Antioxidant properties of dimethyl sulfoxide and its viability as a solvent in the evaluation of neuroprotective antioxidants.

INTRODUCTION: Dimethyl sulfoxide is an amphiphilic compound whose miscibility with water and its ability to dissolve lipophilic compounds make it an appreciated solvent in biomedical research. However, its reported antioxidant properties raise doubts about its use as a solvent in evaluating new antioxidants. The goal of this investigation was to evaluate its antioxidant properties and carry out a comparative study on the antioxidant properties of some known neuroprotective antioxidants in the presence and absence of dimethyl sulfoxide. METHODS: The antioxidant properties of dimethyl sulfoxide were studied in rat brain homogenates by determining its ability to reduce both lipid peroxidation (TBARS formation) and protein oxidation (increase in protein carbonyl content and decrease in free thiol content) induced by ferrous chloride/hydrogen peroxide. Its ability to reduce the production of hydroxyl radicals by 6-hydroxydopamine autoxidation was also estimated. The same study was also performed with three known antioxidants (α-phenyl-N-tert-butylnitrone; 2-methyl-2-nitrosopropane; 5,5-dimethyl-1-pyrroline N-oxide) in the presence and absence of dimethyl sulfoxide. RESULTS: Our results showed that dimethyl sulfoxide is able to reduce both lipid peroxidation and protein carbonyl formation induced by ferrous chloride/hydrogen peroxide in rat brain homogenates. It can also reduce the production of hydroxyl radicals during 6-hydroxydopamine autoxidation. However, it increases the oxidation of protein thiol groups caused by ferrous chloride/hydrogen peroxide in rat brain homogenate. DISCUSSION: Despite the here reported antioxidant and pro-oxidant properties of dimethyl sulfoxide, the results obtained with α-phenyl-N-tert-butylnitrone, 2-methyl-2-nitrosopropane, and 5,5-dimethyl-1-pyrroline N-oxide corroborate the antioxidant properties attributed to these compounds and support the potential use of dimethyl sulfoxide as a solvent in the study of the antioxidant properties of lipophilic compounds. CONCLUSION: Dimethyl sulfoxide is a very useful solvent that may be used at relatively low concentrations in the development of new antioxidants with neuroprotective properties.

Study on the ability of 1,2,3,4-tetrahydropapaveroline to cause oxidative stress: Mechanisms and potential implications in relation to parkinson's disease.

Tetrahydropapaveroline (THP) is a compound derived from dopamine monoamine oxidase-mediated metabolism, particularly present in the brain of parkinsonian patients receiving L-dopa therapy, and is capable of causing dopaminergic neurodegeneration. The aim of this work was to evaluate the potential of THP to cause oxidative stress on mitochondrial preparations and to gain insight into the molecular mechanisms responsible for its neurotoxicity. Our data show that THP autoxidation occurs with a continuous generation of hydroxyl radicals (*OH) and without the involvement of the Fenton reaction. The presence of ascorbate enhances this process by establishing a redox cycle, which regenerates THP from its quinolic forms. It has been shown that the production of *OH is not affected by the presence of either ferrous or ferric iron. Although THP does not affect lipid peroxidation, it is capable of reducing the high levels of thiobarbituric acid-reactive substances obtained in the presence of ascorbate and/or iron. However, THP autoxidation in the presence of ascorbate causes both an increase in protein carbonyl content and a reduction in protein-free thiol content. THP also increases protein carbonyl content when the autoxidation occurs in the presence of iron. The remarkable role played by ascorbate in the production of oxidative stress by THP autoxidation is of particular interest.

Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: role of ferrous and ferric ions.

The autoxidation and monoamine oxidase (MAO)-mediated metabolism of dopamine (3-hydroxytyramine; DA) cause a continuous production of hydroxyl radical (*OH), which is further enhanced by the presence of iron (ferrous iron, Fe(2+) and ferric ion, Fe(3+)). The accumulation of hydrogen peroxide (H2O2) in the presence of Fe(2+) appears to discard the involvement of the Fenton reaction in this process. It has been found that the presence of DA significantly reduces the formation of thiobarbituric acid reagent substances (TBARS), which under physiological conditions takes place in mitochondrial preparations. The presence of DA is also able to reduce TBARS formation in mitochondrial preparations even in the presence of iron (Fe(2+) and Fe(3+)). However, DA boosted the carbonyl content of mitochondrial proteins, which was further increased in the presence of iron (Fe(2+) and Fe(3+)). This latter effect is also accompanied by a significant reduction in thiol content of mitochondrial proteins. It has also been observed how the pre-incubation of mitochondria with pargyline, an acetylenic MAO inhibitor, reduces the production of *OH and increases the formation of TBARS. Although, the MAO-mediated metabolism of DA increases MAO-B activity, the presence of iron inhibits both MAO-A and MAO-B activities. Consequently, DA has been shown to be a double-edged sword, because it displays antioxidant properties in relation to both the Fenton reaction and lipid peroxidation and exhibits pro-oxidant properties by causing both generation *OH and oxidation of mitochondrial proteins. Evidently, these pro-oxidant properties of DA help explain the long-term side effects derived from l-DOPA treatment of Parkinson's disease and its exacerbation by the concomitant use of DA metabolism inhibitors.