An investigation of the mechanisms of delayed neurodegeneration caused by direct injection of quinolinate into the rat striatum in vivo.
Injection of the N-methyl-D-aspartate receptor agonist quinolinate, or N-methyl-D-aspartate itself, into the rat brain produces neurodegeneration which can be prevented by N-methyl-D-aspartate receptor antagonists administered up to 5 h after excitotoxin injection. The present study was designed to investigate aspects of the mechanisms involved in this delayed form of neurodegeneration. Following its injection into the rat striatum, extracellular levels of [3H]quinolinate were monitored using a microdialysis probe located 1 mm from the site of injection. Peak concentrations were observed 10-20 min after injection and [3H]quinolinate levels decayed in a biexponential fashion, the initial component having an apparent t1/2 of 13.7 +/- 5.2 min (n = 3). Estimations of the extracellular concentrations of quinolinate after an injection of 200 nmol indicated a peak level of 13.7 +/- 6.0 mM (n = 3) at 10-20 min which declined to 1.2 +/- 0.13 mM (n = 3) by 2 h and substantial levels were present up to 5 h, the period over which N-methyl-D-aspartate receptor antagonists are effective in this model. Administration of dizocilpine at 1, 2, 3 or 5 h after injection of 100, 200 or 400 nmol quinolinate resulted in a similar temporal profile of neuroprotection, as assessed by measuring the activities of choline acetyltransferase and glutamate decarboxylase in striatal homogenates, which was independent of the degree of neurodegeneration produced by the different excitotoxin doses. Overall, these results suggest that the neuronal degeneration caused by quinolinate in vivo is critically dependent upon events occurring after the initial peak of excitoxin levels in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
M H
MH
Bakker
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AC
Foster
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D003292:Convulsants / Q000008:administration & dosage / Q000633:toxicity*; D003342:Corpus Striatum; D003956:Dialysis; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007051:Ibotenic Acid / Q000494:pharmacology; D007267:Injections; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects / Q000502:physiology*; D010875:Pipecolic Acids / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013238:Stereotaxic Techniques
D000317:Adrenergic alpha-Antagonists; D000927:Anticonvulsants; D003292:Convulsants; D010875:Pipecolic Acids; D010879:Piperazines; D010880:Piperidines; D011805:Quinolinic Acids; D007051:Ibotenic Acid; C029262:2,3-piperidinedicarboxylic acid; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid; D006220:Haloperidol; D003975:Diazepam; C010739:ifenprodil