In vivo intracerebral microdialysis studies in rats of MPP+ (1-methyl-4-phenylpyridinium) analogs and related charged species
In vivo intracerebral microdialysis studies in rats of MPP+ (1-methyl-4-phenylpyridinium) analogs and related charged species
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MPP（1-甲基-4-苯基吡啶鎓）类似物和相关带电物质的大鼠体内脑内微透析研究
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发表时间：
1990
期刊：
影响因子：
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通讯作者：
N. Castagnoli
中科院分区：
文献类型：
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作者：
H. Rollema;E. Johnson;R. Booth;P. Caldera;P. Lampen;S. Youngster;A. Trevor;N. Naiman;N. Castagnoli
采用清醒大鼠纹状体内微透析法研究了45种MPTP和MPP+类似物及相关化合物的体内多巴胺能神经毒性。MPP（+）样毒性，如通过对DA释放的不可逆作用和乳酸盐形成的增强所证明的，在各种结构类型中观察到，尽管没有化合物比MPP+毒性更大。结果表明：（1）只有带永久电荷的化合物具有神经毒性作用，（2）除氨基外，亲水性取代基可消除毒性作用，（3）亲脂性取代基可增强活性，但氮原子周围空间体积的增加会降低活性;（4）非芳香族、四元体系（MPTP的甲碘、胍盐衍生物）仅具有弱毒性;（5）某些双环和三环体系，包括潜在内源性MPTP样化合物的推定代谢物，具有弱毒性。DA本身灌注后缺乏毒性作用证实MPTP多巴胺能神经毒性不太可能由MPP（+）诱导的DA释放介导。除了一些有趣的例外情况，这些体内数据与这些化合物的神经末梢摄取特性和对线粒体呼吸抑制作用的体外数据相关性相当好。
: The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.