D'Hooge R, Pei Y Q, Marescau B, De Deyn P P
Laboratory of Neurochemistry, Born-Bunge Foundation, University of Antwerp (UIA), Belgium.
J Neurol Sci. 1992 Oct;112(1-2):96-105. doi: 10.1016/0022-510x(92)90138-b.
Four guanidino compounds that are known to accumulate in uremia, namely creatinine, guanidine, guanidinosuccinic acid and methylguanidine, were administered intraperitoneally and intracerebroventricularly to adult albino mice and the compounds epileptogenic and toxic properties were behaviorally assessed. After intraperitoneal injection, brain concentration of the compounds as a function of injected dose was monitored additionally. Guanidino compound brain concentration was determined by cation exchange chromatography with fluorescence ninhydrin detection. After systemic administration, especially guanidinosuccinic acid and methylguanidine induced long-lasting generalized convulsions which gradually increased in severity. Increasing the dose injected intraperitoneally resulted in linear increase in brain concentration of the injected compounds, in parallel with increase in proportion of animals presenting with convulsions and/or severity of convulsions. Guanidinosuccinic acid brain concentration increased more slowly than that of the other 3 compounds and guanidinosuccinic acid also exerted its effect later than the others. Since none of the other metabolically related guanidino compounds determined was significantly increased in the brains of the injected animals, the observed behavior was most certainly induced by the compounds injected and not by some secondary metabolite. Epileptogenic properties of the four compounds were markedly and qualitatively different in systemic administration, but rather similar in intracerebral administration. A tentative epileptogenic potency order was inferred from the combined behavioral and biochemical results. All 4 of the compounds tested displayed the ability to induce full-blown clonic-tonic convulsions and they did so in a dose-related manner. Guanidinosuccinic acid appeared to be slightly more potent than methylguanidine, but both guanidinosuccinic acid and methylguanidine were considerably more potent than guanidine. Creatinine was many times less potent than the other 3 guanidino compounds. Revised epileptogenic potency order on the basis of guanidino compound brain concentration after systemic administration as well as potency order after intracerebral administration paralleled the potency order of these compounds in their GABA antagonism reported earlier. It was therefore postulated that the GABA antagonism of uremic guanidino compounds could underlie their epileptogenic character. Moreover, these compounds could very likely be at the basis of the neurological complications including epilepsy of uremic patients in whom they accumulate in physiological fluids and brain.
已知在尿毒症中会蓄积的四种胍基化合物，即肌酐、胍、胍基琥珀酸和甲基胍，通过腹腔内和脑室内注射给予成年白化小鼠，并对这些化合物的致癫痫和毒性特性进行行为学评估。腹腔注射后，额外监测化合物在脑中的浓度与注射剂量的关系。胍基化合物在脑中的浓度通过阳离子交换色谱法和荧光茚三酮检测来确定。全身给药后，尤其是胍基琥珀酸和甲基胍会引发持久的全身性惊厥，惊厥严重程度逐渐增加。腹腔注射剂量增加导致注射化合物在脑中的浓度呈线性增加，同时出现惊厥的动物比例和/或惊厥严重程度也增加。胍基琥珀酸在脑中的浓度比其他三种化合物增加得更慢，其作用也比其他化合物出现得更晚。由于在所检测的注射动物脑中，其他代谢相关的胍基化合物均未显著增加，因此观察到的行为肯定是由注射的化合物引起的，而非某些次级代谢产物。这四种化合物在全身给药时的致癫痫特性在程度和性质上有显著差异，但在脑内给药时则较为相似。根据行为学和生化结果综合推断出一个暂定的致癫痫效力顺序。所有测试的四种化合物都显示出诱发全面阵挛 - 强直惊厥的能力，且呈剂量相关。胍基琥珀酸似乎比甲基胍的效力稍强，但胍基琥珀酸和甲基胍都比胍的效力强得多。肌酐的效力比其他三种胍基化合物低很多倍。基于全身给药后胍基化合物在脑中的浓度以及脑内给药后的效力顺序，修订后的致癫痫效力顺序与这些化合物早期报道的GABA拮抗作用效力顺序平行。因此推测尿毒症胍基化合物的GABA拮抗作用可能是其致癫痫特性的基础。此外，这些化合物很可能是尿毒症患者神经并发症（包括癫痫）的病因，因为它们在生理体液和脑中蓄积。
