Sadan Ofer, Bahat-Stromza Merav, Gilgun-Sherki Yossi, Atlas Daphne, Melamed Eldad, Offen Daniel
Department of Neurology and Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100 Israel.
Clin Neuropharmacol. 2005 Nov-Dec;28(6):285-8. doi: 10.1097/01.wnf.0000191331.54649.e3.
Tardive dyskinesia (TD), characterized by abnormal movements, is the major late-onset chronic side effect of antipsychotic treatment found in about 30% of those patients. The association of oxidative stress and the release of free radicals is one of the hallmarks of dopaminergic malfunctions and is one of the leading theories suggested for the pathophysiology of TD. To this day, no brain-targeted antioxidant has been tested as a potential treatment of TD. In light of this assumption, the authors chose a novel, low-molecular weight thiol antioxidant, N-acetyl cysteine amide (AD4), that crosses the blood-brain barrier as a possible treatment of TD.
To examine the protective effects of the novel brain-penetrating antioxidant AD4 on TD experimental models.
The typical vacuous chewing movement occurs in rats following chronic haloperidol injections (1.5 mg/kg/day intraperitoneally for 21 days). This purposeless mouth opening in the vertical plane is similar to TD symptoms in humans. The authors tested rats treated with haloperidol without or with AD4 in the drinking water (1 g/kg orally). Thiobarbituric acid reactive substances and anticarbonyl antibodies were used to measure oxidation of membranes and proteins.
Haloperidol increased the vacuous chewing movements to 66.5 +/- 7.6 movements/5 minutes compared with 16.4 +/- 2.4 movements/5 minutes in untreated rats (P < 0.01). Coadministration of haloperidol and AD4 decreased the vacuous chewing movements level to 42.1 +/- 6.7 movements/5 minutes (P < 0.05). Haloperidol also increased the level of lipid peroxidation and protein oxidation in the rat brain, whereas coadministration with AD4 preserved their normal levels.
Haloperidol causes behavioral abnormalities associated with oxidative stress in rats, similar to TD. AD4, the brain-targeted potent antioxidant, reduces the cellular oxidation markers and improves the typical clinical behavior. Hence, AD4 is a potential new treatment of antipsychotic-induced TD.
迟发性运动障碍（TD）以异常运动为特征，是抗精神病药物治疗的主要迟发性慢性副作用，约30%的患者会出现。氧化应激与自由基释放的关联是多巴胺能功能障碍的标志之一，也是TD病理生理学的主要理论之一。时至今日，尚无脑靶向抗氧化剂作为TD的潜在治疗方法进行过测试。基于这一假设，作者选择了一种新型的低分子量硫醇抗氧化剂N - 乙酰半胱氨酸酰胺（AD4），它能够穿过血脑屏障，作为TD的一种可能治疗方法。
研究新型脑穿透性抗氧化剂AD4对TD实验模型的保护作用。
慢性注射氟哌啶醇（1.5毫克/千克/天，腹腔注射，持续21天）后，大鼠会出现典型的空嚼运动。这种在垂直平面上无目的的张口动作类似于人类的TD症状。作者测试了在饮用水中添加或不添加AD4（1克/千克，口服）的情况下，用氟哌啶醇治疗的大鼠。使用硫代巴比妥酸反应性物质和抗羰基抗体来测量膜和蛋白质的氧化。
与未治疗的大鼠（16.4±2.4次/5分钟）相比，氟哌啶醇使空嚼运动增加至66.5±7.6次/5分钟（P<0.01）。氟哌啶醇与AD4联合给药使空嚼运动水平降至42.1±6.7次/5分钟（P<0.05）。氟哌啶醇还增加了大鼠脑中脂质过氧化和蛋白质氧化水平，而与AD4联合给药则使其保持在正常水平。
氟哌啶醇在大鼠中引起与氧化应激相关的行为异常，类似于TD。脑靶向强效抗氧化剂AD4可降低细胞氧化标志物水平并改善典型临床行为。因此，AD4是抗精神病药物所致TD的一种潜在新治疗方法。
