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Abstract
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.