3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein.

Lewy body diseases such as Parkinson's disease involve intraneuronal deposition of the protein α-synuclein (AS) and depletion of nigrostriatal dopamine (DA). Interactions of AS with DA oxidation products may link these neurohistopathologic and neurochemical abnormalities via two potential pathways: spontaneous oxidation of DA to dopamine-quinone and enzymatic oxidation of DA catalyzed by monoamine oxidase to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-Q. We compared these two pathways in terms of the ability of DA and DOPAL to modify AS. DOPAL was far more potent than DA both in oligomerizing and forming quinone-protein adducts with (quinonizing) AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by antioxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intracellular quinoproteins that were visualized by near-infrared spectroscopy. We conclude that of the two routes by which oxidation of DA modifies AS and other proteins the route via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation. SIGNIFICANCE STATEMENT: Interactions of the protein α-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson disease: Lewy bodies (which contain abundant AS) and nigrostriatal DA depletion (which produces the characteristic movement disorder). Of the two potential routes by which DA oxidation may alter AS and other proteins, the route via the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPAL-induced protein modifications.

1-Methyl-1,2,3,4-tetrahydroisoquinoline - The toxicological research on an exo/endogenous amine with antidepressant-like activity - In vivo, in vitro and in silico studies.

BACKGROUND: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) demonstrates significant neuroprotective activity. It can interact with agonistic conformation of dopamine (DA) receptors. 1MeTIQ inhibits the formation of 3,4-dihydroxyphenylacetic acid as well as production of free radicals and shifts DA catabolism toward COMT-dependent O-methylation. 1MeTIQ inhibits both MAO-A and B enzymes activity and increases neurotransmitters levels in the brain. It shows significant antidepressant-like effect in forced swim test (FST) in rats. This compound might be effective for depression therapy in a clinical setting but its success is determined not only by good efficacy, but also by an acceptable its ADMET profile. The use of combination in silico prediction with in vivoand in vitro studies greatly simplifies the search for new, safer and effectively acting drugs. METHODS: The aim of this study was to investigate the degree of histopathological changes in different rats tissues after acute and chronic administration of 1MeTIQ. Additionally, prediction of its properties in terms of absorption, distribution, metabolism, elimination and toxicity in the human body was performed. RESULTS: The obtained data did not show extensive and significant toxic effects of tested substance in in vivo and in vitro studies in rats, and in silico ADMET prediction. CONCLUSIONS: These results can help to discover a new effective and safe antidepressant substance and have important significance in the treatment of depression in clinic. Additionally, the use in the treatment of depression substance with neuroprotective, antioxidant and antidepressant-like effects in the CNS and existing endogenously might be also beneficial in controlling the adverse CNS inflammatory processes accompanying depression.

3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells.

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative deamination of dopamine. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs). In a previous study, we found that rotenone, a complex I inhibitor, induced a rapid accumulation of DOPAL and DOPET in the medium of cultured PC12 cells. Here, we examined the potential role of DOPAL in the toxicity induced by complex I inhibition in PC12 cells and compared the effects of rotenone on concentrations of DOPAL and DOPET to those of MPP(+). DOPAL and DOPET levels were increased by rotenone but decreased by MPP(+). Inhibition of ALDH by daidzein reduced the formation of DOPAC and increased the accumulation of DOPAL. Inhibition of ARs (with AL1576) diminished DOPET formation and elevated DOPAL concentrations. Combined inhibition of ALDH and ARs markedly elevated DOPAL concentrations while diminishing DOPET and DOPAC levels. The elevation of DOPAL levels induced by combined inhibition of ALDH and ARs had no effect on cell viability. However, combined inhibition of ALDH and ARs potentiated rotenone-induced toxicity. Both the potentiation of toxicity and the increase in DOPAL levels were blocked by inhibition of monoamine oxidase with clorgyline indicating that accumulation of DOPAL was responsible for the potentiated rotenone-induced toxicity following combined inhibition of ALDH and ARs. Since complex I dysfunction is reported to be involved in the pathogenesis of Parkinson's disease, DOPAL potentiation of the deleterious effects of complex I inhibition may contribute to the specific vulnerability of dopaminergic neurons to injury.