Idebenone attenuates neuronal degeneration induced by intrastriatal injection of excitotoxins.
Previous studies with the N18-RE-105 neuronal-like cell line and primary cortical cultures demonstrate that glutamate can produce a calcium-dependent, delayed form of neuronal degeneration that results from its competitive inhibition of cystine transport, which leads to cellular glutathione depletion and death by oxidative stress. Idebenone, a centrally active antioxidant used to treat multiinfarct dementia, protects cells from this form of glutamate-induced cytotoxicity in vitro. In the present study, we have examined the effects of systemic treatment with idebenone on the neurotoxic consequences of intrastriatal injection of kainic acid, quisqualic acid, or quinolinic acid, an NMDA receptor agonist, on neuronal degeneration. Striatal damage was assessed by quantitative neurochemistry with measurement of choline acetyltransferase activity and glutamate decarboxylase activity, by histochemical analysis for acetylcholinesterase and NADPH diaphorase staining and by behavioral assessment of circling produced by systemic apomorphine treatment 10 days after the unilateral lesion. The results indicate that treatment with idebenone provides significant protection against the neuronal degeneration induced by intrastriatal injection of kainic acid and quisqualic acid, but not the NMDA receptor agonist, quinolinic acid. The results suggest that oxidative stress may contribute to the proximate cause of neuronal degeneration induced by quisqualate and by kainate receptor agonists and that the mechanisms of neuronal degeneration caused by quisqualate/kainate receptor agonists differ from those associated with NMDA receptor agonists.
Miyamoto
M
M
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Coyle
J T
JT
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D016227:Benzoquinones; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006651:Histocytochemistry; D007608:Kainic Acid / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009252:NADPH Dehydrogenase / Q000032:analysis; D009410:Nerve Degeneration / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D014451:Ubiquinone / Q000031:analogs & derivatives
D016227:Benzoquinones; D010069:Oxadiazoles; D011725:Pyridines; D011805:Quinolinic Acids; D011809:Quinones; D014451:Ubiquinone; D016318:Quisqualic Acid; D009252:NADPH Dehydrogenase; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid; C036619:idebenone; D001058:Apomorphine; D007608:Kainic Acid