Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice.
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.
D'Hooge
R
R
Laboratory of Neurochemistry, Born-Bunge Foundation, University of Antwerp (UIA), Belgium.
Pei
Y Q
YQ
Marescau
B
B
De Deyn
P P
PP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D003292:Convulsants / Q000493:pharmacokinetics / Q000633:toxicity*; D003404:Creatinine / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D006146:Guanidines / Q000493:pharmacokinetics / Q000633:toxicity*; D007276:Injections, Intraventricular; D007928:Lethal Dose 50; D008297:Male; D008760:Methylguanidine / Q000493:pharmacokinetics / Q000633:toxicity; D051379:Mice; D013386:Succinates / Q000493:pharmacokinetics / Q000633:toxicity; D014511:Uremia / Q000378:metabolism*
D003292:Convulsants; D006146:Guanidines; D013386:Succinates; D008760:Methylguanidine; C001318:guanidinosuccinic acid; D003404:Creatinine