Manganese increases L-DOPA auto-oxidation in the striatum of the freely moving rat: potential implications to L-DOPA long-term therapy of Parkinson's disease.
We have previously shown that manganese enhances L-dihydroxyphenylanine (L-DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing effect [an increase in L-DOPA and dopamine (DA) auto-oxidation] was studied using microdialysis in the striatum of freely moving rats. Systemic L-DOPA [25 mg kg(-1) intraperitoneally (i.p.) twice in a 12 h interval] significantly increased baseline dialysate concentrations of L-DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were significantly decreased. A L-DOPA oxidation product, presumptively identified as L-DOPA semiquinone, was detected in the dialysate. The L-DOPA semiquinone was detected also following intrastriatal infusion of L-DOPA. In rats given L-DOPA i.p. , intrastriatal infusion of N-acetylcysteine (NAC) significantly increased DA and L-DOPA dialysate concentrations and lowered those of L-DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations. In rats given L-DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L-DOPA dialysate concentrations and greatly increased those of L-DOPA semiquinone. These changes were inhibited by NAC infusion. These findings demonstrate that auto-oxidation of exogenous L-DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L-DOPA auto-oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L-DOPA long-term therapy of Parkinson's disease.
Serra
P A
PA
Department of Pharmacology, University of Sassari, Viale S.Pietro 43B, 07100 Sassari, Italy.
Esposito
G
G
Enrico
P
P
Mura
M A
MA
Migheli
R
R
Delogu
M R
MR
Miele
M
M
Desole
M S
MS
Grella
G
G
Miele
E
E
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D015314:Dialysis Solutions / Q000737:chemistry; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007260:Infusion Pumps; D007980:Levodopa / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D017895:Manganese Compounds / Q000494:pharmacology; D017551:Microdialysis; D009068:Movement; D010084:Oxidation-Reduction / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014527:Uric Acid / Q000378:metabolism
D002712:Chlorides; D015314:Dialysis Solutions; D017895:Manganese Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D014527:Uric Acid; D008345:Manganese; D007980:Levodopa; D001205:Ascorbic Acid; C025340:manganese chloride; D004298:Dopamine; D000111:Acetylcysteine; D006719:Homovanillic Acid