Neuroprotection against Oxidative Stress by Estrogens: Structure-Activity Relationship

Behl, Christian; Skutella, Thomas; Lezoualc’h, Frank; Post, Anke; Widmann, M.; Newton, C. J.; Holsboer, Florian

doi:10.1124/mol.51.4.535

Cited by 711 publications

(531 citation statements)

References 32 publications

(45 reference statements)

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“…Several compounds, including estrogens, have been shown to reduce oxidative stress on neurons [5,6,13,15,17]. In addition to binding to ERs in the cellular membrane, cytoplasm and nucleus [48], estrogens may also interact with lipid-transport proteins [49].…”

Section: Discussionmentioning

confidence: 99%

“…Various in vitro and in vivo models show that estrogens are capable to protect neurons in a concentration range of 0.1 nM to 50 µM suggesting the involvement of different modes of action [11][12][13][14][15]. The complex events by which estrogens orchestrate neuronal survival have not been clearly understood [16].…”

Section: Introductionmentioning

confidence: 99%

“…The selection of, e.g., 17OBu-E2 (1) as an estrogen derivative for in vitro neuroprotection experiments involving HT-22 cells and glutamate-induced oxidative stress is also advantageous, since it permits the studies to focus on non-genomic mechanisms such as the antioxidant action without interference from nuclear ER-dependent genomic mechanisms. In addition, the introduction of this D-ring substitution is expected to have weak, if any, influence on the chemistry of the phenolic A-ring of the steroid, which has been presumed to play an important role in the neuroprotective activity of estrogens by exerting an antioxidant action [13,17]. Here we report the theoretical prediction and the subsequent experimental confirmation of (bio)chemical processes by which 1 may soak up the most toxic ROS, the hydroxyl-radical ( • OH) produced by Fenton reaction [29] and argue for the existence of a previously unrecognized antioxidant cycle that maintains a "chemical shield" raised by lipophilic, neuroprotectant E2 derivatives.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

et al. 2008

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Antioxidant action is an important component of the complex neuroprotective action of estrogens. Combining theoretical prediction and subsequent experimental confirmation by chemical and in vitro paradigms, this study focused on the mechanistic aspects of hydroxyl-radical scavenging by 17β-butoxy-1,3,5(10)-estratrien-3-ol, a synthetic derivative of 17β-estradiol with increased potency to inhibit lipid peroxidation and reduced affinity to estrogen-receptors compared to the endogenous hormone. In the process that acts as a "chemical shield," the phenolic A-ring turns into 10β-hydroxy-17β-butoxy-1,3,5(10)-estratrien-3-one, a non-aromatic para-quinol, upon capturing hydroxyl-radicals, which results in the complete loss of estrogen-receptor affinity and antioxidant activity. However, the parent compound is apparently recovered in brain tissue from this para-quinol via enzyme-catalyzed NAD(P)H-dependent reductive aromatization without causing oxidative stress. Taken together, our report argues for a previously unrecognized antioxidant cycle for synthetic estrogen-derived compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

et al. 2008

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“…It is likely that these protective actions involve a number of other actions of estrogens besides inducing synapses. These include suppression of the production of the toxic form of ␤-amyloid protein (59,153) and inhibition of free radical-induced toxicity (10,48). It should also be noted that estrogens affect many regions of the brain, including the basal forebrain cholinergic systems, the serotonergic system, the dopaminergic system, and the noradrenergic system [for review, see (93,94)], so that the hippocampus is not the only target that may be involved in these cognitive changes.…”

Section: Importance Of Sex Differences and Sex Hormonesmentioning

confidence: 99%

Stress and the Aging Hippocampus

McEwen

1999

Frontiers in Neuroendocrinology

205

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The ''glucocorticoid cascade hypothesis'' of hippocampal aging has stimulated a great deal of research into the neuroendocrine aspects of aging and the role of glucocorticoids, in particular. Besides strengthening the methods for investigating the aging brain, this research has revealed that the interactions between glucocorticoids and hippocampal neurons are far more complicated than originally envisioned and involve the participation of neurotransmitter systems, particularly the excitatory amino acids, as well as calcium ions and neurotrophins. New information has provided insights into the role of early experience in determining individual differences in brain and body aging by setting the reactivity of the hypothalamopituitary-adrenal axis and the autonomic nervous system. As a result of this research and advances in neuroscience and the study of aging, we now have a far more sophisticated view of the interactions among genes, early development, and environmental influences, as well as a greater appreciation of events at the cellular and molecular levels which protect neurons, and a greater appreciation of pathways of neuronal damage and destruction. While documenting the ultimate vulnerability of the brain to stressful challenges and to the aging process, the net result of this research has highlighted the resilience of the brain and offered new hope for treatment strategies for promoting the health of the aging brain. KEY WORDS: stress; hippocampal aging; glucocorticoid cascade hypothesis. 1999 Academic Press INTRODUCTIONThe hippocampus is a particularly vulnerable and sensitive region of the brain that is also very important for declarative and spatial learning and memory (36). Hippocampal neurons are vulnerable to seizures, strokes, and head trauma, as well as responding to stressful experiences (27,92,130). At the same time they show remarkable plasticity, involving long-term synaptic potentiation and depression, dendritic remodeling, synaptic turnover, and neurogenesis in the case of the dentate gyrus (Fig 1) (17,27,92).The work of aus der Muhlen and Ockenfels (3) first drew attention to potentially toxic actions of adrenal steroids. The reported darkly stained neurons in the hippocampus of guinea pigs exposed to high levels of glucocorticoids, an observation that has been confirmed and extended to repeated stress in subsequent studies (41,100), although there are still some doubts as to whether ''dark neurons'' may be artifacts of tissue trauma (18). In 1968, we discovered receptors for adrenal steroids in hippocampus (95), and it is now known that two types of adrenal steroid receptors exist in the hippocampus and other brain regions and mediate a variety of adrenal steroid effects on excitability, neurochemistry, and structure (27). Landfield (68) and then Sapolsky (127,128) provided evidence for a role of adrenal steroids in neuronal aging in the hippocampus, leading to the formulation of the ''glucocorticoid cascade hypothesis '' (130). This hypothesis states that glucocorticoids participate in a ...

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“…Estrone and 17 -estradiol, as well as other steroids containing a phenolic A-ring, are antioxidants with neuroprotective properties that are potentially useful for the treatment of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases [1][2][3][4][5][6]. Since the antioxidant properties of 17 -estradiol are not dependent on the absolute configuration of this steroid, ent-17 -estradiol also has neuroprotective properties [7].…”

Section: Introductionmentioning

confidence: 99%

A facile total synthesis of ent-17β-estradiol and structurally related analogues

Cai

Covey

2007

Steroids

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Neuroprotection against Oxidative Stress by Estrogens: Structure-Activity Relationship

Cited by 711 publications

References 32 publications

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

Stress and the Aging Hippocampus

A facile total synthesis of ent-17β-estradiol and structurally related analogues

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