Effects of alpha-phenyl-tert-butylnitrone and selegiline on hydroxyl free radicals in rat striatum produced by local application of glutamate.
The hydroxyl radical is a very reactive oxygen species that damages biomolecules in the brain and in other tissues. The possible pharmacological intervention to prevent hydroxyl radical formation was studied in vivo using the microdialysis technique in brains of nonanesthetized rats. Hydroxyl radicals form stable adducts [mainly 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-DHBA)] via an aromatic hydroxylation reaction with salicylic acid. 2,3-DHBA was separated and quantified by HPLC and electrochemical detection. Microdialysis probes were implanted into the striatum 1 day before measurement of levels of hydroxyl radicals. The next day, the probes were first perfused for 120 min with a modified Ringer's solution containing 5 mM salicylic acid, to obtain stable baselines. Afterward, the perfusion solution was switched to another solution that in addition contained 50 mM glutamate, to stimulate radical formation. Twenty minutes later, alpha-phenyl-tert-butylnitrone (PBN; 100 mg/kg), selegiline (10 mg/kg), or saline was administered intraperitoneally. The glutamate perfusion produced marked two- to 2.5-fold increases in 2,3-DHBA content. Treatment with PBN significantly antagonized the rise of 2,3-DHBA level, indicating that PBN is a direct radical scavenger not only in vitro but also in vivo. Acute treatment with selegiline failed to reduce significantly the glutamate-induced radical formation. The acute experiments presented here do not support the suggestion that the neuroprotective effects of selegiline described in the literature are due to a potential hydroxyl radical scavenging property of the drug.
Ferger
B
B
Institute for Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Germany.
van Amsterdam
C
C
Seyfried
C
C
Kuschinsky
K
K
D000287:Administration, Topical; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005841:Gentisates; D018698:Glutamic Acid / Q000494:pharmacology*; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000494:pharmacology*
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D005841:Gentisates; D062385:Hydroxybenzoates; D008996:Monoamine Oxidase Inhibitors; D009589:Nitrogen Oxides; D012642:Selegiline; D017665:Hydroxyl Radical; C029217:phenyl-N-tert-butylnitrone; D018698:Glutamic Acid; C009135:2,3-dihydroxybenzoic acid; C010925:2,5-dihydroxybenzoic acid