Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Abstract

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 17␤-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.hydroxyl radical ͉ ischemia ͉ prodrug

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

“…MS/MS product-ion scans were obtained after collision-induced dissociation with helium as the target gas. Compound identification was based on RT, APCI mass spectra and MS/MS with authentic compounds as references [32]. Quantitative analyses were done by LC/APCI-MS/MS and calibration with solutions of known concentrations of the analytes (1 or 2).…”

Estrogen and Brain Protection

“…The phenoxyl radical ring is converted to para-quinol ring by scavenging further free radicals like -OH. This para-quinol ring structure finally becomes the original A ring of 17 -estradiol through NADPH (Prokai et al, 2003;Prokai-Tatrai et al, 2008). The important point of this cyclic reaction is that 17 -estradiol is rejuvenated after it absorbs harmful free radicals (Figure 2).…”

“…The quinol is rapidly converted to the parent estrogen via a NAD(P)Hdependent reductive aromatization to perpetuate the antioxidant action. During this process, •OH is detoxified to H 2 O (Prokai et al, 2003;Prokai-Tatrai et al, 2008).…”

“…Estrogen treatment mitigated reactive oxygen species generation, lipid peroxidation, and protein oxidation (Jung et al 2004(Jung et al , 2006. Estrogen protection against the prooxidant effect of ethanol withdrawal may involve glutamate transmission because glutamate-induced oxidative stress is attenuated by estrogen (Behl & Manthey, 2000) and the quinol derived from estrogen (Prokai et al, 2003). It is also possible that estrogen elevates the levels of endogenous antioxidants, such as glutathione, so that a favorable redox potential for an antioxidant environment is created (Prokai et al, 2003).…”

17β-Estradiol protects the neonatal brain from hypoxia–ischemia

“…17β-estradiol attenuates injury due to stroke (Toung et al, 1998;Green et al, 2001), seizures (Veliskova et al, 2000), oxygen-glucose deprivation (Harms et al, 2001) and oxidative stress (Mize et al, 2003) in the adult central nervous system (CNS). Protection occurs via receptordependent and receptor-independent mechanisms including increasing levels of Bcl-2 (Singer et al, 1998;Dubal et al, 1999;Stoltzner et al, 2001;Zhao et al, 2004), decreasing the production of reactive oxygen species and enhanced uptake of free radicals (Prokai et al, 2003), attenuation of calcium currents (Huang et al, 2004;Hilton et al, 2006), and activation of survival-promoting signal transduction cascades (Linford et al, 2000;Jover et al, 2002). In contrast, little is known regarding the neuroprotective action of 17β-estradiol in the developing CNS.…”