cgp-37849 and guanidinosuccinic-acid

Renal insufficient patients suffer from a variety of complications as direct and indirect consequence of accumulation of retention solutes. Guanidinosuccinic acid (GSA) is an important probable uremic toxin, increased in plasma, urine, cerebrospinal fluid and brain of patients with uremia and supposed to play a role in the pathogenesis of some neurological symptoms. GSA, an NMDA-receptor agonist and GABA-receptor antagonist, is suggested to act as an excitotoxin and shown to be convulsive. The effect of hippocampal (i.h.) GSA injection on behavior and hippocampal volume in mice is presented here. In addition, hippocampal cGMP concentration after systemic injection of GSA was measured. The effect of co-application of NMDA-receptor antagonist CGP37849 with GSA was tested, in vivo, after hippocampal GSA injection and, in vitro, on GSA evoked currents in spinal cord neurons. A significant dose-dependent effect of i.h. injection of GSA on cognitive performance, activity and social exploratory behavior was observed. There was a protective effect of CGP37849 on GSA induced behavioral alterations. Volume of hippocampal cornu ammonis region decreased significantly and dose-dependently after GSA injection. Systemic GSA injection increased cGMP concentration in hippocampal formation. It can be concluded that GSA is an important neurotoxin. As GSA is increased in patients with uremia, it probably contributes to their neurological symptoms. Knowledge of neurotoxic effects and mechanisms of action of GSA and other uremic retention solutes could help in the development of more efficient treatment of uremic patients. Animal models like the 'GSA mouse model' are useful tools for research in this context.

Topics: 2-Amino-5-phosphonovalerate; Animals; Behavior, Animal; Brain Chemistry; Cyclic GMP; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Escape Reaction; Excitatory Amino Acid Antagonists; Exploratory Behavior; Guanidines; Hippocampus; In Vitro Techniques; Maze Learning; Membrane Potentials; Mice; Mice, Inbred C57BL; Neurons; Patch-Clamp Techniques; Psychomotor Performance; Reaction Time; Spinal Cord; Succinates; Time Factors

Renal failure has been viewed as a state of cellular calcium toxicity due to the retention of small fast-acting molecules. We have tested this hypothesis and identified potentially neuroexcitatory compounds among a number of putative uremic neurotoxins by examining the acute in vitro effects of these compounds on cultured central neurons. The in vitro neuroexcitatory and synergistic effects of guanidinosuccinate and spermine were also examined in vivo.. The acute effects of 17 candidate uremic neurotoxins on murine spinal cord neurons in primary dissociated cell culture were investigated using the tight-seal whole-cell recording technique. The compounds studied comprised low-molecular-weight solutes like urea, indoles, guanidino compounds, polyamines, purines and phenoles, homocysteine, orotate, and myoinositol. Currents evoked by these compounds were further examined using various ligand- and voltage-gated ion channel blockers. The acute in vivo effects of guanidinosuccinate and spermine were behaviorally assessed following their injection in mice.. It was shown that 3-indoxyl sulfate, guanidinosuccinate, spermine, and phenol evoked significant whole-cell currents. Inward whole-cell current evoked by 3-indoxyl sulfate was not blocked by any of the applied ligand- or voltage-gated ion channel blockers, and the compound appeared to influence miscellaneous membrane ionic conductances, probably involving voltage-gated Ca2+ channels as well. Phenol-evoked outward whole-cell currents were at least partly due to the activation of voltage-gated K+ channels, but may also involve a variety of other ionic conductances. On the other hand, inward whole-cell currents evoked by guanidinosuccinate and spermine were shown to be due to specific interaction with voltage- and ligand-gated Ca2+ channels. Guanidinosuccinate-evoked current was caused by activation of N-methyl-d-aspartate (NMDA) receptor-associated ion channels. Low (micromol/L) concentrations of spermine potentiated guanidinosuccinate-evoked current through the action of spermine on the polyamine binding site of the NMDA receptor complex, whereas current evoked by high (mmol/L) concentrations of spermine alone involved direct activation of voltage-gated Ca2+ channels. Finally, intracerebroventricular administration of 0.25 micromol/L spermine potentiated clonic convulsions induced by guanidinosuccinate. These neuroexcitatory and synergistic effects of guanidinosuccinate and spermine could take place at pathophysiologic concentrations.. The observed in vitro and in vivo effects of uremic retention solutes suggest that the identified compounds could play a significant role in uremic pathophysiology. Some of the compounds tested displayed in vitro and in vivo neuroexcitatory effects that were mediated by ligand- and voltage-gated Ca2+ channels. The findings suggest a mechanism for the involvement of calcium toxicity in the central nervous system complications in renal failure with particular reference to guanidinosuccinate and spermine.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bicuculline; Calcium Channels; Cells, Cultured; Drug Synergism; Excitatory Amino Acid Antagonists; GABA Antagonists; Guanidines; Membrane Potentials; Mice; Neurons; Nickel; Piperidines; Potassium Channel Blockers; Seizures; Spermine; Spinal Cord; Succinates; Synapses; Tetraethylammonium; Tetrodotoxin; Uremia

Increased levels of the endogenous convulsant guanidinosuccinate (GSA) might contribute to the epileptic symptomatology presenting in patients with renal failure. Little is known, however, about the underlying epileptogenic mechanism of guanidinosuccinate-induced convulsions. In this paper, we present pharmacological evidence for a direct excitatory action of this compound. In particular, the close involvement of N-methyl-D-aspartate (NMDA) receptors in the pathogenesis of GSA-induced generalized convulsions is suggested. GSA potentiated NMDA-induced convulsions significantly, but not L-glutamate- or kainate-induced convulsions. Conversely, and in addition, NMDA receptor antagonists, like D(-)-2-amino-5-phosphonovalerate, CGP 37849 [DL)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoate] or ketamine (but not kynurenate), blocked the convulsions induced by i.c.v. injection of GSA dose dependently whereas anti-epileptic drugs, like carbamazepine, diazepam, phenobarbital or valproate, only abolished the tonic extension phase of these convulsions. Thus, NMDA receptors appear to be involved, at least partly, in GSA-induced convulsions.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Drug Interactions; Female; Glutamates; Glutamic Acid; Guanidines; Kainic Acid; Ketamine; Kynurenic Acid; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures; Succinates