Pendleton Robert G, Parvez Feroz, Sayed Marwa, Hillman Ralph
Temple University, Philadelphia, Pennsylvania, USA.
J Pharmacol Exp Ther. 2002 Jan;300(1):91-6. doi: 10.1124/jpet.300.1.91.
The human gene that codes for the protein alpha-synuclein has been transferred into the Drosophila melanogaster genome. The transgenic flies recapitulate some of the essential features of Parkinson's disease. These include the degeneration of certain dopaminergic neurons in the brain accompanied by the appearance of age-dependent abnormalities in locomotor activity. In the present study, we tested the locomotor response of these transgenic flies to prototypes of the major classes of drugs currently used to treat this disorder. A time course study was first conducted to determine when impaired locomotor activity appeared relative to normal "wild-type" flies. A climbing or negative geotaxis assay measuring the ability of the organisms to climb up the walls of a plastic vial was used. Based on the results obtained, normal and transgenic flies were treated with each of the drugs in their food for 13 days and then assayed. The activity of transgenic flies treated with L-DOPA was restored to normal. Similarly, the dopamine agonists pergolide, bromocriptine, and 2,3,4,5-tetrahydro-7,8-dihydroxy- 1-phenyl-1H-3-benzazepine (SK&F 38393) were substantially effective. Atropine, the prototypical muscarinic cholinergic receptor antagonist, was also effective but to a lesser extent than the other antiparkinson compounds. p-Chlorophenylalanine, an inhibitor of serotonin synthesis, was without beneficial effect as was alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis. This behavioral study further demonstrates the utility of this model in studying Parkinson's disease and reinforces the concept that inhibition of the action of alpha-synuclein may be useful in its treatment as may dopamine D(1) receptor agonists.
编码蛋白质α-突触核蛋白的人类基因已被转入黑腹果蝇基因组。转基因果蝇再现了帕金森病的一些基本特征。这些特征包括大脑中某些多巴胺能神经元的退化，同时伴有与年龄相关的运动活动异常。在本研究中，我们测试了这些转基因果蝇对目前用于治疗该疾病的主要药物类型原型的运动反应。首先进行了一项时间进程研究，以确定相对于正常“野生型”果蝇，运动活动受损何时出现。使用了一种攀爬或负趋地性测定法，测量生物体爬上塑料瓶壁的能力。根据所得结果，正常果蝇和转基因果蝇在其食物中分别用每种药物处理13天，然后进行测定。用左旋多巴处理的转基因果蝇的活动恢复到正常水平。同样，多巴胺激动剂培高利特、溴隐亭和2,3,4,5-四氢-7,8-二羟基-1-苯基-1H-3-苯并氮杂卓（SK&F 38393）也有显著效果。典型的毒蕈碱胆碱能受体拮抗剂阿托品也有效，但程度低于其他抗帕金森化合物效果。对氯苯丙氨酸是一种血清素合成抑制剂，与α-甲基-对-酪氨酸一样没有有益作用，α-甲基-对-酪氨酸是酪氨酸羟化酶的抑制剂，而酪氨酸羟化酶是儿茶酚胺生物合成中的限速步骤。这项行为学研究进一步证明了该模型在研究帕金森病中的实用性，并强化了这样一种观念，即抑制α-突触核蛋白的作用可能对其治疗有用，多巴胺D(1)受体激动剂也可能有用。
