Study on the ability of 1,2,3,4‐tetrahydropapaveroline to cause oxidative stress: Mechanisms and potential implications in relation to parkinson's disease

Abstract

Tetrahydropapaveroline (THP) is a compound derived from dopamine monoamine oxidase-mediated metabolism, particularly present in the brain of parkinsonian patients receiving L-dopa therapy, and is capable of causing dopaminergic neurodegeneration. The aim of this work was to evaluate the potential of THP to cause oxidative stress on mitochondrial preparations and to gain insight into the molecular mechanisms responsible for its neurotoxicity. Our data show that THP autoxidation occurs with a continuous generation of hydroxyl radicals (*OH) and without the involvement of the Fenton reaction. The presence of ascorbate enhances this process by establishing a redox cycle, which regenerates THP from its quinolic forms. It has been shown that the production of *OH is not affected by the presence of either ferrous or ferric iron. Although THP does not affect lipid peroxidation, it is capable of reducing the high levels of thiobarbituric acid-reactive substances obtained in the presence of ascorbate and/or iron. However, THP autoxidation in the presence of ascorbate causes both an increase in protein carbonyl content and a reduction in protein-free thiol content. THP also increases protein carbonyl content when the autoxidation occurs in the presence of iron. The remarkable role played by ascorbate in the production of oxidative stress by THP autoxidation is of particular interest.

Tetrahydropapaveroline, an Endogenous Dicatechol Isoquinoline Neurotoxin

“…Although minute amounts of THP are likely to be present in normal brain, easy detection of the compound in parkinsonian patients receiving L-DOPA medication and experimental animals treated with L-DOPA seems to be a consequence of the high levels of dopamine derived from its prodrug [4]. Under such circumstances, excess dopamine may inhibit aldehyde dehydrogenase [18], thereby blocking the conversion of 3,4-dihydroxyphenylacetaldehyde into 3,4-dihydroxyphenylacetic acid.…”

“…Under such circumstances, excess dopamine may inhibit aldehyde dehydrogenase [18], thereby blocking the conversion of 3,4-dihydroxyphenylacetaldehyde into 3,4-dihydroxyphenylacetic acid. The resulting accumulation of a relatively high concentration of 3,4-dihydroxyphenylacetaldehyde, together with the high levels of dopamine derived from L-DOPA administration, may favor the formation of THP [4]. 30 (3,4-dihydroxyphenylacetaldehyde) produced by monoamine oxidase (MAO) yields racemic THP, (S)-enantiomer is predominantly found in the brain of man, suggesting the occurrence of enzymatic synthesis.…”

“…MPTP is converted by MAO to the 1-methyl-4-phenyl-pyridinium ion (MPP + ), which is capable of selectively killing the nigrostriatal dopaminergic neurons [6]. Endogenous isoquinoline derivatives, structurally related to MPTP and its active metabolite MPP + , have been found in the brain of patients with Parkinson's disease, and they are suspected to contribute, in part, to dopaminergic neurodegeneration in Parkinson's disease [1][2][3][4][5][6]22]. Among them, some THIQs and their N-methylated metabolites were identified in the brain of postmortem specimens of Parkinson's patients, and their levels were about 10 times higher than those in the normal brain [23].…”

“…THP is a potential dopaminergic neurotoxin that has been considered to contribute to the etiology of Parkinson's disease [3][4][5]. Though present in normal human brain, THP has been detected in a larger quantity in the brain [6] and urine [2,7] of parkinsonian patients undergoing 3,4-dihydroxyphenylalanine (L-DOPA) therapy [14].…”

Oxidative Modification of Neurofilament-L Induced by Endogenous Neurotoxin, Salsolinol

“…5). Protein carbonyls are generally detected at increased levels in both PD 24 and AD. 25 Oxidative modification of proteins by either the α-amidation pathway or oxidation of glutamyl side chains leads to formation of a peptide in which the N-terminal amino acid is blocked by an α-ketoacyl derivative.…”