The possible role of one-electron reduction of aminochrome in the neurodegenerative process of the dopaminergic system

Abstract

We present for discussion a possible molecular mechanism explaining the formation of reactive oxygen species involved in the neurodegenerative process of dopaminergic system in Parkinson's disease. This new hypothesis involves one-electron reduction of aminochrome to o-semiquinone radical, which seems to be the reaction responsible for neurodegenerative process of dopaminergic system. Leukoaminochrome o-semiquinone is extremely reactive with oxygen, which reoxidizes by reducing oxygen to superoxide radicals. Superoxide radicals enzymatically or spontaneously dismutate to dioxygen and hydrogen peroxide which is a precursor of hydroxyl radicals. ESR-experiments have showed that aminochrome o-semiquinone is extremely reactive in the presence of oxygen compared to dopamine o-semiquinone. In addition, the antioxidant enzymes superoxide dismutase and catalase play a prooxidant role by increasing the autoxidation rate and formation of superoxide radicals. One electron reduction of aminochrome to o-semiquinone can be performed by flavoenzymes which use NADPH and NADH as electron donator. The ability of aminochrome o-semiquinone to autoxidize in the presence of oxygen gives rise to a redox cycling process which will continue until oxygen, NADH and/or NADPH are depleted. Depletion of NADPH will prevent glutathione reductase from reducing glutathione, which is one of the main antioxidants in the cell. In addition depletion of NADH will prevent the formation of ATP in the electron transport chain in the mitochondria. Two antioxidants, probably, neuroprotective reactions are also discussed.

Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat

“…In agreement, it has been reported that reserpine, but not a-methyl-p-tyrosine, enhances the longlasting DA depletion induced by Meth (Wagner et al 1983), and that Meth produces a redistribution from vesicular to cytosolic DA pools (Sulzer et al 1995;Frey et al 1997; Effect of methamphetamine on basal ganglia neurotransmission 651 Brown et al 2000). This results in an increase of cytosolic DA metabolism, which has been suggested to be neurotoxic via formation of free-radicals (see Sulzer and Zecca 2000), and/or o-semiquinone-radical species from aminochrome (Segura-Aguilar et al 2001). Under normal conditions DT-diaphorase, an enzyme present in DA neurones (Schultzberg et al 1988), prevents the auto-oxidation and the redox cycling process produced during aminochrome metabolism (see Segura-Aguilar et al 2001).…”

“…This results in an increase of cytosolic DA metabolism, which has been suggested to be neurotoxic via formation of free-radicals (see Sulzer and Zecca 2000), and/or o-semiquinone-radical species from aminochrome (Segura-Aguilar et al 2001). Under normal conditions DT-diaphorase, an enzyme present in DA neurones (Schultzberg et al 1988), prevents the auto-oxidation and the redox cycling process produced during aminochrome metabolism (see Segura-Aguilar et al 2001). Thus, it is tempting to hypothesize that Meth might not only inhibit MAO, but also DT-diaphorase, supporting the hypothesis of increased formation of DA-derived reactive species in Meth toxicity (Cadet et al 1994;Culbells et al 1994).…”

A new approach to studying the autoxidation of adrenaline: possibility of the determination of superoxide dismutase activity and the antioxidant properties of various preparations by polarography

“…Известна кардио-и нейротоксичность продуктов окисления катехоламинов [2,9,[14][15][16][17][22][23][24]. Предполагается, что кардиотоксичность адреналина обусловлена не только адренохромом, но и в большей степени АФК, образующимися в процессе окисления адреналина [14].…”

“…Они известны также как адреномиметики, обладающие галлюциногенными свойствами [25]. Участие аминохромов обсуждается и в этиологии болезни Паркинсона [23,24]. Выявлена интересная особенность: больные шизофренией практически не имеют онкологических заболеваний [26].…”

MPP+-induced degeneration is potentiated by dicoumarol in cultures of the RCSN-3 dopaminergic cell line. Implications of neuromelanin in oxidative metabolism of dopamine neurotoxicity

“…In addition, the antioxidant enzymes, superoxide dismutase and catalase, have been reported to play a prooxidant role during one-electron reduction of aminochrome by increasing the autoxidation rate of leukoaminochrome o-semiquinone radical (Baez et al, 1995). Under normal conditions, the potential ability of aminochrome to induce neurotoxicity during its oneelectron reduction is prevented by DT-diaphorase (Segura-Aguilar andLind, 1989;Baez et al, 1995;Paris et al, 2001;Segura-Aguilar et al, 2001). This is further supported by the fact that the presence of a polymorphism in base 609 (C'T), which yields an inactive form of DT-diaphorase, increases the risk of developing PD by 3.8-fold (Shao et al, 2001).…”