Endogenous guanidino compounds as uremic neurotoxins

Epileptic and cognitive symptomatologies are among the most typical manifes tations of urcmic encephalopathy. Several guanidino compounds (GCs) may pla y an important role in the etiology of urcmic encephalopathy. Four GCs appe ared to be highly increased as well in serum, cerebrospinal fluid, and brai n of urcmic patients, whereas the levels of other metabolically relevant GC s were not or only moderately increased and others were even decreased. The se highly increased compounds or "uremic" GCs are creatinine (CTN), guanidi ne (G), guanidinosuccinic acid (GSA), and methylguanidine (MCT). All four c ompounds were shown to be experimental convulsants in brain concentrations similar to those found in uremic brain. We have described a possible mechan ism for the contribution of GCs to uremic hyperexcitability, referring to t he in vitro effects of uremic GCs on inhibitory and excitatory amino acid r eceptors. The excitatory effects of urcmic GCs on the central nervous syste m may be explained by the activation of N-methyl-D-aspartate (NMDA) recepto rs by GSA, concomitant inhibition of GABA(A) receptors by uremic GCs, and o ther depolarizing effects. These effects might also indicate the putative c ontribution of uremic GCs to the etiology of uremic encephalopathy.