In vivo hydroxylation of the neurotoxin, 1-methyl-4-phenylpyridinium, and the effect of monoamine oxidase inhibitors: electrospray-MS analysis of intra-striatal microdialysates.
The neurotoxin 1-methyl-4-phenylpyridinium (MPP+) has been shown to increase hydroxyl radical formation in the striatum. The production of hydroxyl radicals correlates with the MPP(+)-driven dopamine release which presumably leads to increased metabolism via monoamine oxidase or increased dopamine autoxidation. Both processes result in enhanced production of hydrogen peroxide, which in the presence of iron(II) ions decomposes to the hydroxyl radical. Monoamine oxidase inhibitors decrease the production of hydroxyl radicals as measured by salicylate and 4-hydroxybenzoate trapping. As both MPP+ and monoamine oxidase inhibitors, such as deprenyl and MDL-72,974A, possess aromatic rings, hydroxyl radical adduct formation was investigated in vitro in defined Fenton systems and also in vivo using intra-striatal microdialysis to infuse MPP+ to rats pretreated systemically with either deprenyl or MDL-72,974A. Electrospray mass spectrometric analysis, using full-scan, fragment ion and constant neutral loss spectra, demonstrated ring hydroxylation of all three compounds in the Fenton systems. Spectral comparison of microdialysis samples with spectra from the Fenton reactions indicated the in vivo hydroxyl radical adduct attachment to MPP+, deprenyl and possibly MDL-72,974A.
Centre de recherche Louis-Charles Simard, Montréal, Québec.
D
D
Boismenu
O
O
Mamer
L
L
Ste-Marie
L
L
Vachon
J
J
Montgomery
D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics*; D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D002082:Butylamines / Q000494:pharmacology; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D017665:Hydroxyl Radical; D006900:Hydroxylation; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000498:Allyl Compounds; D002082:Butylamines; D015259:Dopamine Agents; D008996:Monoamine Oxidase Inhibitors; C058000:mofegiline; D012642:Selegiline; D017665:Hydroxyl Radical; D015655:1-Methyl-4-phenylpyridinium