title: Chronic high dose L-DOPA alone or in combination with the COMT inhibitor entacapone does not increase oxidative damage or impair the function of the nigro-striatal pathway in normal cynomologus monkeys.
abstract: Parkinson's disease (PD) is characterised by a loss of pigmented dopaminergic neurones in the zona compacta of substantia nigra. The mechanisms underlying nigral cell death remain unknown but may involve oxidative damage. There has been concern that L-DOPA treatment may accelerate nigral pathology in PD through chemical and enzymatic oxidation to reactive oxygen species. In the present study, we examined tissues from normal macaque monkeys treated for 13 weeks with high doses of L-DOPA (in combination with the peripheral decarboxylase inhibitor, carbidopa) and/or the COMT inhibitor, entacapone. Plasma was analysed for changes in protein carbonyls as a marker of oxidative damage to protein. Cortical tissue was examined for changes in levels of protein carbonyls, lipid peroxidation and oxidative damage to DNA. The integrity of the nigro-striatal pathway was assessed by nigral tyrosine hydroxylase mRNA levels and specific [(3)H]mazindol binding to dopaminergic terminals in caudate-putamen. No alterations in plasma protein carbonyls were observed in any treatment group. An increase was found in the levels of protein carbonyls, lipid peroxidation and 5-OH uracil, but not other products of oxidative DNA damage, in cerebral cortex of monkeys treated with L-DOPA plus carbidopa or with L-DOPA plus carbidopa and entacapone but this was only statistically significant in the latter group. There was no change in nigral tyrosine hydroxylase mRNA levels or specific striatal [(3)H]mazindol binding in brain tissue from monkeys treated with either L-DOPA plus carbidopa or L-DOPA plus carbidopa and entacapone. The results show that in the normal monkeys L-DOPA does not provoke marked oxidative damage even at high doses, and that there is little or no potentiation of its effects by entacapone. Neither L-DOPA plus carbidopa nor L-DOPA plus carbidopa and entacapone led to obvious damage to the nigro-striatal pathway.
authors.affiliation: Neurodegenerative Disease Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Lyras
authors.forename: B-Y
authors.initials: BY
authors.lastname: Zeng
authors.forename: G
authors.initials: G
authors.lastname: McKenzie
authors.forename: R K B
authors.initials: RK
authors.lastname: Pearce
authors.forename: B
authors.initials: B
authors.lastname: Halliwell
authors.forename: P
authors.initials: P
authors.lastname: Jenner
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D007980:Levodopa / Q000008:administration & dosage* / Q000494:pharmacology; D008252:Macaca fascicularis; D008454:Mazindol / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D012333:RNA, Messenger; D007980:Levodopa; C071192:entacapone; D008454:Mazindol; D014446:Tyrosine 3-Monooxygenase; D002230:Carbidopa