**6. Conclusion**

There are some lingering controversies in the neuroprotective effects and underlying mechanisms of estrogen. Nevertheless, numerous studies indicate the profound neuroprotective effects of 17β-estradiol on neurodegenerative diseases including ischemia, Alzheimer's disease, Parkinson's disease, and ethanol withdrawal syndromes. Diverse mechanisms mediate estrogen's protection through neurotrophic, neuroprotective, antiapoptotic, and antioxidant activities. Furthermore, estrogen exerts its neuroprotection through inhibiting inflammation and preserving the homeostasis of neurotransmitters. Estrogen receptors appear to mediate some of estrogen's protection, although it is not yet entirely clear whether it is estrogen receptor-α, estrogen receptor-β, or membrane estrogen receptors. At the mitochondrial level, estrogen inhibits peroxidation, eliminates reactive oxygen species, and maintains the homeostasis of mitochondrial membranes/respiration.

The extent to which estrogen can actually ameliorate neurodegenerative diseases in clinical settings may depend on well controlled systematic clinical studies that are largely absent in current situations. Nevertheless, it may be a matter of time that this amazing molecule alleviates the human burden of devastating brain diseases.

#### **7. Acknowledgment**

This work was supported by National Institute on Alcohol Abuse and Alcoholism (AA015982 and AA018747). We wish to thank Claudia Martinez and David Julovich for their editorial assistance.

#### **8. References**

150 Sex Steroids

with cell survival or differentiation. However, excess activation generally correlates with pathological conditions (Barca et al., 2008). P38 is activated upon phosphorylation (Moriguchi et al., 1996) and thus, pP38 is often measured as an indicator of P38 activation. A previous study reported that the P38 inhibitor SB203580 attenuated ethanol-induced cell death (Ku et al., 2007), suggesting that P38 activation mediates cytotoxic ethanol. Acute ethanol treatment led to P38 activation (Norkina et al., 2007) and augmented endotoxininduced pP38 levels in a manner attenuated by P38 inhibitor in human monocytes (Drechsler et al., 2006). Recently, we have demonstrated that estrogen protected against ethanol withdrawal-induced hyperactivation of P38, suggesting that there is a crucial link between estrogen, P38, and ethanol withdrawal (Jung et al., 2010). In that study, middle-age female rats (12-15 month old) were more vulnerable to the ethanol withdrawal-induced P38 activation than young or older rats (Jung et al., 2010). Importantly, chronic estrogen treatment abolished the age difference in P38 activation. These studies indicate that ethanol withdrawal interferes with signaling pathways, including P38, in a manner that depends on

In conclusion, findings from our and others' laboratories suggest that ethanol withdrawal distress is more than a neurotransmitter disorder. It is attributed to the perturbation of redox balance, protein kinase signaling, and mitochondria, all of which can be mitigated by estrogen treatment. Understanding the interaction between ethanol withdrawal and estrogen may contribute to the improvement of the pharmacological treatment of ethanol

There are some lingering controversies in the neuroprotective effects and underlying mechanisms of estrogen. Nevertheless, numerous studies indicate the profound neuroprotective effects of 17β-estradiol on neurodegenerative diseases including ischemia, Alzheimer's disease, Parkinson's disease, and ethanol withdrawal syndromes. Diverse mechanisms mediate estrogen's protection through neurotrophic, neuroprotective, antiapoptotic, and antioxidant activities. Furthermore, estrogen exerts its neuroprotection through inhibiting inflammation and preserving the homeostasis of neurotransmitters. Estrogen receptors appear to mediate some of estrogen's protection, although it is not yet entirely clear whether it is estrogen receptor-α, estrogen receptor-β, or membrane estrogen receptors. At the mitochondrial level, estrogen inhibits peroxidation, eliminates reactive oxygen species, and maintains the homeostasis of

The extent to which estrogen can actually ameliorate neurodegenerative diseases in clinical settings may depend on well controlled systematic clinical studies that are largely absent in current situations. Nevertheless, it may be a matter of time that this amazing molecule

This work was supported by National Institute on Alcohol Abuse and Alcoholism (AA015982 and AA018747). We wish to thank Claudia Martinez and David Julovich for

age and that is protected by estrogen.

mitochondrial membranes/respiration.

**7. Acknowledgment** 

their editorial assistance.

alleviates the human burden of devastating brain diseases.

withdrawal.

**6. Conclusion** 


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**8** 

*1Italy 2Brazil* 

**Estrogen Influences on Cognition** 

*2Department of Physiological Sciences, Laboratory of Neurosciences and Behavior,Institute of Biology, University of Brasília, Brasília, DF,* 

Sex steroids are hormones produced mainly by the reproductive glands, either the ovaries or testes, which share a similar basic structure of three hexane rings and a pentane ring. They include estrogens, androgens, and progestogens, and each has major effects on reproductive physiology (Henderson, 2009; Osterlund & Hurd, 2001). Estrogens are required for normal female sexual maturation; they promote growth and differentiation of the breast, uterus, fallopian tubes, vagina, and ovaries (Carr, 1998). Male reproductive tissues, such as testis and prostate, are also estrogen target tissues (Clark et al., 1992). In addition, estrogens have an important role in bone maintenance (Turner et al., 1994), and

Even though estrogens (e.g., 17β-estradiol) and progestogens (e.g., progesterone) are classified as female sex hormones and androgens (e.g., testosterone) as male sex hormones, this categorization is misleading. In fact, for example, estrogens are found both in men and women, and they have effects in both sexes; besides, they arise in tissues other than the

Among the sex steroids, estrogens are the best studied with respect to human nonreproductive behaviors. They exert a broad range of effects throughout the body, including the central nervous system (CNS), where their actions are not limited to the regulation of reproductive neuroendocrinology and sexual behavior (Henderson 2009, 2010, 2011; Ziegler & Gallagher, 2005). In fact, accumulating evidence points to their involvement in influencing the function of numerous neural systems and, presumably, different behavioral domains (McEwen & Alves, 1999; McEwen et al, 2001; McEwen, 2010; Ziegler & Gallagher, 2005). Recent studies have highlighted a number of important, global issues regarding the influence of estrogen on cognitive functions (Lacreuse, 2006; Luine, 2007, 2008; Markou et al., 2007). A possible explanation for this effect can be represented by the modulator role exerted by estrogens on several neurotransmitter systems (such as acetylcholine, catecholamines, serotonin, and GABA), both in animals and humans (Amin et al, 2006; Dumas et al 2006). Another reason may lie in the widespread presence of estrogen receptors (ERs) in many regions involved in cognitive processes, such as learning and memory, including the

protection of the cardiovascular system (Farhat et al., 1996) .

ovaries (Osterlund & Hurd, 2001).

**1. Introduction** 

Antonella Gasbarri1 and Carlos Tomaz2 *1Department of Biomedical Sciences and Technologies,* 

*University of L'Aquila, L'Aquila,* 

