An evaluation of the role of extracellular amino acids in the delayed neurodegeneration induced by quinolinic acid in the rat striatum.
The effect of the N-methyl-D-aspartate receptor agonist quinolinic acid on extracellular levels of striatal amino acids, following its injection directly into the rat striatum, has been investigated using intracerebral dialysis in the attempt to elucidate the cellular mechanisms underlying delayed neurodegeneration. A neurotoxic dose (200 nmol) of quinolinic acid caused an elevation in the levels of aspartate (x 6), glutamate (x 2), asparagine (x 2), serine (x 2.5), glycine (x 3), and threonine (x 2) which peaked in the fractions 20-40 min after the injection and achieved statistical significance for aspartate and asparagine. The dialysate content of these amino acids returned to basal values within 1 h and no further changes were observed in the following 4 h. Injection of an equivalent dose of nicotinic acid did not mimic the effect of quinolinate, indicating that osmotic and/or mechanical damage was not responsible for the observed phenomena. Pretreatment with the N-methyl-D-aspartate receptor channel blocker dizocilpine (MK-801) completely blocked the quinolinate-induced increase of the amino acids, thus confirming that N-methyl-D-aspartate receptor activation is required for this effect to occur. Seven days after the injection of quinolinate, histological analysis showed an extensive loss of neuronal elements in the injected striatum, which was completely prevented in the dizocilpine-treated animals. Sections from striata of animals injected with nicotinic acid showed normal-appearing neurons and no differences were detectable from controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Fedele
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Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
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D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001216:Asparagine / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D003956:Dialysis; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D005998:Glycine / Q000378:metabolism; D008297:Male; D008845:Microinjections / Q000295:instrumentation / Q000379:methods; D009410:Nerve Degeneration / Q000187:drug effects; D009525:Niacin / Q000008:administration & dosage / Q000494:pharmacology; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D000596:Amino Acids; D005971:Glutamates; D009525:Niacin; D013912:Threonine; D001224:Aspartic Acid; D018698:Glutamic Acid; D012694:Serine; D016291:Dizocilpine Maleate; D001216:Asparagine; D017378:Quinolinic Acid; D005998:Glycine