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