Products of Oxidative Stress Inhibit Aldehyde Oxidation and Reduction Pathways in Dopamine Catabolism Yielding Elevated Levels of a Reactive Intermediate

Abstract

Dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration as observed for Parkinson’s disease (PD). In addition, oxidative stress and lipid peroxidation are hypothesized culprits in PD pathogenesis. DA undergoes catabolism by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). As a minor and compensatory metabolic pathway, DOPAL can be reduced to 3,4-dihydroxyphenylethanol (DOPET) via cytosolic aldehyde or aldose reductase (AR). Previous studies have found DOPAL to be significantly more toxic to DA cells than DA and that the major lipid peroxidation products, i.e. 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit DOPAL oxidation via ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the toxic aldehyde intermediate. To test this hypothesis, nerve-growth factor differentiated PC6-3 cells were used as a model for DA neurons. Cell viability in the presence of 4HNE and MDA (2-100 μM) was measured by MTT assay and it was found that only 100 μM 4HNE exhibited significant cytotoxicity. Treatment of cells with varying concentrations of 4HNE and MDA resulted in reduced DOPAC production and significant elevation of DOPAL levels, suggesting inhibition of ALDH. In cells treated with 4HNE that exhibited elevated DOPAL, there was a significant increase in DOPET. However, elevated DOPET was not observed for the cells treated with MDA, suggesting MDA to be an inhibitor of AR. Using isolated cytosolic AR, it was found that MDA but not 4HNE inhibited reductase activity toward DOPAL, surprisingly. These data demonstrate that the oxidative stress products 4HNE and MDA inhibit the aldehyde biotransformation step of DA catabolism yielding elevated levels of the endogenous neurotoxin DOPAL, which may link oxidative stress to selective neurodegeneration as seen in PD.

Mentha piperita as a pivotal neuro-protective agent against gamma irradiation induced DNA fragmentation and apoptosis

“…Moreover, various studies reported that the exposure to radiation induced oxidative damage in several organs (Bhatia and Manda 2004;Hassan et al 2010, Wang et al 2010) and mitochondrial membranes (Kamat et al 2000). Moreover, the oxidative stress linked to dopaminergic neurons damage might be owned to lipid peroxidation products 4-hydroxynonenal (4HNE) and malondialdehyde (MDA) which inhibit the aldehyde biotransformation step of DA catabolism to 3,4-dihydroxyphenylacetic acid (DOPAC) yielding elevated levels of the endogenous neurotoxin 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is more toxic to dopaminergic neurons than DA quinones (Jinsmaa et al 2009). …”

Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases

“…Lipid peroxidation products interfere with detoxification of DOPAL (39) by inhibiting aldehyde dehydrogenase and aldehyde reductase (40), stimulating a potentially deadly positive feedback loop. Consistent with a pathogenetic role of catecholaldehydes in Lewy body diseases, a recent postmortem study noted a high ratio of DOPAL/DA in the putamen of patients with end-stage PD (41).…”

Autonomic dysfunction in PD: A window to early detection?

“…Enzymatic deamination of monoamines generates hydrogen peroxide, which by way of reaction with metal ions produces toxic hydroxyl radicals. Moreover, lipid peroxidation products inhibit aldehyde dehydrogenase and aldose/ aldehyde reductase, interfering with the detoxification of the aldehydes [27]. Importantly, the aldehyde produced by enzymatic deamination of cytosolic dopamine, dihydroxyphenylacetaldehyde (DOPAL), potently oligomerizes alpha-synuclein in vitro and precipitates alpha-synuclein in catecholaminergic cells [28], possibly inducing destabilizing positive feedback loops.…”