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Review
. 2007 Apr;114(1):1-12.
doi: 10.1016/j.pharmthera.2007.01.006. Epub 2007 Feb 2.

Structure-nongenomic neuroprotection relationship of estrogens and estrogen-derived compounds

Laszlo Prokai  1 , James W Simpkins
Affiliations
Review

Structure-nongenomic neuroprotection relationship of estrogens and estrogen-derived compounds

Laszlo Prokai et al. Pharmacol Ther. 2007 Apr.

Abstract

Nongenomic estrogen signaling pathways involve extranuclear estrogen receptors or function independently from estrogen receptors. These pathways participate in neuroprotection elicited by the hormone. Additional nongenomic neuroprotective effects are attributable to antioxidant and antiinflammatory actions of estrogens. Numerous chemical modifications to afford neuroprotective compounds from estrogens while eliminating estrogenicity and maintaining or enhancing nongenomic neuroprotection have been described. This review highlights recent structure-activity studies that revealed the importance of antioxidant effects for neuroprotective estrogen analogues and derivatives.

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Figures

Fig. 1
Fig. 1
A simplified model for the genomic action of estrogen. Estrogen, ER, co-regulator (co-r) and the nuclear DNA are symbolized by the filled circles, rounded rectangles and elongated rectangle showing an ERE (shaded area), respectively.
Fig. 2
Fig. 2
Indirect action of estrogen via interaction with intracellular signaling pathways. As in Fig. 1, estrogen, ER and the nuclear DNA are represented by the filled circles, rounded rectangles and elongated rectangle indicating a regulated gene promoter (shaded area), respectively. An ER-interacting protein (↔ PI3K) is also shown by a rounded rectangle.
Fig. 3
Fig. 3
Free-radical scavenging effect of estrogens according to the classical phenolic antioxidant mechanism. The scheme only shows the part of the molecule that participates in this mode of action. The solid arrows represent the chain-braking H-atom transfer, while the dashed arrows indicate the conversion of the phenoxyl radical back to the phenolic compound by an endogenous reductant (AH).
Fig. 4
Fig. 4
Hydroxyl-radical scavenging effect of estrogens according to a para-quinol-based antioxidant mechanism. The scheme only shows the part of the molecule that participates in this mode of action.
Fig. 5
Fig. 5
17β-Estradiol [estra-1,3,5(10)-triene-3,17β-diol] and 17α-estradiol [estra-1,3,5(10)-triene-3,17α-diol].
Fig. 6
Fig. 6
Chemical nomenclature of the steroid scaffold that shows rings A–D and positions 1–17 referred to in the text.
Fig. 7
Fig. 7
Estrone (E1), estriol (E3), ethinylestradiol (EE) and catechol estrogens (2-OH-17β-E2 and 4-OH-17β-E2).
Fig. 8
Fig. 8
3-O-substituted estrogens.
Fig. 9
Fig. 9
An enantiomer of 17β-E2 (ent-E2, top) and its 17-desoxy analogue (bottom).
Fig. 10
Fig. 10
A-ring substituted estratrienes with high potency to protect mouse hippocampal HT22 cells in vitro.
Fig. 11
Fig. 11
2-(1-Adamantyl)-3-hydroxyestra-1, 3, 5(10)-trien-17-one (top), 2-(1-adamantyl)-4-methyl-3-hydroxyestra-1, 3, 5(10)-trien-17-one (middle) and 2-(1-adamantyl)-4-methyl-estra-1, 3, 5(10)-triene-3,17β-diol (bottom), which do not bind to either ERα or ERβ, are effective in vivo in rat against ischemia-reperfusion injury as a model for stroke.
Fig. 12
Fig. 12
17β-O-alkyl ethers with improved potency to protect HT22 cells against glutamate neurotoxicity in vitro.
Fig. 13
Fig. 13
Examples of steroids with antioxidant effect stronger than that of 17β-E2.
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