Norepinephrine transmitter metabolite induces apoptosis in differentiated rat pheochromocytoma cells

doi:10.1016/S0006-8993(97)00447-2

Brain Research

Volume 760, Issues 1–2, 20 June 1997, Pages 290-293

https://doi.org/10.1016/S0006-8993(97)00447-2 Get rights and content

Abstract

3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL) is the monoamine oxidase A metabolite of norepinephrine and epinephrine. DOPEGAL, but not other metabolites, kills differentiated PC-12 cells. However, the type of DOPEGAL induced cell death, whether necrosis or apoptosis, is not known. To determine the type of cell death triggered by DOPEGAL, PC-12 cells cultured in the presence or absence of 30 μM DOPEGAL were examined by electron microscopy and DNA agarose gel electrophoresis for characteristic features of apoptosis. Results indicate that DOPEGAL induces apoptosis in these cells. Implications for degenerative diseases are discussed.

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Acknowledgements

This work was supported by a grant from the Veterans Affairs Research Program.

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The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer’s disease (AD) and Parkinson’s disease (PD) and potential therapeutic targets in Alzheimer’s disease and Parkinson’s disease.
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Parkinson’s disease (PD) is a major cause of age-related morbidity and mortality, present in nearly 1% of individuals at ages 70–79 and ∼2.5% of individuals at age 85. L-DOPA (L-dihydroxyphenylalanine), which is metabolized to dopamine by dopa decarboxylase, is the primary therapy for PD, but may also contribute to disease progression. Association between mitochondrial dysfunction, monoamine oxidase (MAO) activity, and dopaminergic neurotoxicity has been repeatedly observed, but the mechanisms underlying selective dopaminergic neuron depletion in aging and neurodegenerative disorders remain unclear. We now report that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the MAO metabolite of dopamine, is more cytotoxic in neuronally differentiated PC12 cells than dopamine and several of its metabolites. In isolated, energetically compromised mitochondria, physiological concentrations of DOPAL induced the permeability transition (PT), a trigger for cell death. Dopamine was > 1000-fold less potent. PT inhibitors protected both mitochondria and cells against DOPAL. Sensitivity to DOPAL was reduced ≥ 30-fold in fully energized mitochondria, suggesting that mitochondrial respiration may increase resistance to PT induction by the endogenous DOPAL in the substantia nigra. These data provide a potential mechanism of action for L-DOPA-mediated neurotoxicity and suggest two potentially interactive mechanisms for the selective vulnerability of neurons exposed to dopamine.
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Citation Excerpt :
This mechanism is characterized by activation of mitochondrial PT by a free radical formed from DOPEGAL [10] or by the reactive aldehyde group of DOPEGAL itself as predicted by Blashko [4]. PT activation, in turn, releases cytochrome C [42] and other apoptosis-inducing factors which trigger a caspase cascade leading to apoptosis [9]. Coincidentally, the location of DOPEGAL synthesis, on the outer mitochondrial membrane in proximity to the PT pore on the inner membrane, makes DOPEGAL an ideal candidate for a neuronal death messenger.
3,4-Dihydroxyphenylglycolaldehyde is the monoamine oxidase-A metabolite of two catecholamine neurotransmitters, epinephrine and norepinephrine. This aldehyde metabolite and its synthesizing enzymes increase in cell bodies of catecholamine neurons in Alzheimer’s disease. To test the hypothesis that 3,4-dihydroxyphenylglycolaldehyde, but not epinephrine or its major metabolite 4-hydroxy-3-methoxyphenylglycol, is a neurotoxin, we injected 3,4-dihydroxyphenylglycolaldehyde onto adrenergic neurons in the rostral ventrolateral medulla. Injections of epinephrine or 4-hydroxy-3-methoxyphenylglycol were made into the same area of controls. A dose response and time study were performed. Adrenergic neurons were identified by their content of the epinephrine synthesizing enzyme, phenylethanolamine N-methyltransferase, immunohistochemically. Apoptosis was evaluated by in situ terminal deoxynucleotidyl-transferase mediated dUTP nick end label staining. Injection of 3,4-dihydroxyphenylglycolaldehyde in amounts as low as 50 ng results in loss of adrenergic neurons and apoptosis after 18 h. The degree of neurotoxicity is dose and time dependent. Doses of 3,4-dihydroxyphenylglycolaldehyde 10-fold higher produce necrosis. Neither epinephrine nor 4-hydroxy-3-methoxyphenylglycol are toxic. A 2.5 μg injection of 3,4-dihydroxyphenylglycolaldehyde is toxic to cortical neurons but not glia. Active uptake of the catecholamine-derived aldehyde into differentiated PC-12 cells is demonstrated. Implications of these findings for catecholamine neuron death in neurodegenerative diseases are discussed.
17β-Estradiol protects lymphocytes against dopamine and iron-induced apoptosis by a genomic-independent mechanism - Implication in Parkinson's disease
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Dopamine (DA) in combination with iron (Fe²⁺) has been demonstrated to induce apoptosis in neuronal-like PC12 cells by an oxidative stress mechanism. To get a better insight of cell death and protective mechanisms in DA/Fe²⁺-induced toxicity, we investigated the effects of DA/Fe²⁺ and the antioxidant action of 17β-estradiol (E2) in peripheral blood lymphocytes (PBL). We found that DA/Fe²⁺-induces apoptosis in PBL via a hydrogen peroxide (H₂O₂)-mediated oxidative mechanism, which in turn triggers a cascade of molecular events requiring RNA and de novo protein synthesis. We have also demonstrated that E2 prevents significantly DA/Fe²⁺-induced apoptosis in PBL by directly inhibiting the intracellular accumulation of peroxides generated by DA/Fe²⁺-reaction. This protective activity is independent of the presence or activation of the estrogen receptors (ERs). These data further support and validate our previous hypothesis that DA/Fe²⁺/H₂O₂ could be a general mediator of oxidative stress through a common cell death mechanism in both neuronal and nonneuronal cells. These findings may be particularly relevant to the potential approaches to rescue and prolong the survival of neurons by estrogens in patients with Parkinson's disease (PD).
Quantitation of 3,4-dihydroxyphenylacetaldehyde and 3,4- dihydroxyphenylglycolaldehyde, the monoamine oxidase metabolites of dopamine and noradrenaline, in human tissues by microcolumn high-performance liquid chromatography
1999, Analytical Biochemistry
We recently described the chemical synthesis of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde, the monamine oxidase metabolites of dopamine and noradrenaline, respectively. We demonstrated the neurotoxicity of these compounds. Catecholamine nerve cells which synthesize these aldehydes die in degenerative brain diseases, such as Parkinson's and Alzheimer's. Here we describe a sensitive method for separating these catecholaldehydes from catecholamines and their other oxidative and methylated metabolites by microcolumn high-performance liquid chromatography with electrochemical detection. We then quantitate catecholamines and their major metabolites in human brain, plasma, and urine. The method can be used to determine the role of these catecholaldehydes in human disease.

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Short communicationNorepinephrine transmitter metabolite induces apoptosis in differentiated rat pheochromocytoma cells

Abstract

Section snippets

Acknowledgements

Neuron

Anal. Biochem.

Brain Res.

Brain Res.

Anal. Biochem.

Brain Res.

Bioorg. Chem.

Exp. Neurol.

Neuroscience

Catecholaminergic neurons in the ventrolateral medulla and nucleus of the solitary tract in the human

J. Comp. Neurol.

The relation of programmed cell death to development and reproduction: comparative studies and an attempt at classification

Int. Rev. Cytol.

Amine oxidase and amine metabolism

Pharmac. Rev.

Loss of neurons of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia

Neurology

Evidence for decreased transport of PNMT protein in advanced Alzheimer's disease

J. Am. Geriatr. Soc.

Short communication
Norepinephrine transmitter metabolite induces apoptosis in differentiated rat pheochromocytoma cells