GMP prevents excitotoxicity mediated by NMDA receptor activation but not by reversal activity of glutamate transporters in rat hippocampal slices

• Published in: Brain research Vol. 1231; pp. 113 - 120
• Main Authors: Molz, Simone, Tharine, Dal-Cim, Decker, Helena, Tasca, Carla I
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 22-09-2008; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Aspartic Acid - pharmacology; Biochemistry and metabolism; Biological and medical sciences; Brain Diseases, Metabolic - drug therapy; Brain Diseases, Metabolic - metabolism; Brain Diseases, Metabolic - physiopathology; Cell Survival - drug effects; Cell Survival - physiology; Central nervous system; DNA Fragmentation - drug effects; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; Glutamate; Glutamate transporter; Glutamic Acid - metabolism; Glutamic Acid - toxicity; Guanosine Monophosphate - pharmacology; Guanosine Monophosphate - therapeutic use; Guanosine-5′-monophosphate; Hippocampal slice; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; Male; N-Methylaspartate - antagonists & inhibitors; N-Methylaspartate - metabolism; N-Methylaspartate - toxicity; Neurology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurotoxins - antagonists & inhibitors; Neurotoxins - metabolism; Neurotoxins - toxicity; NMDA; Organ Culture Techniques; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Vertebrates: nervous system and sense organs; Vesicular Glutamate Transport Proteins - antagonists & inhibitors; Vesicular Glutamate Transport Proteins - metabolism; N-methyl- d-aspartate; GMP; DL-threo-β-benzyloxyaspartic acid; Glutamate; MTT; 3-(4,5-dimethylthiazol-2-yl)-,5-diphenyltetrazolium bromide; Glu; MK-801; (+)–5–methyl–10,11–dihydro–5H–dibenzo[ a,d]cyclohepten–5,10-imine maleate; Glutamate transporter; NMDA; Hippocampal slice; DL-TBOA; Guanosine-5′-monophosphate; Guanosine-S'-monophosphate; Rat; Toxicity; Guanosine; Rodentia; Central nervous system; Glutamate receptor; Activation; Encephalon; Vertebrata; Mammalia; Animal; Excitotoxicity; Excitatory aminoacid; Neurotransmitter; NMDA receptor; Hippocampus; Carrier protein
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2008.07.009

Abstract Glutamate is the main excitatory neurotransmitter in the mammalian nervous system and is essential for its normal functions. However, overstimulation of glutamatergic system due to hyperactivation of NMDA receptors and/or impairment of glutamate reuptake system has been implicated in many acute and chronic neurological diseases. Regulation of extracellular glutamate concentrations relies on the function of glutamate transporters which can be reversed in situations related to excitotoxicity. Guanosine-5′-monophosphate (GMP), a guanine nucleotide which displays important extracellular roles, such as trophic effects to neurons and astrocytes, behaves as antagonist of glutamate receptors and is neuroprotective in hippocampal slices against excitotoxicity or ischemic conditions. Hippocampal slices exposed to 1 or 10 mM glutamate, or 100 μM NMDA with 10 μM glycine for 1 h and evaluated after 6 or 18 h, showed reduced cell viability and DNA fragmentation, respectively. Glutamate- or NMDA-induced cell death was prevented by 50 μM MK-801, but only NMDA-induced cell damage was prevented by GMP (1 mM). Glutamate-induced cell viability impairment and glutamate-induced l -[3 H]glutamate release were both prevented by adding DL-TBOA (10 μM). Otherwise, NMDA-induced cell viability loss was not prevented by 10 μM of DL-TBOA and NMDA did not induce l -[3 H]glutamate release. Our results demonstrate that GMP is neuroprotective when acting selectively at NMDA receptors. Glutamate-induced hippocampal slice damage and glutamate release were blocked by glutamate transporter inhibitor, indicating that glutamate-induced toxicity also involves the reversal of glutamate uptake, which cannot be prevented by GMP.