Search Results (5)

Dithiocarbamate fungicides, including benomyl (methyl 1-butylcarbamoyl-2-benzimidazolecarbamate), share a common mechanism of toxicity by inhibiting aldehyde dehydrogenases (ALDHs), enzymes essential for detoxifying reactive aldehydes. One such aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), a dopamine metabolite, is implicated in the catecholaldehyde hypothesis of Parkinson’s disease. This study examines ALDH inhibition as the molecular initiating event (MIE) within an adverse outcome pathway (AOP) leading to neurotoxicity. Caenorhabditis elegans at the L4 stage were exposed for 24 h to 10 or 100 μM benomyl. While 10 μM had no significant effect on lethality, growth, or reproduction, 100 μM induced adverse effects, albeit with low lethality. Both doses inhibited ALH activity, an effect mitigated by Alda-1, a selective ALDH activator. Alda-1 alone increased ALH-1 protein levels but did not alter benomyl-induced protein localization and relative abundance. Benomyl exposure also elevated oxidative stress markers—superoxide dismutase, catalase, and lipid peroxidation—which Alda-1 reduced. Neurotoxicity was evidenced by dopaminergic dysfunction, including impaired basal slowing response, neuronal morphological abnormalities, and reduced locomotion upon optogenetic activation. Fluorescent reporter assays confirmed ALH-1 presence in dopaminergic neurons. These results identify ALH inhibition as the MIE in benomyl-induced neurotoxicity, linking dopaminergic degeneration and redox imbalance to the catecholaldehyde hypothesis, and providing mechanistic insights into an AOP relevant to neurodegenerative disorders. Full article

A wide range of water-soluble quaternary ammonium acylhydrazones based on catecholaldehyde were synthesized and characterized using NMR, IR spectroscopy, and elemental analysis. The total antioxidant capacity of the acylhydrazones discussed herein was estimated via coulometric titration with electrogenerated bromine. Pyridinium derivatives 11a–e exhibited the highest antioxidant capacity. Quaternary ammonium acylhydrazones demonstrated high antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus strains. Furthermore, low hemo- and cytotoxicity and the absence of a negative effect on the hemostatic system were confirmed for the studied compounds. According to the results of a CV test, the antimicrobial effect of the most active acylhydrazones, namely, 9a, 10b, 10c, and 11a, is associated with the destruction of the bacterial cell wall. High or moderate activity against phytopathogens of bacterial origin was observed for all the acylhydrazones evaluated. Anti-aggregation activity was observed for compound 10b; the extent was 1.6-fold greater than that exhibited by acetylsalicylic acid. On the contrary, compound 9d exhibited a pro-aggregant effect (with a 6.3% increase in platelet aggregation and a >15% decrease in the latent period compared to the control). Thus, the data obtained can be considered the basis for further pharmaceutical development of these effective drugs with antithrombotic and hemostatic potential. Full article

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. Full article

Neurogenerative diseases, such as Parkinson’s disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is well known to exhibit toxic effects on neuronal cells. Both catecholic and aldehyde groups seem to be associated with the neurotoxicity of DOPAL. However, the exact cause of toxicity caused by this compound remains unknown. Since the reactivity of DOPAL could be attributed to its immediate oxidation product, DOPAL-quinone, we examined the potential reactions of this toxic metabolite. The oxidation of DOPAL by mushroom tyrosinase at pH 5.3 produced conventional DOPAL-quinone, but oxidation at pH 7.4 produced the tautomeric quinone-methide, which gave rise to 3,4-dihydroxyphenylglycolaldehyde and 3,4-dihydroxybenzaldehyde as products through a series of reactions. When the oxidation reaction was performed in the presence of ascorbic acid, two additional products were detected, which were tentatively identified as the cyclized products, 5,6-dihydroxybenzofuran and 3,5,6-trihydroxybenzofuran. Physiological concentrations of Cu(II) ions could also cause the oxidation of DOPAL to DOPAL-quinone. DOPAL-quinone exhibited reactivity towards the cysteine residues of serum albumin. DOPAL-oligomer, the oxidation product of DOPAL, exhibited pro-oxidant activity oxidizing GSH to GSSG and producing hydrogen peroxide. These results indicate that DOPAL-quinone generates several toxic compounds that could augment the neurotoxicity of DOPAL. Full article

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments. Full article