障碍作用是否会在重复治疗后产生耐受性，以及该药物是否会干扰 l-DOPA 的引发作用。单侧黑质致密部多巴胺耗竭的成年雄性 Wistar 大鼠（200-250g）用 l-DOPA（30mg/kg）治疗 34 天。在第 1 天，6 只大鼠接受腹腔注射生理盐水，6 只大鼠接受腹腔注射 7-NI（30mg/kg），然后给予 l-DOPA。从第 2 天到第 26 天，所有大鼠每天接受 l-DOPA，从第 27 天到第 34 天，在给予 l-DOPA 之前，他们还接受 7-NI。在给予药物之前和给予 l-DOPA 后 1 小时，使用异常不自主运动量表和步态测试对动物进行评估。所有大鼠都有类似的初始运动缺陷。7-NI 降低了 l-DOPA 诱导的异常不自主运动，并且在实验过程中，在 7-NI 之前，这种效果一直保持着，中位数（四分位间距），第 26 天：16.75（15.88-17.00）；第 28 天：0.00（0.00-9.63）；第 29 天：13.75（2.25-15.50）；第 30 天：0.5（0.00-6.25）；第 31 天：4.00（0.00-7.13），第 34 天：0.5（0.00-14.63），弗里德曼检验后威尔科克森检验，与第 26 天相比，P<0.05；。在第一次给予药物之前使用 7-NI 不会改变对 l-DOPA 单独给药的反应（l-DOPA 与时间的相互作用，F1,10=1.5，无统计学意义）。这些数据表明，在短期重复给药期间，神经元型一氧化氮合酶抑制剂的抗运动障碍作用不会产生耐受性。这些观察结果为帕金森病患者慢性 l-DOPA 治疗的运动并发症提供了一种新的可能治疗方法。
