Elsevier

NeuroToxicology

Volume 25, Issues 1–2, January 2004, Pages 101-115
NeuroToxicology

Neurotoxicity of MAO Metabolites of Catecholamine Neurotransmitters: Role in Neurodegenerative Diseases

https://doi.org/10.1016/S0161-813X(03)00090-1Get rights and content

Abstract

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.

Section snippets

INTRODUCTION

3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL) are the products of the action of monamine oxidase (MAO) on catecholamines (CA). There are three major CA in human tissues: norepinephrine (NE), epinephrine (EPI), and dopamine (DA). All three are central neurotransmitters and, in addition, NE is released by peripheral sympathetic nerves onto blood vessels and both NE and EPI are hormones secreted by the adrenal medulla. In the brain, the nerve cell bodies

SYNTHESIS AND CHEMISTRY OF DOPEGAL AND DOPAL

A number of early studies used MAO to synthesize DOPEGAL enzymatically (Davis et al., 1979; Duncan, 1975, Duncan and Sourkes, 1974, Leeper et al., 1958, Renson et al., 1964). A variety of purification of procedures were used including aqueous/ether extraction or ion exchange with or without alumina chromatography. Methods to identify it included paper chromatography and colorimetric reaction with 2,3-dinitrophenylhydrazine. These procedures did not produce a sufficient quantity of chemically

In Vitro Toxicity

Blashko predicted the toxicity of aldehydes derived from MAO action on amines based on their chemical reactivity (Blashko, 1952). Our synthesis of chemically pure DOPEGAL (Li et al., 1994) and DOPAL (Li et al., 1998) allowed us to test Blashko’s longstanding hypothesis. We showed that DOPEGAL is selectively toxic to PC-12 cells in tissue culture, a model for CA neurons. DOPEGAL, but not NE or its oxidative or methylated metabolies, kills PC-12 cells in a time and dose-dependent manner with

MECHANISM OF TOXICITY

As described under toxicity, we showed that the cellular mechanism of death produced by CA aldehydes includes apoptosis both in vitro and in vivo. However, these findings do not exclude the possibility that at higher concentrations aldehydes may induce necrosis or intermediate forms of cell death. In fact, some of the mitochondrial mechanisms involved in apoptosis may also be activated in necrosis. In this section, we discuss subcellular and chemical mechanisms which underlie toxicity of

Alzheimer’s Disease

Clinical symptoms in degenerative diseases are due to loss of specific subsets of neurons. Both NE neurons in the locus ceruleus (Bondareff et al., 1982) and EPI neurons in the C-1 area of RVLM (Burke et al., 1990a, Burke et al., 1994a) undergo degeneration in AD. Alterations in attention, sleep, mood, behavior and blood pressure regulation in AD (Bondareff et al., 1982, Burke et al., 1994b) are likely due, in part, to loss of these CA neurons. Neurons in AD appear to die by apoptosis (Lassman

POTENTIAL THERAPEUTIC TARGETS IN ALZHEIMER’S AND PARKINSON’S DISEASE

Drug therapy has two goals in AD and PD. The first goal is neurotransmitter replacement which in AD is provided by acetylcholinesterase inhibitors and in PD by l-DOPA. A more recent goal is to halt the progression of these diseases by preventing neuron loss. This latter goal is the topic of this section.

Acknowledgements

This work was supported by grants from the Veterans Affairs Research Program (WJB); the Missouri Alzheimer’s and Related Disorders Board (WJB); the National Institute on Aging AG 15354 (BSK) and AG 14390 (BSK); the National Institutes of Health NS 23805 (DSZ) and NS 36363 (DAR).

References (91)

  • J Busciglio et al.

    B-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding

    Neuron

    (1995)
  • V.E Davis et al.

    Alteration of norepinephrine metabolism by barbiturates

    Biochem. Pharmacol.

    (1974)
  • F Filloux et al.

    Pre- and postsynaptic neurotoxic effects of dopamine demonstrated by intrastriatal injection

    Exp. Neurol.

    (1993)
  • F Fornai et al.

    Modulation of dihydroxyphenylacetaldehyde extracellular levels in vivo in the rat striatum after different kinds of pharmacological treatment

    Brain Res.

    (2000)
  • B Halliwell et al.

    Hydroxylation of salicylate as an assay for hydroxyl radicals: a cautionary note

    Free Radic. Biol. Med.

    (1991)
  • M Hashimoto et al.

    Role of cytochrome C as a stimulator of alpha-synuclein aggregation in Lewy body disease

    J. Biol. Chem.

    (1999)
  • K Iqbal et al.

    Defective microtubule assembly in Alzheimer’s disease

    Lancet

    (1986)
  • B.S Kristal et al.

    4-Hydroxyenal is a potent inducer of the mitochondrial permeability transition

    J. Biol. Chem.

    (1996)
  • B.S Kristal et al.

    Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria

    Free Radic. Biol. Med.

    (2001)
  • I Lamensdorf et al.

    3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC 12 cells

    Brain Res.

    (2000)
  • H.J Lee et al.

    Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors

    J. Biol. Chem.

    (2002)
  • L Leeper et al.

    Studies on the metabolism of norepinephrine, epi nephrine and their O-methyl analogs by partially purified enzyme preparations

    Arch. Biochem. Biophys.

    (1958)
  • S.W Li et al.

    Synthesis of a biochemically important aldehyde, 3,4-dihydroxyphenylglycolaldehyde

    Bioorg. Chem.

    (1994)
  • S.W Li et al.

    Synthesis of a biochemically important aldehyde, 3,4-dihydroxyphenylacetaldehyde

    Bioorg. Chem.

    (1998)
  • J Liu et al.

    Monoamine metabolism provides an antioxidant defense in brain against oxidant-and free radical-induced damage

    Arch. Biochem. Biophys.

    (1993)
  • M.B Mattammal et al.

    Confirmation of a dopamine metabolite in Parkinsonian brain tissue by gas chromatography-mass spectrometry

    J. Chromatogr.

    (1993)
  • J.H Robbins

    Preparation and properties of p-hydroxyphenylacetaldehyde and 3-methoxy-4-hydroxyphenylacetaldehyde

    Arch. Biochem. Biophys.

    (1966)
  • D.A Stoyanovsky et al.

    ESR and HPLC-EC of ethanol oxidation to 1-hydroxyethylradical: rapid reduction and quantification of PDBN and PBN nitroxides

    Free Radic. Biol. Med.

    (1998)
  • W.J Strittmatter et al.

    Hypothesis: microtubule instability and paired helical filament formation in Alzheimer disease brain are related to apoliporotein E genotype

    Exp. Neurol.

    (1994)
  • O Tottmar

    Assay of brain aldehyde dehydrogenase activity using high-performance liquid chromatography with electrochemical detection

    Anal. Biochem.

    (1986)
  • S Turnbull et al.

    Alpha-synuclein implicated Parkinson’s disease catalyzes the formation of hydrogen peroxide in vitro

    Free Radic. Biol. Med.

    (2001)
  • J.C Adair et al.

    Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease

    Neurology

    (2001)
  • R Betarbet et al.

    Chronic systemic pesticide exposure reproduces features of Parkinson’s disease

    Nat. Neurosci.

    (2000)
  • W Bondareff et al.

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

    Neurology

    (1982)
  • H Blashko

    Amine oxidase and amine metabolism

    Pharmacol. Rev.

    (1952)
  • H Blashko et al.

    Oxidation of adrenaline and noradrenaline by amine oxidase

    J. Phyisol.

    (1951)
  • W.J Burke et al.

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

    J. Am. Geriatr. Soc.

    (1990)
  • Burke WJ, Chung HD, Marshall GL, Park DH, Joh TH, Commins DL, et al. Defective axonal transport: a mechanism in the...
  • W.J Burke et al.

    Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells

    Life Sci.

    (1994)
  • Burke WJ, Li SW, Schmitt CA, Zahm DS, Chung HD, Conway AD, et al. Catecholamine-derived aldehyde neurotoxins. In:...
  • W.J Burke et al.

    The mechanism of DOPEGAL neurotoxicity: implications for loss of adrenergic neurons in Alzheimer’s disease

    Neurology

    (2000)
  • Burke WJ, Li SW, Williams EA, Zahm DS. 3,4-Dihydroxyphenylacetaldehyde is toxic to dopamine neurons in vivo:...
  • A Colzi et al.

    Identification and determination of 3,4-dihydroxyphenylacetaldehyde, the dopamine metabolite, in in vivo dialysate from rat striatum

    J. Neurochem.

    (1996)
  • K.A Conway et al.

    Kinetic stabilization of the α-synuclein adduct

    Science

    (2001)
  • V.E Davis et al.

    Augmentation of alkaloid formation from dopamine by alcohol and acetaldehyde in vitro

    J. Pharmacol. Exp. Therap.

    (1970)
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