Modulation of glutamate-induced intracellular energy failure in neonatal cerebral cortical slices by kynurenic acid, dizocilpine, and NBQX.
The severity and rapidity of acute, glutamate-induced energy failure were compared in live cerebral cortical slices. In each experiment 80 live cerebral cortical slices (350 microns thick) were obtained from neonatal Sprague-Dawley rats, suspended and perfused in a nuclear magnetic resonance (NMR) tube, and studied at 4.7 T with interleaved 31P/1H NMR spectroscopy. NMR spectra, obtained continually, were determined as 5-min averages. Slices were perfused for 60 min with artificial cerebrospinal fluid (ACSF) containing either glutamate alone or glutamate mixed with one of three glutamate-receptor antagonists: kynurenate, dizocilpine (MK-801), and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX). Dose-dependent decreases in high-energy phosphates were studied during glutamate exposure (0.5 to 10 mM), with and without antagonist protection. Energy recovery after glutamate exposures was measured during a 60-min washout with glutamate-free, antagonist-free ACSF. Reversible and irreversible energy failures were characterized by changes in intracellular pH, and by changes in relative concentrations of ATP, phosphocreatine (PCr), and inorganic phosphate. No changes were observed in intracellular levels of N-acetylaspartate and lactate. Some special studies were also done using R-(-)-2-amino-5-phosphonovaleric acid (100 microM) and tetrodotoxin (1 mM) to examine glutamate receptor specificity in this tissue model. Dizocilpine (150 microM) best ameliorated the energy failure caused by 2.0 mM glutamate. With dizocilpine the maximum ATP decrease was only 6 +/- 5%, instead of 35 +/- 7%.(ABSTRACT TRUNCATED AT 250 WORDS)
Espanol
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MT
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Xu
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Litt
L
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Yang
G Y
GY
Chang
L H
LH
James
T L
TL
Weinstein
P
P
Chan
P H
PH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004734:Energy Metabolism; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D007736:Kynurenic Acid / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D005971:Glutamates; D009498:Neurotoxins; D011810:Quinoxalines; D010725:Phosphocreatine; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; D007736:Kynurenic Acid