Quinol-Based Cyclic Antioxidant Mechanism in Estrogen Neuroprotection

Substantial evidence now exists that intrinsic free-radical scavenging contributes to the receptor-independent neuroprotective effects of estrogens. This activity is inherently associated with the presence of a phenolic A-ring in the steroid. We report a previously unrecognized antioxidant cycle tha...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-09, Vol.100 (20), p.11741-11746
Main Authors: Prokai, Laszlo, Prokai-Tatrai, Katalin, Perjesi, Pal, Zharikova, Alevtina D., Perez, Evelyn J., Liu, Ran, Simpkins, James W.
Format: Article
Language:English
Subjects:
Animals
Antioxidants
Antioxidants - pharmacology
Biological Sciences
Brain damage
Brain Ischemia - prevention & control
Chromatography, Liquid
Cultured cells
Enzymes
Estrogens
Estrogens - pharmacology
Female
Free Radical Scavengers - pharmacology
Free radicals
Hydroquinones
Hydroquinones - pharmacology
Hydroxyl Radical
Mass Spectrometry
Neurology
Neuroprotective Agents - pharmacology
Oxidation
Oxidative Stress
Prodrugs
Proteins
Rats
Rats, Sprague-Dawley
Reactive oxygen species
Reperfusion
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Summary:Substantial evidence now exists that intrinsic free-radical scavenging contributes to the receptor-independent neuroprotective effects of estrogens. This activity is inherently associated with the presence of a phenolic A-ring in the steroid. We report a previously unrecognized antioxidant cycle that maintains the "chemical shield" raised by estrogens against the most harmful reactive oxygen species, the hydroxyl radical$(^\bullet OH)$produced by the Fenton reaction. In this cycle, the capture of$^\bullet OH$was shown to produce a nonphenolic quinol with no affinity to the estrogen receptors. This quinol is then rapidly converted back to the parent estrogen via an enzyme-catalyzed reduction by using NAD(P)H as a coenzyme (reductant) and, unlike redox cycling of catechol estrogens, without the production of reactive oxygen species. Due to this process, protection of neuronal cells against oxidative stress is also possible by quinols that essentially act as prodrugs for the active hormone. We have shown that the quinol obtained from a 17β-estradiol derivative was, indeed, able to attenuate glutamate-induced oxidative stress in cultured hippocampus-derived HT-22 cells. Estrone quinol was also equipotent with its parent estrogen in reducing lesion volume in ovariectomized rats after transient middle carotid artery occlusion followed by a 24-h reperfusion. These findings may establish the foundation for a rational design of neuroprotective antioxidants focusing on steroidal quinols as unique molecular leads.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2032621100