Biochemical and toxicological properties of the oxidation products of catecholamines

Bindoli, Alberto; Rigobello, Maria Pia; Deeble, David J.

doi:10.1016/0891-5849(92)90182-g

Cited by 260 publications

(207 citation statements)

References 137 publications

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“…Although further research is clearly warranted and alternative explanations are available, considering the fact that DA is easily oxidized (Bindoli et al, 1992), it is tempting to propose a mechanism in which GSH is used to protect susceptible parts of the transport system against the potentially toxic interaction with DA oxidation products during DA uptake. Apparently, during this process GSH is transformed into a compound, for instance, a glutathionyl conjugate (Nappi and Vass, 1994), which escapes detection by our enzyme recycling method, which is rather specific for GSH and GSSG (Redegeld et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Glutathione Is Involved in the Granular Storage of Dopamine in Rat PC12 Pheochromocytoma Cells: Implications for the Pathogenesis of Parkinson’s Disease

Drukarch¹,

Jongenelen²,

Schepens³

et al. 1996

J. Neurosci.

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Parkinson's disease (PD) is characterized by degeneration of dopamine (DA)-containing nigro-striatal neurons. Loss of the antioxidant glutathione (GSH) has been implicated in the pathogenesis of PD. Previously, we showed that the oxidant hydrogen peroxide inhibits vesicular uptake of DA in nigro-striatal neurons. Hydrogen peroxide is scavenged by GSH and, therefore, we investigated a possible link between the process of vesicular storage of DA and GSH metabolism. For this purpose, we used rat pheochromocytoma-derived PC12 cells, a model system applied extensively for studying monoamine storage mechanisms. We show that depletion of endogenous DA stores with reserpine was accompanied in PC12 cells by a longlasting, significant increase in GSH content the extent of which appeared to be inversely related to the rate of GSH synthesis. A similar increase in GSH content was observed after depletion of DA stores with the tyrosine hydroxylase inhibitor ␣-methylp-tyrosine. In the presence of ␣-methyl-p-tyrosine, refilling of the DA stores by exogenous DA reduced GSH content back to control level. Lowering of PC12 GSH content, via blockade of its synthesis with buthionine sulfoximine, however, led to a significantly decreased accumulation of exogenous [ 3 H]DA without affecting uptake of the acetylcholine precursor [ 14 C]choline. These data suggest that GSH is involved in the granular storage of DA in PC12 cells and that, considering the molecular characteristics of the granular transport system, it is likely that GSH is used to protect susceptible parts of this system against (possibly DA-induced) oxidative damage. Key words: Parkinson's disease; oxidative stress; glutathione; dopamine; PC12 cells; neurotransmitter uptake; vesicular storageParkinson's disease (PD) is characterized primarily by a loss of dopamine (DA) in the striatum caused by degeneration of DAergic neurons in the zona compacta of the substantia nigra (SN) (Gibb and Lees, 1991). Although the cause of PD is still unknown, oxidative stress has been implicated as a pathogenetic factor. According to this so called "free radical hypothesis," the degeneration of the nigro-striatal system in PD is related to the relatively high exposure of these neurons to reactive oxygen species (ROS), in particular hydrogen peroxide (H 2 O 2 ), produced during both the enzymatic (monoamine oxidase-catalyzed) and nonenzymatic (auto-oxidative) breakdown of DA (Adams and Odunze, 1991;Olanow, 1992). Thus, DAergic cell death in PD may be caused by an overproduction of ROS and/or a diminished protection against them. Evidence to support the "free radical hypothesis" has come from postmortem investigations of PD brains, which consistently show an increase in the indices of oxidative stress in the SN at the time of death (Hirsch et al., 1991;Jenner, 1993). One of these indices, possibly even preceding the loss of DA (Dexter et al., 1994), is a decrease in the level of glutathione (GSH) in the Parkinsonian SN (Riederer et al., 1989;Sofic et al., 1992;Jenner, 1993). GSH, the most abund...

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Section: Discussionmentioning

confidence: 99%

Glutathione Is Involved in the Granular Storage of Dopamine in Rat PC12 Pheochromocytoma Cells: Implications for the Pathogenesis of Parkinson’s Disease

Drukarch¹,

Jongenelen²,

Schepens³

et al. 1996

J. Neurosci.

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“…The oxidation products of catecholamines have been known for some time to cause damage to myocardial tissue (Yates and Dhalla 1975;Dhalla et al 1978) although it is not known if they are more or less harmful than adrenaline itself (Bindoli et al 1992;Behonick et al 2001). It has been demonstrated that oxidation of catecholamines is partially responsible for the increased levels of free radicals observed during ischaemia.…”

Section: Oxidation Of Catecholaminesmentioning

confidence: 99%

Vasopressors for cardiopulmonary resuscitation

Penson

Ford

Broadley

2007

Pharmacology & Therapeutics

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“…Apomorphine displays antiparkinsonian properties similar to those of L-DOPA and has been shown to be useful for treating PD patients, especially in the late stages of the disease (12)(13)(14). Increasing evidence suggests that some of the effects of dopamine and dopamine receptor agonists might be mediated by their quinone and semiquinone oxidation derivatives (15)(16)(17)(18)(19). Dopamine's oxidation derivatives such as dopamine o-quinone and o-semiquinone occur in the normal brain (20).…”

Section: Introductionmentioning

confidence: 99%

“…Dopamine's oxidation derivatives such as dopamine o-quinone and o-semiquinone occur in the normal brain (20). Dopamine, apomorphine, and L-DOPA easily autoxidize, producing quinone and semiquinone derivatives that may lead to the formation of toxic products and superoxide radicals (15)(16)(17)(18)(19). The oxidation-related properties of apomorphine lead to apparently paradoxical activities of the drug, which may act either as an antioxidant or as a prooxidant (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 99%

“…Since increasing evidence suggests that some of the neuronal effects of dopamine, L-DOPA, and apomorphine are mediated by their oxidation derivatives (16,19), we propose that the investigation of the neurobiological actions of isolated oxidation derivatives of apomorphine is clinically relevant and might help to elucidate the mechanisms involved in oxidative stress-mediated neuronal damage in schizophrenia (18), neurodegeneration associated with PD, and the effects of dopaminergic therapies in PD patients. We described the isolation of an apomorphine autoxidation semiquinone derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), and demonstrated for the first time its mutagenic activity in vitro (24,25).…”

Section: Introductionmentioning

confidence: 99%

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Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

Picada

Roesler

Henriques

2005

Braz J Med Biol Res

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Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/ microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation) in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites. Correspondence

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Biochemical and toxicological properties of the oxidation products of catecholamines

Cited by 260 publications

References 137 publications

Glutathione Is Involved in the Granular Storage of Dopamine in Rat PC12 Pheochromocytoma Cells: Implications for the Pathogenesis of Parkinson’s Disease

Glutathione Is Involved in the Granular Storage of Dopamine in Rat PC12 Pheochromocytoma Cells: Implications for the Pathogenesis of Parkinson’s Disease

Vasopressors for cardiopulmonary resuscitation

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

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