Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease

Abstract

The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.

Keywords: DOPAL; Parkinson’s disease; catecholaldehydes; monoaminoxidase inhibitor; n-acetylcysteine.

Figure 1

Concept diagram showing enzymatic steps in the synthesis, vesicular storage, release, reuptake, and metabolism of dopamine (DA) and norepinephrine (NE). DA is synthesized in the neuronal cytoplasmic via tyrosine hydroxylase (TH) acting on tyrosine to form DOPA and then L-aromatic-amino-acid decarboxylase (LAAAD) acting on DOPA. Most of cytoplasmic DA is taken up into vesicles via the vesicular monoamine transporter (VMAT), but a minority undergoes enzymatic oxidation catalyzed by monoamine oxidase (MAO) to form 3,4-dihydroxyphenylacetaldehyde (DOPAL). DOPAL is metabolized by aldehyde dehydrogenase (ALDH) to form 3,4-dihydroxyphenylacetic acid (DOPAC), which exits the cell. DA in the vesicles undergoes enzymatic hydroxylation catalyzed by DA-beta-hydroxylase (DBH) to form NE. Catecholamines released into the extracellular fluid is taken back up into the cytoplasm via the cell membrane DA transporter (DAT) or cell membrane NE transporter (NET). NE in the cytoplasm can undergo vesicular uptake or MAO-catalyzed oxidative deamination to form 3,4-dihydroxyphenylglycolaldehdyde (DOPEGAL), which is reduced by aldehyde/aldose reductase (AR) to form 3,4-dihydroxyphenylglycol (DHPG). DHPG rapidly exits the neuron. The six endogenous catechols in white rectangles were measured simultaneously. Font sizes correspond roughly to tissue concentrations of the analytes in rat striatum and peri-striatal tissue.

Figure 2

Change (logarithmic scale), compared to vehicle (VEH) in the activity of vesicular monoamine transporter type 2 (VMAT2), as expressed by DA/DOPAL, DA/DOPAC, NE/DHPG, and DA/ALL ratios; and aldehyde dehydrogenase (ALDH), expressed by DOPAC/DOPAL ratio, in rats treated with rotenone (ROT), ROT and deprenyl (DEP), and ROT with DEP and N-acetylcysteine (NAC). Mean values of the intervention group were divided by the mean value of the vehicle in each ratio (Table 2). Note the decrease in the activity of these processes with rotenone and the mitigating effect of the intervention with DEP alone or with NAC. Abbreviations of catechols: DHPG: 3,4-dihydroxyphenylglycol; NE: norepinephrine; DOPAL: 3,4-dihydroxyphenylacetaldehyde; DA: dopamine; DOPAC: 3,4-dihydroxyphenylacetic acid.