Corasaniti M T, Strongoli M C, Rotiroti D, Bagetta G, Nisticò G
Chair of Pharmacology, Faculty of Pharmacy, University of Catanzaro, Italy.
Pharmacol Toxicol. 1998 Jul;83(1):1-7. doi: 10.1111/j.1600-0773.1998.tb01434.x.
The present article reviews the results of experimental studies on paraquat neurotoxicity, started by our group several years ago--when clinical and experimental reports had increased the interest for the possibility that environmental chemicals, including paraquat, may be related to the development of Parkinson's disease-, and which are still continuing since paraquat appears to be a promising tool to study the mechanisms of neuronal cell death in vivo. Our observations have demonstrated that paraquat causes evident neurotoxic effects after intracerebroventricular or intracerebral injection in experimental animals; however, it seems that the herbicide does not exibit a selective neurotoxicity towards the dopaminergic nigro-striatal system since potent behavioural and electrocortical changes are induced by paraquat after injection in brain areas other than the substantia nigra and caudate nucleus. By studying the mechanisms through which paraquat induces neurotoxic effects in vivo, it was shown that either free radical production and activation of cholinergic and glutamatergic transmission may be regarded as related events which play a crucial role in paraquat-induced neurotoxicity. In addition, it was observed that in rats paraquat penetrates the blood-brain barrier following systemic administration to give rise to a differential brain regional distribution; the latter observation rises some concern over the hazard of paraquat as a potential environmental neurotoxin. Indeed, paraquat, administered systemically in rats produces behavioural excitation and brain damage. The brain damage appears to be selective for the pyriform cortex and this does not seem to be strictly related to the high concentrations reached by the herbicide in this area but to the higher vulnerability of this cortical area to the enhanced cholinergic transmission. The recent observation that paraquat, injected into the rat hippocampus, induces the expression of apoptotic neuronal cell death, appears of valuable interest also with a view to paraquat as an useful experimental model in the development of neuroprotective drugs able to block the molecular events which, once activated, are responsible for the induction of neuronal cell death.
本文回顾了我们小组几年前开始的关于百草枯神经毒性的实验研究结果——当时临床和实验报告增加了人们对包括百草枯在内的环境化学物质可能与帕金森病发展有关的可能性的兴趣——并且由于百草枯似乎是研究体内神经元细胞死亡机制的一个有前景的工具，这些研究仍在继续。我们的观察表明，在实验动物中，经脑室内或脑内注射后，百草枯会产生明显的神经毒性作用；然而，这种除草剂似乎对多巴胺能黑质-纹状体系统没有表现出选择性神经毒性，因为在黑质和尾状核以外的脑区注射百草枯后会诱导强烈的行为和脑电图变化。通过研究百草枯在体内诱导神经毒性作用的机制，发现自由基的产生以及胆碱能和谷氨酸能传递的激活都可能被视为在百草枯诱导的神经毒性中起关键作用的相关事件。此外，观察到在大鼠中，全身给药后百草枯可穿透血脑屏障，导致脑区分布差异；后一观察结果引发了对百草枯作为潜在环境神经毒素危害的一些担忧。事实上，在大鼠中全身给药的百草枯会产生行为兴奋和脑损伤。脑损伤似乎对梨状皮质具有选择性，这似乎并不严格与该除草剂在该区域达到的高浓度相关，而是与该皮质区域对增强的胆碱能传递更高的易感性有关。最近的观察发现，将百草枯注入大鼠海马体可诱导凋亡性神经元细胞死亡的表达，从百草枯作为开发能够阻断一旦激活就导致神经元细胞死亡的分子事件的神经保护药物的有用实验模型的角度来看，这也具有重要意义。
