Minireview: Neuroprotective Effects of Estrogen—New Insights into Mechanisms of Action

Abstract

An accumulating body of evidence clearly establishes that estradiol is a potent neuroprotective and neurotrophic factor in the adult: it influences memory and cognition, decreases the risk and delays the onset of neurological diseases such as Alzheimer's disease, and attenuates the extent of cell death that results from brain injuries such as cerebrovascular stroke and neurotrauma. Thus, estradiol appears to act at two levels: 1) it decreases the risk of disease or injury; and/or 2) it decreases the extent of injury incurred by suppressing the neurotoxic stimulus itself or increasing the resilience of the brain to a given injury. During the past century, the average life span of women has increased dramatically, whereas the time of the menopause has remained essentially constant. Thus, more women will live a larger fraction of their lives in a postmenopausal, hypoestrogenic state than ever before. Clearly, it is critical for us understand the circumstances under which estradiol exerts protective actions and the cellular and molecular mechanisms that underlie these novel, nonreproductive actions.

17β‐Estradiol activates ICI 182,780‐sensitive estrogen receptors and cyclic GMP‐dependent thioredoxin expression for neuroprotection

“…The present proposal of the role of •NO-cGMP-PKG in the mediation of estrogen-dependent new protein expression of Trx and MnSOD for neuroprotection is unique. To the best of our knowledge, this notion has never been discussed in prior proposals on neuroprotective mechanisms of estrogen (51,(78)(79)(80)(81)(82). The present molecular and pharmacological evidence, thus, supports our working hypothesis (83) that physiological concentrations of estrogen induces NOS1 and activates the cGMP-dependent signal transduction pathway, thereby leading to a sustained expression of Trx and MnSOD for improving cell viability through both antioxidative and antiapoptotic mechanisms.…”

A caspase‐3‐dependent pathway is predominantly activated by the excitotoxin pregnenolone sulfate and requires early and late cytochrome c release and cell‐specific caspase‐2 activation in the retinal cell death

“…6b). By contrast, treatment with 17b-E2 used at the concentration of 5 lM, known to promote neuroprotection against excitotoxic-mediated neuronal death (Garcia-Segura et al 2001;Wise et al 2001) and attenuate retinal ischaemia (Nonaka et al 2000), prevented activation of caspase-3 and caspase-2 and cytochrome c release from mitochondria caused by PS at 3 and 7 h (Fig. 7a).…”

“…Decreased levels of dehydroepiandrosterone (DHEA) 10 during aging make neurones more vulnerable to be damaged (Cardounel et al 1999); DHEA and DHEA-sulfate (DHEAS) are effective neuroprotective agents (for review, see Schumacher et al 2000). Sex steroid hormones, progesterone and oestrogen, may influence the outcome of ischaemic and traumatic injury in female and male brain, and differently promote reduction in the consequences of the injury cascade (for reviews see Stein 2001 andWise et al 2001). Also in peripheral nervous system, a local synthesis of progesterone has been shown to have a role in myelin formation during the regenerating processes of injured peripheral nerves (Schumacher et al 2000).…”

Glial Aromatization Decreases Neural Injury in the Zebra Finch (Taeniopygia guttata): Influence on Apoptosis

“…Locally up-regulated aromatase may increase oestrogen levels surrounding the injury. Oestradiol may protect the brain by actions on traditional intranuclear oestrogen receptors (ER) or via nongenomic pathways (34). This action may involve several cell types including neurones, astrocytes, endothelia and microglia (34).…”