Quinolinic acid lesion of the nigrostriatal pathway: effect on turning behaviour and protection by elevation of endogenous kynurenic acid in Rattus norvegicus.
Endogenous excitotoxins have been implicated in degeneration of nigral dopaminergic neurons in Parkinson's disease. It may be possible to reduce neurodegeneration by blocking the effects of these endogenous agents. The present study shows that contralateral turning seen following quinolinic acid-induced lesions of the nigrostriatal dopaminergic pathway was reversed by a treatment that increased brain levels of kynurenic acid, an endogenous excitatory amino acid antagonist. The treatment consisted of nicotinylalanine (5.6 nmol/5 microl i.c.v.), an inhibitor of kynureninase and kynurenine hydroxylase plus the precursor kynurenine (450 mg/kg i.p.) plus probenencid (200 mg/kg i.p.), an inhibitor of organic acid transport. Thus, neuroprotection by increasing brain kynurenic acid in vivo may be useful in retarding cell loss in Parkinson's and other neurodegenerative diseases involving excitotoxicity.
Miranda
A F
AF
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Sutton
M A
MA
Beninger
R J
RJ
Jhamandas
K
K
Boegman
R J
RJ
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology; D050601:Kynurenine 3-Monooxygenase; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009525:Niacin / Q000031:analogs & derivatives / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011339:Probenecid / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; C071261:nicotinylalanine; D009525:Niacin; D007737:Kynurenine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D014446:Tyrosine 3-Monooxygenase; D006867:Hydrolases; C021480:kynureninase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D000409:Alanine; D011339:Probenecid