Knoll J
Wien Med Wochenschr Suppl. 1986;98:1-18.
The striatum, in which the nigrostriatal dopaminergic neurons terminate, contains the highest amount of dopamine DA) in the brain. DA, released in the striatum, plays the rate limiting role in the control of motor functions by continuously inhibiting the release of acetylcholine (ACh) from the cholinergic interneurons of the caudate nucleus. DA content of the human caudate nucleus decreases by 13% per decade over the age of 45. Parkinson's disease seems to be a kind of selective, highly accelerated 'premature aging' of the nigrostriatal dopaminergic system, and the DA content of this neuron system shrinks within a short time to less than 10% of the normal level in the premorbid state. Clinical symptoms occur when the striatum loses more than 70% of its DA content. The chemical lesioning of the nigrostriatal dopaminergic neuron in the rat by 6-OH-dopamine (6-OHDA) leads to an increase of cholinergic activity in the striatum. The striatum taken from a rat pretreated with 6-OH dopamine is a useful experimental model for the rapid screening of compounds with potential therapeutic benefit in Parkinson's disease. A more specific neurotoxin than 6-OHDA is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which kills the cells in the substantia nigra with high specificity and induces rapidly parkinsonian-like condition in men and monkeys. (-)Deprenyl, the selective inhibitor of B-type MAO protects the striatum from the neurotoxic effects of 6-OHDA and MPTP. The amount of ACh released from the striatum of the rat increases from 372.8 +/- 31.4 to 746.5 +/- 44.0 pmol/g/min in 6-OHDA treated rats, it remains normal (371.1 +/- 34.7) if (-)deprenyl is given 30 minutes before 6-OHDA administration, hut is further increased (956.3 +/- 79.3 pmol/g/min), if clorgyline os injected 30 minutes before 6-OHDA. (-)Deprenyl prevents in a similar manner the neurotoxicity of MPTP in monkeys, whereas clorgyline, the selective inhibitor of MAO-A, is ineffective. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences without eliciting an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine.(ABSTRACT TRUNCATED AT 400 WORDS)
黑质纹状体多巴胺能神经元的终末部位——纹状体，是脑内多巴胺（DA）含量最高的区域。纹状体内释放的DA，通过持续抑制尾状核胆碱能中间神经元释放乙酰胆碱（ACh），在运动功能控制中发挥限速作用。45岁以后，人类尾状核中的DA含量每十年下降13%。帕金森病似乎是黑质纹状体多巴胺能系统一种选择性、高度加速的“早衰”，该神经元系统中的DA含量在短时间内萎缩至病前状态正常水平的不到10%。当纹状体中DA含量损失超过70%时，临床症状就会出现。用6-羟基多巴胺（6-OHDA）对大鼠黑质纹状体多巴胺能神经元进行化学损伤，会导致纹状体胆碱能活性增加。取自经6-羟基多巴胺预处理大鼠的纹状体，是快速筛选对帕金森病有潜在治疗益处化合物的有用实验模型。一种比6-OHDA更具特异性的神经毒素是1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），它能高度特异性地杀死黑质中的细胞，并在人和猴中迅速诱发帕金森样症状。（-）司来吉兰，B型单胺氧化酶的选择性抑制剂，可保护纹状体免受6-OHDA和MPTP的神经毒性作用。在6-OHDA处理的大鼠中，纹状体释放的ACh量从372.8±31.4增加到746.5±44.0 pmol/g/分钟；如果在给予6-OHDA前30分钟给予（-）司来吉兰，ACh量保持正常（371.1±34.7），但如果在给予6-OHDA前30分钟注射氯吉兰，ACh量会进一步增加（956.3±79.3 pmol/g/分钟）。（-）司来吉兰以类似方式预防MPTP对猴的神经毒性，而A型单胺氧化酶的选择性抑制剂氯吉兰则无效。司来吉兰在脑内最重要的作用是使多巴胺能神经元对生理和药理影响敏感，而不引起多巴胺能活性急性增加。司来吉兰的作用一方面归因于对单胺氧化酶-B的抑制，另一方面归因于对多巴胺摄取的抑制。（摘要截选至400字）
