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Local striatal infusion of MPP+ does not result in increased hydroxylation after systemic administration of
L Ste-Marie1, L Vachon, C Bémeur
1Centre de recherche, Hôpital Notre-Dame, Centre hospitalier de l'Université de Montréal, Département de nutrition, Canada.
Abstract:
In vivo bilateral microdialysis in the rat striatum was used to investigate hydroxyl radical formation under basal conditions and after intrastriatal administration of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). After a short equilibration period, 4-hydroxybenzoate (4HBZ), which scavenges hydroxyl radicals to produce 3,4-dihydroxybenzoate (34DHB), was injected intraperitoneally 15 min before infusion of MPP+. To evaluate the enzymatic contribution to hydroxyl radical formation, two other series of microdialyses were performed following administration of monoamine oxidase B inhibitors, either 1-deprenyl (selegiline) or MDL 72,974A [(E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride]. Microdialysate samples were analyzed by high-performance liquid chromatography for catecholamines, 3,4-dihydroxyphenylacetate (DOPAC), homovanillate (HVA), along with the hydroxyl radical adduct, 34DHB and its precursor, 4HBZ. MPP+ administration resulted in a massive release of dopamine along with a decrease in DOPAC and HVA in all three groups. A striking effect in all three groups was noted in which MPP+ resulted in a decrease in interstitial 4HBZ to < 50% of the non-MPP+ -treated side. In absolute terms, the amount of 34DHB produced was low but similar in all three groups, even after unilateral MPP+ infusion. When 34DHB was normalized to 4HBZ release to account for differences in precursor availability, there were no significant differences in the 34DHB/4HBZ ratios either with or without MAO inhibitor treatment or after local MPP+ infusion. Systemic 4HBZ administration appears to result predominantly in intra-cellular sampling of hydroxyl radicals which produces different results from local infusion of trapping agents such as salicylate.
Insights
Hydroxyl radical formation in rat striatum was studied using 4-hydroxybenzoate (4HBZ). Neurotoxin MPP+ decreased 4HBZ levels, but normalized hydroxyl radical production remained unchanged, suggesting intracellular radical scavenging.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Hydroxyl radical formation is implicated in neurotoxicity.
- 1-methyl-4-phenylpyridinium (MPP+) is a neurotoxin used to model Parkinson's disease.
- 4-hydroxybenzoate (4HBZ) is a scavenger of hydroxyl radicals.
Purpose of the Study:
- To investigate hydroxyl radical formation in the rat striatum.
- To assess the impact of the neurotoxin MPP+ on hydroxyl radical production.
- To evaluate the role of monoamine oxidase B (MAO-B) in hydroxyl radical formation.
Main Methods:
- In vivo bilateral microdialysis in rat striatum.
- Administration of 4-hydroxybenzoate (4HBZ) and MPP+.
- Use of MAO-B inhibitors (1-deprenyl and MDL 72,974A).
- High-performance liquid chromatography (HPLC) analysis of microdialysate.
Main Results:
- MPP+ administration caused massive dopamine release and decreased DOPAC and HVA.
- MPP+ significantly reduced interstitial 4HBZ levels.
- Normalized 3,4-dihydroxybenzoate (34DHB) to 4HBZ ratios showed no significant changes.
- MAO-B inhibition did not alter the 34DHB/4HBZ ratio after MPP+ infusion.
Conclusions:
- Systemic administration of 4HBZ primarily samples intracellular hydroxyl radicals.
- MPP+-induced neurotoxicity does not significantly alter the overall hydroxyl radical scavenging capacity when normalized for precursor availability.
- The study suggests that local infusion of trapping agents may provide different insights compared to systemic administration.