TY - JOUR
T1 - Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection
AU - Prokai, Laszlo
AU - Prokai-Tatrai, Katalin
AU - Perjesi, Pal
AU - Zharikova, Alevtina D.
AU - Perez, Evelyn J.
AU - Liu, Ran
AU - Simpkins, James W.
PY - 2003/9/30
Y1 - 2003/9/30
N2 - 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 (.OH) produced by the Fenton reaction. In this cycle, the capture of .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.
AB - 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 (.OH) produced by the Fenton reaction. In this cycle, the capture of .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.
KW - Hydroxyl radical
KW - Ischemia
KW - Prodrug
UR - http://www.scopus.com/inward/record.url?scp=0141593536&partnerID=8YFLogxK
U2 - 10.1073/pnas.2032621100
DO - 10.1073/pnas.2032621100
M3 - Article
C2 - 14504383
AN - SCOPUS:0141593536
SN - 0027-8424
VL - 100
SP - 11741
EP - 11746
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -