GSA: behavioral, histological, electrophysiological and neurochemical effects.
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.
Torremans
An
A
Laboratory of Neurochemistry and Behavior, Born Bunge Foundation, University of Antwerp-Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerp, Wilrijk, Belgium.
Marescau
Bart
B
Van Dam
Debby
D
Van Ginneken
Chris
C
Van Meir
Frans
F
Van Bogaert
Pierre-Paul
PP
D'Hooge
Rudi
R
de Vente
Jan
J
De Deyn
Peter Paul
PP
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004924:Escape Reaction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology; D013386:Succinates / Q000494:pharmacology*; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D013386:Succinates; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; C001318:guanidinosuccinic acid; D015763:2-Amino-5-phosphonovalerate; D006152:Cyclic GMP