title: Glutathione deficiency potentiates manganese toxicity in rat striatum and brainstem and in PC12 cells.
abstract: Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), glutathione (GSH), ascorbic acid (AA), dehydroascorbic acid (DHAA) and uric acid (UA) were determined in the striatum and/or in the brainstem of 3-month-old male Wistar rats after subchronic oral exposure to MnCl2 (20 mg kg-1 daily) alone or associated to buthionine (S,R)sulphoximine-ethyl ester (BSO-E), an inhibitor of GSH synthesis. The NA, DA, DOPAC, GSH and glutathione disulphide (GSSG) concentrations were also determined in PC12 cells incubated with Mn alone or associated with either BSO-E or AA. When PC12 cells were incubated with AA, cellular AA and DHAA concentrations were also determined. It was found that BSO-E: (a) decreased GSH levels in the striatum and in the brainstem; (b) potentiated the Mn-induced increase in AA oxidation and uric acid formation in both brain regions; and (c) potentiated the Mn-induced DA and NA depletion in the brainstem. Moreover, the changes in striatal DA metabolism induced by the BSO-E association with Mn (decrease in DA, DOPAC and HVA levels and in the DOPAC + HVA/DA ratio) are consistent with the hypothesis of a loss of dopaminergic neurons. In PC12 cells, BSO-E decreased GSH and GSSG levels and potentiated the Mn-induced decrease-in DA and NA concentrations. On the contrary, AA antagonised the Mn-induced DA and NA depletion. AA antagonised also the Mn- and MN+ BSO-induced decrease in PC12 cells viability. In conclusion, the impairment of neuronal antioxidant system activity plays a permissive role in the oxidative stress-mediated Mn neurotoxicity.
authors.affiliation: Institute of Pharmacology, University of Sassari, Italy.
authors.forename: M S
authors.initials: MS
authors.lastname: Desole
authors.forename: G
authors.initials: G
authors.lastname: Esposito
authors.forename: R
authors.initials: R
authors.lastname: Migheli
authors.forename: S
authors.initials: S
authors.lastname: Sircana
authors.forename: M R
authors.initials: MR
authors.lastname: Delogu
authors.forename: L
authors.initials: L
authors.lastname: Fresu
authors.forename: M
authors.initials: M
authors.lastname: Miele
authors.forename: G
authors.initials: G
authors.lastname: de Natale
authors.forename: E
authors.initials: E
authors.lastname: Miele
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D005978:Glutathione / Q000172:deficiency*; D008297:Male; D017895:Manganese Compounds; D020149:Manganese Poisoning; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; C065566:buthionine sulfoximine ethyl ester; D008717:Methionine Sulfoximine; D005978:Glutathione; D001205:Ascorbic Acid; C025340:manganese chloride; D004298:Dopamine