Glutathione deficiency potentiates manganese-induced increases in compounds associated with high-energy phosphate degradation in discrete brain areas of young and aged rats.
Aging is a factor known to increase neuronal vulnerability to oxidative stress, which is widely accepted as a mechanism of manganese-induced neuronal damage. We previously showed that subchronic exposure to manganese induced greater energy impairment (as revealed by increases in hypoxanthine, xanthine and uric acid levels) in the striatum and brainstem of aged rats vs young rats. This study shows that inhibition of glutathione (GSH) synthesis, by means of buthionine (SR) sulfoximine, decreased GSH levels and increased the ascorbic acid oxidation status in the striatum and limbic forebrain of both young and aged rats. In addition, inhibition of GSH synthesis greatly potentiated the manganese-induced increase in inosine, hypoxanthine, xanthine and uric acid levels in both regions of aged rats; moreover, inhibition of GSH synthesis significantly increased inosine, hypoxanthine, xanthine and uric acid levels in both regions of young rats, compared with the manganese-treated group. These results suggest that an impairment in the neuronal antioxidant system renders young rats susceptible to manganese-induced energetic impairment, and further support the hypothesis that an impairment in this system plays a permissive role in the increase of neuronal vulnerability that occurs with aging.
Desole
M S
MS
Department of Pharmacology, Gynecology and Obstetrics, Faculty of Medicine, University of Sassari, UK. Pharmaco@ssmain.uniss.it
Serra
P A
PA
Esposito
G
G
Delogu
M R
MR
Migheli
R
R
Fresu
L
L
Rocchitta
G
G
Miele
M
M
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003683:Dehydroascorbic Acid / Q000378:metabolism; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D019271:Hypoxanthine / Q000378:metabolism; D007288:Inosine / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014527:Uric Acid / Q000378:metabolism; D019820:Xanthine / Q000378:metabolism
D000963:Antimetabolites; D010710:Phosphates; D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine; D008345:Manganese; D019328:Buthionine Sulfoximine; D007288:Inosine; D005978:Glutathione; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid