Molecular Pharmacology, Vol 8, 241-248, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Further Studies on the Generation of Hydrogen Peroxide by 6-Hydroxydopamine

Potentiation by Ascorbic Acid

¹ College of Physicians and Surgeons, Columbia University, and the New York State Psychiatric Institute, New York, New York 10032

We studied the inhibitory action of various compounds, including hydrogen peroxide, on the uptake of [³H]dopamine by rat brain slices. Dialuric acid, 6-hydroxydopamine, and 5-hydroxydopamine consumed oxygen and generated hydrogen peroxide in solution as a result of aerobic oxidation, as measured with an oxygen electrode. The regeneration by catalase of half the oxygen consumed by 6-hydroxydopamine confirmed that oxygen consumption was equal to H₂0₂ production. The rate of oxygen uptake (H₂0₂ production by dialuric acid or 6-hydroxydopamine was augmented by the addition of ascorbic acid. In addition, alloxan, which is the oxidized form of dialuric acid, consumed oxygen when ascorbate was added. The mechanism for this can be envisaged as reduction of the oxidized compounds by ascorbate, followed by reoxidation to form more H₂0₂, with continuous recycling. Concomitant with increased production of H₂0₂, there was increased inhibition of [³H]dopamine uptake. Ascorbate by itself did not inhibit the uptake of [³H]dopamine and did not produce measurable quantities of H₂0₂. 6-Hydroxydopamine, a compound that causes nerve terminal degeneration in vivo, was compared with 5-hydroxydopamine, which does not. As both compounds are structural analogues of dopamine, they can inhibit the uptake of [³H]dopamine into brain slices by competing for the uptake mechanisms. Additionally, both may inhibit uptake irreversibly by generating H₂O₂, which causes oxidative damage. 6-Hydroxydopamine produced H₂0₂ at about 12 times the rate yielded by 5-hydroxydopamine. Ascorbate potentiated H₂O₂ production by 6-hydroxydopamine but suppressed that from 5-hydroxydopamine. These findings are consistent with an important role for H²O² in the 6-hydroxydopamine-induced degeneration of nerve terminals and may explain why 5-hydroxydopamine does not produce degenerative changes.

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ACKNOWLEDGMENT We thank Felicitas Cabbat for her expert technical assistance.

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