TY - JOUR
T1 - Glutathione deficiency potentiates manganese toxicity in rat striatum and brainstem and in PC12 cells
AU - Desole, Maria S.
AU - Esposito, Giovanni
AU - Migheli, Rossana
AU - Sircana, Sara
AU - Delogu, Maria R.
AU - Fresu, Luigia
AU - Miele, Maddalena
AU - De Natale, Guglielmo
AU - Miele, Egidio
N1 - Funding Information:
The research was supported by MURST (ex 40% quota, Targeted Project ‘New Assessment Approaches in Toxicology’ 1996 and 60% quota, 1996). We are grateful to Prof. G. Grella for synthesis of BS0-E.
PY - 1997/10
Y1 - 1997/10
N2 - 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.
AB - 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.
KW - Brainstem
KW - Glutathione synthesis inhibition
KW - Manganese neurotoxicity
KW - Oxidative stress
KW - PC12 cells
KW - Striatum
UR - http://www.scopus.com/inward/record.url?scp=0031257743&partnerID=8YFLogxK
U2 - 10.1006/phrs.1997.0197
DO - 10.1006/phrs.1997.0197
M3 - Article
SN - 1043-6618
VL - 36
SP - 285
EP - 292
JO - Pharmacological Research
JF - Pharmacological Research
IS - 4
ER -