Endogenous guanidino compounds as uremic neurotoxins

Endogenous guanidino compounds as uremic toxins. Epileptic and cognitive symptomaatologies are among the most typical manifestations of luremic encephalopathy, Several guanidino compounds (GCs) may play an important role in the etiology of uremic encephalopathy. Four GCs appeared to be highly increased as well in serum, cerebrospinal fluid, and brain of uremic patients, whereas the levels of other metabolically relevant GCs were not or only moderately increased and others were even decreased. These highly increased compounds or “uremic” GCs are creatinine (CTN), guanidine (G), guanidino-sucinic acid (GSA), and methylguanidine (MG). All four compounds were shown to be experimental convulsants in brain concentrations similar to those found in uremic brain. We have described a possible mechanism for the contribution of GCs to uremic hyperexcitability, referring to the in vitro effects of uremic GCs on inhibitory and excitatory amino acid receptors. The excitatory effects of uremic GCs on the central nervous system may be explained by the activation ofN-methyl-d-asparate (NMDA) receptors by GSA, concomitant inhibition of GABAA receptors by uremic GCs, and other depolarizing effects. These effects might also indicate the putative contribution or uremic GCs to the etiology of uremic encephalopathy