Exercise: a behavioral intervention to enhance brain health and plasticity

Consensus statement on Concussion in Sport - The 4th International Conference on Concussion in Sport held in Zurich, November 2012

The new 2012 Zurich Consensus statement is designed to build on the principles outlined in the previous documents and to develop further conceptual understanding of this problem using a formal consensus-based approach. A detailed description of the consensus process is outlined at the end of this document under the Background section. This document is developed primarily for use by physicians and healthcare professionals who are involved in the care of injured athletes, whether at the recreational, elite or professional level.

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Consensus statement on concussion in sport

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings

Estradiol protects against brain injury, neurodegeneration, and cognitive decline. Our previous work demonstrates that physiological levels of estradiol protect against stroke injury and that this protection may be mediated through receptor-dependent alterations of gene expression. In this report, we tested the hypothesis that estrogen receptors play a pivotal role in mediating neuroprotective actions of estradiol and dissected the potential biological roles of each estrogen receptor (ER) subtype, ERα and ERβ, in the injured brain. To investigate and delineate these mechanisms, we used ERα-knockout (ERαKO) and ERβ-knockout (ERβKO) mice in an animal model of stroke. We performed our studies by using a controlled endocrine paradigm, because endogenous levels of estradiol differ dramatically among ERαKO, ERβKO, and wild-type mice. We ovariectomized ERαKO, ERβKO, and the respective wild-type mice and implanted them with capsules filled with oil (vehicle) or a dose of 17β-estradiol that produces physiological hormone levels in serum. One week later, mice underwent ischemia. Our results demonstrate that deletion of ERα completely abolishes the protective actions of estradiol in all regions of the brain; whereas the ability of estradiol to protect against brain injury is totally preserved in the absence of ERβ. Thus, our results clearly establish that the ERα subtype is a critical mechanistic link in mediating the protective effects of physiological levels of estradiol in brain injury. Our discovery that ERα mediates protection of the brain carries far-reaching implications for the selective targeting of ERs in the treatment and prevention of neural dysfunction associated with normal aging or brain injury.

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Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury

Clinical studies demonstrate that estrogen replacement therapy in postmenopausal women may enhance cognitive function and reduce neurodegeneration associated with Alzheimer's disease and stroke. This study assesses whether physiologic levels of estradiol prevent brain injury in an in vivo model of permanent focal ischemia. Sprague-Dawley rats were ovariectomized; they then were implanted, immediately or at the onset of ischemia, with capsules that produced physiologically low or physiologically high 17beta-estradiol levels in serum (10 or 60 pg/mL, respectively). One week after ovariectomy, ischemia was induced. Estradiol pretreatment significantly reduced overall infarct volume compared with oil-pretreated controls (mean+/-SD: oil = 241+/-88; low = 139+/-91; high = 132+/-88 mm3); this protective effect was regionally specific to the cortex, since no protection was observed in the striatum. Baseline and ischemic regional CBF did not differ between oil and estradiol pretreated rats, as measured by laser Doppler flowmetry. Acute estradiol treatment did not protect against ischemic injury. Our finding that estradiol pretreatment reduces injury demonstrates that physiologic levels of estradiol can protect against neurodegeneration.

http://jcb.sagepub.com/content/18/11/1253.full.pdf

Estradiol Protects Against Ischemic Injury

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERα and ERβ in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2 , as expression of other members of the bcl-2 family ( bax, bcl-x L , bcl-x S, and bad ) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERβ expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERβ protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.

https://www.jneurosci.org/content/jneuro/19/15/6385.full.pdf

Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors

I. Introduction We have followed an arduous and often tortuous route to reach our current understanding of the physiological role of catecholamines (CAs) in the regulation of gonadotropin secretion. More often than not, the vast amounts of confusing literature on this subject have bewildered the novice and discouraged the faint of heart and, as such, research into the complexities of this system have waxed and waned over the 32 or more years since CAs first were implicated as regulators of gonadotropin secretion. Much of this confusion was due to: 1) lack of adequate methodology to measure CA secretion; 2) the use of complex and at times unusual experimental animal preparations and paradigms; 3) an inadequate understanding of the neuroanatomy of CA pathways in the brain; and 4) the use of many drugs which lack the specificity required to delineate the interplay that exists between CAs and the secretion of gonadotropic hormones. This is not to say that we now have deciphered the many complex central nervou...

The Role of Catecholamines in the Regulation of Pituitary Luteinizing Hormone and Follicle-Stimulating Hormone Secretion

The results of the Women's Health Initiative, a study anticipated to provide definitive answers about health benefits and risks of postmenopausal hormone therapy, have generated debate and confusion among clinicians, researchers, and the lay public. The ovarian hormones estrogen and progesterone, which decline at menopause, normally elicit complex tissue-specific responses throughout the body. Major advances are providing a detailed molecular definition of how that differential action is achieved. Here we review estrogen and progestin actions, discuss how effectively knowledge of steroid hormone endocrinology has been incorporated into clinical studies, and consider the impact on modern hormone therapy protocols and pharmaceutical development.

Phyllis M. Wise

Papers

Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury

Estradiol Protects Against Ischemic Injury

Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors

The Role of Catecholamines in the Regulation of Pituitary Luteinizing Hormone and Follicle-Stimulating Hormone Secretion

Hormone therapy: Physiological complexity belies therapeutic simplicity