Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland.
Neurotox Res. 2009 Jan;15(1):15-23. doi: 10.1007/s12640-009-9001-9. Epub 2009 Feb 10.
1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause a parkinsonism-like syndrome in rodents and primates. In this study we evaluated the effects of single and multiple 1BnTIQ (50 mg/kg i.p.) administration on the concentrations of dopamine, serotonin, and respective metabolites (homovanillic acid, HVA; 3,4-dihydroxyphenylacetic acid, DOPAC; 3-methoxytyramine, 3-MT; and 5-hydroxyindolacetic acid, 5-HIAA), in substantia nigra, striatum (STR), and nucleus accumbens of Wistar rats. In addition, the effect of 1BnTIQ on locomotor activity and dopamine release in vivo was also estimated in rat STR. In a behavioral study, acute administration of 1BnTIQ (50 mg/kg i.p.) produced a significant decrease in exploratory locomotor activity. A high-performance liquid chromatography with electrochemical detection ex vivo study showed that a single injection of 1BnTIQ produced a dramatic fall in the dopamine concentration in the noted brain regions (approximately 65%; P < 0.01), but not in striatal serotonin. Moreover, 1BnTIQ reduced the content of the extraneuronal dopamine metabolite 3-MT by 70% (P < 0.01). Conversely, levels of DOPAC, HVA, and 5-HIAA were elevated by 220, 320, and 185%, respectively (P < 0.01). Interestingly, multiple 1BnTIQ treatments (50 mg/kg/day i.p. x 10 days) resulted in development of tolerance to its dopamine depressing effect, while the impairment of dopamine synthesis was persisted. An in vivo microdialysis study demonstrated that 1BnTIQ (50 mg/kg i.p.) produced a profound and long-lasting decrease in extraneuronal striatal dopamine. Concurrently, however, DOPAC and HVA were elevated. This comparison between ex vivo and in vivo effects of 1BnTIQ provides greater insight into the neurotoxic actions of 1BnTIQ specific to dopamine neurons. 1BnTIQ neurotoxicity may be related to an impairment of dopamine storage, leading to a fall in intraneuronal dopamine and enhanced dopamine catabolism through a monoamine oxidize-dependent oxidative pathway that results in free radical production and ultimate cell death. Because 1BnTIQ is an endogenous compound, it may be one of the factors responsible for idiopathic Parkinson's disease.
1-苄基-1,2,3,4-四氢异喹啉（1BnTIQ）是一种内源性神经毒素，已知它会在啮齿动物和灵长类动物中引起类似帕金森病的综合征。在这项研究中，我们评估了单次和多次 1BnTIQ（50mg/kg，ip）给药对多巴胺、血清素及其相应代谢物（高香草酸，HVA；3,4-二羟基苯乙酸，DOPAC；3-甲氧基酪胺，3-MT；和 5-羟吲哚乙酸，5-HIAA）浓度的影响，在纹状体（STR）和伏隔核中。此外，还估计了 1BnTIQ 在体内对大鼠 STR 中运动活动和多巴胺释放的影响。在行为研究中，急性给予 1BnTIQ（50mg/kg，ip）导致探索性运动活动明显减少。高效液相色谱电化学检测的离体研究表明，单次注射 1BnTIQ 会导致所述脑区的多巴胺浓度急剧下降（约 65%；P<0.01），但纹状体内的血清素不受影响。此外，1BnTIQ 将细胞外多巴胺代谢物 3-MT 的含量减少了 70%（P<0.01）。相反，DOPAC、HVA 和 5-HIAA 的水平分别升高了 220%、320%和 185%（P<0.01）。有趣的是，多次 1BnTIQ 治疗（50mg/kg/天，ip.x10 天）导致其对多巴胺抑制作用产生了耐受性，而多巴胺合成的损害仍然存在。体内微透析研究表明，1BnTIQ（50mg/kg，ip）导致细胞外纹状体多巴胺显著而持久的下降。同时，DOPAC 和 HVA 升高。1BnTIQ 的这种离体和体内作用的比较，更深入地了解了 1BnTIQ 对多巴胺神经元的神经毒性作用。1BnTIQ 的神经毒性可能与多巴胺储存的损害有关，导致细胞内多巴胺水平下降，并通过单胺氧化酶依赖性氧化途径增强多巴胺代谢，导致自由基产生和最终细胞死亡。由于 1BnTIQ 是一种内源性化合物，它可能是特发性帕金森病的一个因素。
