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<h1>Estrogen and brain aging in men and women: Depression, energy, stress</h1>
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<div style="text-align: center;">
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<a href="/"><img class="epic" src="/icons/chads/chad.png"></a>
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<hr>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
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<p>From the <a href="https://raypeat.com/articles/articles/estrogen-age-stress.shtml" target="_blank">original article</a> in 2009. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
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<p>Although
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the incidence of Alzheimer's disease is 2 or 3 times as high among women
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as among men, there is a major campaign under way to convince the public
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that taking estrogen supplements will prevent the disease. Estrogen
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is now mainly promoted to prevent osteoporosis (another problem that
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is more common in women) and heart disease (which is more common in
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men). </p>
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<p>This
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substance, which came into medical use as "the female hormone"
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for the treatment of "female problems," especially for improving
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fertility, and then for preventing fertility as the oral contraceptive,
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is now being aimed primarily at the post-reproductive population, for
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problems that are essentially unrelated to femininity. It is,
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in fact, being presented to the public as something to prevent major
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age-related conditions.</p>
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<p>Brain
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degeneration, like osteoporosis, takes years to develop. Analysis
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of letters written by young women, for example, showed limited mental
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functioning in those who many years later developed Alzheimer's disease,
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and young women who have small bones are the ones most likely to develop
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osteoporosis later.<strong> It seems clear that the course of degenerative
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aging processes is set in young adulthood (or even earlier), and that
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it is never too early to be concerned with correcting processes that
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are going in the wrong direction.</strong> (See Walker, et al., 1988,
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and Smith, et al., 1992.) </p>
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<p>In
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"The Biological Generality of Progesterone" (1979) I proposed
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that the life-long trajectory of energy production and longevity was
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strongly influenced by prenatal nutrition and progesterone. This
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idea was based on work by people such as Marion Diamond, who showed
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that prenatal progesterone enlarges the cortex of the brain, and that
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estrogen makes it smaller, and Leonell Strong, who showed that a treatment
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that lowered the estrogen function in a young mouse could produce cancer-free
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offspring for several generations. Strong's work was very encouraging,
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because it showed that biological problems that had been "bred
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in" over many generations could be corrected by some simple metabolic
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treatments.</p>
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<p>Seeing
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these profoundly toxic long-range effects of estrogen, which shaped
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the animal's growth, development, function, and even its heredity, made
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it important to learn how estrogen works, because such fundamental changes
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covering the whole range of biology, produced by a simple little molecule,
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promised to reveal interesting things about the nature of life.
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</p>
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<p>Aging
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is an energy problem, and in the brain, which has extremely high energy
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requirements, interference with the energy supply quickly causes cells
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to die.</p>
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<p>I
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believe that estrogen's "principle," in all of its actions,
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is to interfere with the respiratory mode of energy production.
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This is an integrating principle that explains estrogen's immediate,
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direct effects on cells and organisms, which aren't explained by the
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idea that it acts on the genes through a specific "estrogen receptor."
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(It's hard to imagine, for example, how the "estrogen receptor"
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doctrine could explain the fact that a single injection of estrogen
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can kill a large portion of brain cells.) It explains why estrogen
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causes cells to take up water, allowing calcium to enter, activating
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various enzymes and cell division. On the organismic level, it
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explains why estrogen mimics "shock," releasing histamine
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and activating the nervous and glandular stress response system.
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The inefficiency of metabolism which doesn't use oxygen in the normal
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way causes glucose to be used rapidly, and this in itself is enough
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to trigger the release of pituitary ACTH and adrenal cortisol.
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The ACTH, and related hormones, liberate free fatty acids, which cells
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take up instead of glucose, and this (in the so-called Randall cycle)
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further limits the body's ability to oxidize glucose.
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</p>
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<p>People
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have spoken of "cascades" in relation to the adrenal glucocorticoids
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(e.g., cortisol) and estrogen, leading to cell damage, but really both
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of these hormonal cascades have to be seen as part of a more general
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collapse of adaptive systems, as a result of both chronic and immediate
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inadequacies of energy production.</p>
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<p><strong>Estrogen
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activates the adrenal stress reaction by way of the hypothalamus and
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pituitary, by direct actions on the adrenal glands, and by a variety
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of indirect effects, such as the increase of free fatty acids.
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It activates the excitotoxic glutamic acid pathway, and interferes with
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protective adenosine inhibition of nerves. It has both direct
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and indirect ways of promoting the formation of nitric oxide and carbon
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monoxide. These, and other estrogen-promoted factors, quickly
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and seriously interfere with mitochondrial respiration. Many of
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these effects contribute to increased intracellular calcium and free
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radical production, contributing to both the excitatory excess and the
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energy deficit.</strong></p>
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<p>The
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biochemical details of these cascades are mainly interesting because
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they show how many different kinds of stress converge on a few physiological
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processess--mitochondrial energy production, cellular excitation, and
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intercellular communication--which, when damaged thousands of times,
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lead to the familiar states of old age. These few functions, damaged
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by an infinite variety of stresses, have their own complexly adaptive
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ways of deteriorating, producing the various degenerative diseases.</p>
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<p>This
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perspective brings dementia, heart failure, autoimmunity, immunodeficiency
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and other diseases of aging together, in ways that allow generalized
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therapeutic and preventive approaches.</p>
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<p>The
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antistress, antiestrogen approaches become fundamental to prevention
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of aging. </p>
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<p>The
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pro-estrogenic nature of the unsaturated fatty acids is probably the
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biggest barrier to the radical elimination of degenerative diseases.
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Various saturated fatty acids, including butyric, octanoic, and palmitic,
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have protective effects on mitochondrial respiration.</p>
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<p><strong>Progesterone
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is the basic brain-protective antiestrogen. It works to protect
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the brain at many levels (preventing lipid peroxidation, exitotoxicity,
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nitric oxide damage, energy deficit, edema, etc.) and it promotes repair
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and recovery.</strong> </p>
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<p>Progesterone
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in most cases has effects opposite to estrogen's, improving mitochondrial
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energy production while preventing excessive excitation. Along
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with pregnenolone, progesterone is recognized as a neurosteroid with
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anti-excitotoxic actions, with the ability to promote repair and regeneration
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of the nervous system. (Roof, Stein, Faden; Schumacher, et al.; Baulieu.) </p>
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<p>The
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use of aspirin, which reduces inflammation and inhibits the formation
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of neurotoxic prostaglandins, is known to be associated with a lower
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incidence of Alzheimer's disease, and in other contexts, it offers protection
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against estrogen. Naloxone, the antiendorphin, has been found
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to reverse some of the cumulative effects of stress, restoring some
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pituitary and ovarian function, and it promotes recovery after brain
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injury<strong>;</strong> in a variety of ways, it corrects some of estrogen's
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toxic effects. </p>
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<p>Adenosine
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helps to maintain brain glycogen stores, which are lost in stress and
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aging. Vitamin B12 protects against nitric oxide, and improves
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alertness. </p>
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<p>Pyruvic
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acid has brain-protective effects, apparently through its decarboxylation
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(producing carbon dioxide) rather than through its use as an energy
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source, since other ketoacids are similarly protective. (The ketoacids
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occur in some natural foods.) The directly brain-protective effect of
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carbon dioxide offers many clues that should be interpreted in relation
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to estrogen's toxicity, since many of their effects on nerves are opposite. <strong>
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Estrogen blocks the production of energy while it stimulates nerve cells
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to use energy more rapidly, and carbon dioxide promotes the production
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of energy, while restraining the excitation which expends energy. </strong>
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The presence of carbon dioxide is an indicator of proper mitochondrial
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respiratory functioning.</p>
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<p>Pharmaceutical
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blockers of glutamic acid transmission, and of calcium and sodium uptake,
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prevent some deterioration following brain injury, but the most physiological
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way to protect against those toxic processes is to maintain metabolic
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energy at a high level. Magnesium, which is protective against
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excitatory damage and is a calcium antagonist, tends to be retained
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in proportion to the activity of thyroid hormone.</p>
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<p>As
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I have discussed previously, progesterone alone has brought people out
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of post-epileptic dementia and senile dementia, but it is reasonable
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to use a combined physiological approach, including thyroid.</p>
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<p>Besides
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providing new insights into biological energy and aging, the recognition
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that estrogen activates the stress hormone system--the pituitary-adrenal
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system--also provides clear insights into other problems, such as the
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polycystic ovary syndrome, hirsutism, adrenal hyperplasia, Cushing's
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disease, etc.</p>
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<h2>References</h2>
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<small>
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<p> [The
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references are clustered into groups, showing estrogen's indirect toxicity
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through its activation of the adrenal hormones, its direct brain-toxicity,
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and some of the interactions between these and fats, nitric oxide, etc.]</p>
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<p>Stress 1996 Jul;1(1):1-19 <strong>
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Stress, Glucocorticoids, and Damage to the Nervous System: The Current
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State of Confusion.</strong> Sapolsky RM Department of Biological Sciences,
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Stanford University, Stanford, CA 94305. <strong>An extensive literature
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demonstrates that glucocorticoids (GCs), the adrenal steroids secreted
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during stress, can have a broad range of deleterious effects in the
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brain. The actions occur predominately, but not exclusively, in the
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hippocampus, a structure rich in corticosteroid receptors and particularly
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sensitive to GCs. The first half of this review considers three types
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of GC effects: a) GC-induced atrophy, in which a few weeks' exposure
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to high GC concentrations or to stress causes reversible atrophy of
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dendritic processes in the hippocampus; b) GC neurotoxicity where, over
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the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment,
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in which elevated GC concentrations at the time of a neurological insult
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such as a stroke or seizure impairs the ability of neurons to survive
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the insult. The second half considers the rather confusing literature
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as to the possible mechanisms underlying</strong> these deleterious GC actions.
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Five broad themes are discerned: a) that GCs induce a metabolic vulnerability
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in neurons due to inhibition of glucose uptake; b) that GCs exacerbate
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various steps in a<strong> damaging cascade of glutamate excess, calcium
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mobilization and oxygen radical generation. In a review a number of
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years ago, I concluded that these two components accounted for the deleterious
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GC effects. Specifically, the energetic vulnerability induced by GCs
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left neurons metabolically compromised, and less able to carry out the
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costly task of containing glutamate, calcium and oxygen radicals. More
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recent work has shown this conclusion to be simplistic, and GC actions
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are shown to probably involve at least three additional components:
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c) that GCs impair a variety of neuronal defenses against neurologic
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insults; d) that GCs disrupt the mobilization of neurotrophins; e) that
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GCs have a variety of electrophysiological effects which can damage
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neurons. </strong>The relevance of each of those mechanisms to GC-induced
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atrophy, neurotoxicity and neuroendangerment is considered, as are the
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likely interactions among them. </p>
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<p>J Clin Endocrinol Metab 1996
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Oct;81(10):3639-43 <strong>Short-term estradiol treatment enhances pituitary-adrenal
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axis and sympathetic responses to psychosocial stress in healthy young
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men.</strong> Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers
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M, Rohleder N, Untiedt A, Hanker J, Pirke KM, Hellhammer DH Center for
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Psychobiological, University of Trier, Germany. <strong> Evidence from animal
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studies and clinical observations suggest that the activity of the pituitary-adrenal
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axis is under significant influence of sex steroids. The present study
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investigated how a short term elevation of estradiol levels affects
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ACTH, cortisol, norepinephrine, and heart rate responses to mental stress
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in healthy men. </strong>In a double blind study, 16 men received a patch
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delivering 0.1 mg estradiol/day transdermally, and age- and body mass
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index-matched control subjects received a placebo patch. Twenty-four
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to 48 h later, they were exposed to a brief psychosocial stressor (free
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speech and mental arithmetic in front of an audience). In response to
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the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart
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rate were increased in both experimental groups (all P < 0.0001).
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However, the<strong> estradiol-treated subjects showed exaggerated peak ACTH
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(P < 0.001) and cortisol (P < 0.002) responses compared to the
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placebo group. Also, the norepinephrine area under the response curve
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was greater in the estradiol group </strong>
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(P < 0.05). Although heart rate responses differences failed to reach
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statistical significance, they, too, tended to be larger in the estradiol
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group. Neither mood ratings before or after the stressor, nor ratings
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of the perception of the stressor could explain the observed endocrine
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response differences. In conclusion, <strong>short term estradiol administration
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resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine
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to psychosocial stress in healthy young men independent of psychological
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effects, </strong>as assessed in this study. </p>
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<p>J Appl Physiol 1996 Mar;80(3):931-9 <strong>
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Treadmill exercise training and estradiol increase plasma ACTH and prolactin
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after novel footshock.</strong> White-Welkley JE, Warren GL, Bunnell BN,
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Mougey EH, Meyerhoff JL, Dishman RK "We examined whether
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rats that were treadmill exercise trained (Tr) or chronically immobilized
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(CI) had similar responses by the hypothalamic-pituitary-adrenal (HPA)
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cortical axis to acute stress and whether the HPA responses interacted
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with the hypothalamic-pituitary-gonadal (HPG) axis." <strong>"[ACTH]
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and [prolactin</strong>] after<strong> footshock were higher in Tr rats with E2
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compared with CI and sedentary rats without E2;</strong> recovery levels
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for sedentary animals were higher after Run compared with Im. The elevation
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in [corticosterone] from minute 1 to 15 of recovery was higher after
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the familiar Run and Im conditions. Our findings are consistent with
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an increased responsiveness of the HPA axis to novel footshock after
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treadmill exercise training that is additionally modulated by the HPG
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axis." </p>
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<p>Endocrinology 1992 Sep;131(3):1261-9. <strong>
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Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone
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secretion, and glucocorticoid receptor-mediated functions in female
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rats.</strong> Burgess LH, Handa RJ "The effect of estrogen (E) on the
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hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley
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rats." "...the ACTH and CORT secretory responses to ether
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stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid
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receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls
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(P less than 0.05), <strong>but not in E-treated animals.</strong> These data
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suggest that E can impair glucocorticoid receptor-mediated delayed or
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slow negative feedback." "Thus, E<strong> treatment results in
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a loss of the glucocorticoid receptor's ability to autoregulate; this
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suggests that E may cause a functional impairment of the glucocorticoid
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receptor even though receptor binding appears normal. These findings
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suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis
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after stress in E-treated rats is due in part to impaired glucocorticoid
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receptor-mediated slow negative feedback." </strong></p>
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<p>Am J Physiol 1994 Jul;267(1
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Pt 1):E32-8 <strong>Lesions of hypothalamic paraventricular nuclei
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do not prevent the effect of estradiol on energy and fat balance.</strong>
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Dagnault A, Richard D. <strong>"Plasma levels of corticosterone
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and ACTH were higher in E2-treated rats than in animals receiving the
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placebo treatment. The present results provide evidence that the hypothalamic
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PVH is not an essential neuroanatomical structure in the effects of
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E2 on energy and fat balances." </strong></p>
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<p>Fertil Steril 1994 Oct;62(4):738-43 <strong>
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Ovarian suppression reduces clinical and endocrine expression of late-onset
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congenital adrenal hyperplasia due to 21-hydroxylase deficiency.</strong>
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Carmina E, Lobo RA "OBJECTIVE: To determine the effectiveness of
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GnRH-agonist (GnRH-a) treatment in women with late onset congenital
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adrenal hyperplasia." "CONCLUSIONS: Suppression of the ovary
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with GnRH-a treatment was beneficial in these patients with late-onset
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congenital adrenal hyperplasia. An ovarian influence on the clinical
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and biochemical findings of the disorder is suggested." </p>
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<p>Life Sci 1995;57(9):833-7. <strong>
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Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical
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cells of the rat adrenal cortex.</strong> Nowak KW, Neri G, Nussdorfer GG,
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Malendowicz LK "The effect of 17 beta-estradiol and testosterone
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on glucocorticoid secretion were studied in vitro by using dispersed
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inner adrenocortical cells obtained from gonadectomized female and male
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rats. Independently of the sex of animals, estradiol enhanced basal,
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but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone
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inhibited ACTH-stimulated, but not basal B output." "Testosterone
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inhibited by about 30% ACTH-stimulated PREG production and by about
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54% total post-PREG secretion (B was decreased to 56% of the control
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value, and other steroid hormones were below the limit of sensitivity
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of our assay system). These findings indicate that sex hormones directly
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affect rat adrenocortical secretion,<strong> mainly by acting on the rate-limiting
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step of steroidogenesis (i.e. the conversion of cholesterol to PREG);
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moreover, they suggest that testosterone is also able depress the activity
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of the enzymes operating distally to cholesterol side-chain cleavage." </strong></p>
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<p>J Endocrinol 1995 Feb;144(2):311-21 <strong>
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The influence of ovarian steroids on hypothalamic-pituitary-adrenal
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regulation in the female rat.</strong> Carey MP, Deterd CH, de Koning J,
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Helmerhorst F, de Kloet ER "The present study examined the
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association between hypothalamic- pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian
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axes. HPA activity determined by plasma levels of adrenocorticotropin
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(ACTH) and corticosterone (B) was assessed in intact female rats as
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a function of oestrous cycle stage under resting conditions and after
|
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exposure to a 20 min restraint stress. To delineate the roles of oestradiol
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and progesterone in HPA axis modulation, plasma concentrations of ACTH
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and B were determined in ovariectomised (OVX) animals treated with oestradiol
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and/or progesterone under resting conditions and during exposure to
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the stress of a novel environment. The effects of these steroid treatments
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on the transcription and/or binding properties of the two corticosteroid
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receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors,
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were also examined in hippocampal tissue, (i) Fluctuations in basal
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and<strong> stress-induced plasma ACTH and B concentrations were found during
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the oestrous cycle with highest levels at late pro-oestrus. (ii) In
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OVX steroid-replaced animals, basal and stress-induced activity was
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enhanced in oestradiol and oestradiol plus progesterone-treated animals
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compared with OVX controls." </strong>
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"In conclusion, we find that sex steroids modulate HPA activity
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and<strong> suggest that the observed effects of these steroids on hippocampal
|
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MR may underlie their concerted mechanism of action in inducing an enhanced
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activity at the period of late pro-oestrus." </strong></p>
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<p> J Clin Endocrinol Metab 1995
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Feb;80(2):603-7 <strong>The impact of estrogen on adrenal androgen sensitivity
|
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and secretion in polycystic ovary syndrome.</strong> Ditkoff EC, Fruzzetti
|
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F, Chang L, Stancyzk FZ, Lobo RA <strong>"Adrenal hyperandrogenism
|
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is a common feature of patients with polycystic ovary syndrome (PCO). </strong>
|
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This may be due to enhanced adrenal sensitivity to ACTH.<strong> Because
|
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enhanced ovarian androgen secretion does not appear to explain this
|
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phenomenon, we explored the role of estrogen in inducing enhanced adrenal
|
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sensitivity, in that a state of relative hyperestrogenism exists in
|
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PCO." </strong>"Steroid ratio<strong> responses to oCRH suggested that
|
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17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone)
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was lowered with estrogen suppression and increased again after transdermal
|
|
E2 administration."</strong> "In conclusion, these data provide<strong>
|
|
evidence that estrogen is at least one factor that influences adrenal
|
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androgen sensitivity in PCO and may help explain the frequent finding
|
|
of adrenal hyperandrogenism in this syndrome." </strong></p>
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<p>Endocrinology 1993 Nov;133(5):2284-91 <strong>
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Estrogen and hydroxysteroid sulfotransferases in guinea pig adrenal
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|
cortex: cellular and subcellular distributions.</strong> Whitnall MH, Driscoll
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|
WJ, Lee YC, Strott CA "The high concentration of EST immunoreactivity
|
|
in nuclei suggests that EST may play a role in modulating the<strong> ability
|
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of active estrogens to regulate gene expression in ACTH-responsive cells.
|
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The distribution of HST labeling suggests that sulfonation of adrenocortical
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|
3-hydroxysteroids takes place largely within smooth endoplasmic reticulum
|
|
in the zona reticularis in adult guinea pigs." </strong></p>
|
|
<p>J Clin Endocrinol Metab 1993
|
|
Sep;77(3):754-8. <strong>Interaction of insulin-like growth factor-II and
|
|
estradiol directs steroidogenesis in the human fetal adrenal toward
|
|
dehydroepiandrosterone sulfate production. </strong>
|
|
Mesiano S, Jaffe RB </p>
|
|
<p>J Clin Endocrinol Metab 1993
|
|
Aug;77(2):494-7. <strong>Estradiol stimulates cortisol production by adrenal
|
|
cells in estrogen-dependent primary adrenocortical nodular dysplasia.</strong>
|
|
Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe
|
|
JJ, Barrow R. Adrenal glands from a patient with ACTH-independent Cushing's
|
|
syndrome, whose symptoms worsened during pregnancy and oral contraceptive
|
|
use, were cultured in different concentrations of estradiol. Estradiol
|
|
stimulated cortisol secretion in a dose-response manner in the absence
|
|
of ACTH." . "This is the first description of estradiol stimulation
|
|
of cortisol production by cultured adrenal cells in ACTH-independent
|
|
Cushing's syndrome." </p>
|
|
<p>Endocrinology 1992 Nov;131(5):2430-6 <strong>
|
|
Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated
|
|
hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological
|
|
sexual dimorphism.</strong> Spinedi E, Suescun MO, Hadid R, Daneva T, Gaillard
|
|
RC "Bacterial lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal
|
|
axis by a mechanism involving the release of cytokines, which activate
|
|
the CRH-ACTH system and, as a result, increase glucocorticoid secretion. <strong>
|
|
In the present study we investigated the possibility that endogenous
|
|
sex hormones modulate the in vivo endotoxin-stimulated adrenal and immune
|
|
responses in adult BALB/c mice."</strong> "Our results indicate
|
|
that 1)<strong> randomly cycling female mice have significantly more pronounced
|
|
corticosterone secretion than males 2 h after endotoxin </strong>
|
|
injection, although the tumor necrosis factor responses were similar....". </p>
|
|
<p>J Neurosci Res 1995 Oct 1;42(2):228-35 <strong>
|
|
Activation of the hypothalamo-anterior pituitary corticotropin- releasing
|
|
hormone, adrenocorticotropin hormone and beta-endorphin systems during
|
|
the estradiol 17 beta-induced plasma LH surge in the ovariectomized
|
|
monkey.</strong> Kerdelhue B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik
|
|
Parsadaniantz S, Williams RF, Hodgen GD. "These results suggest
|
|
that there<strong> may be a marked activation of the hypothalamo-anterior
|
|
pituitary-adrenal axis during the negative and positive feedback phases
|
|
of the E2B-induced LH surge in the ovariectomized monkey." </strong>
|
|
</p>
|
|
<p>Biol Reprod 1995 Nov;53(5):996-1002 <strong>
|
|
Activation of the baboon fetal pituitary-adrenocortical axis at midgestation
|
|
by estrogen: responsivity of the fetal adrenal gland to adrenocorticotropic
|
|
hormone in vitro.</strong> Berghorn KA, Albrecht ED, Pepe G.J. </p>
|
|
<p>Fertil Steril 1996 May;65(5):950-3 <strong>
|
|
Ovarian hyperstimulation augments adrenal dehydro- epiandrosterone sulfate
|
|
secretion.</strong> Casson PR, Kristiansen SB, Umstot E, Carson SA, Buster
|
|
JE.</p>
|
|
<p>Hinyokika Kiyo 1997 Apr;43(4):275-8 <strong>
|
|
[A case of concurrent bilateral adrenocortical adenoma causing Cushing's
|
|
syndrome].</strong> Koga F, Sumi S, Umeda H, Maeda S, Honda M, Hosoya
|
|
Y, Yano M, Konita A, Suzuki S, Yoshida K. "All 14 previously reported
|
|
cases of bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome
|
|
as well as the present case were<strong> concurrent and dominant in females
|
|
of reproductive age. This suggests that some cofactors other than ACTH,
|
|
such as estrogen, contribute to the pathogenesis of BAA." </strong></p>
|
|
<p>Endocrinology 1991 Nov;129(5):2503-11 <strong>
|
|
Variations in the hypothalamic-pituitary-adrenal response to stress
|
|
during the estrous cycle in the rat.</strong> Viau V, Meaney MJ. <strong>"In
|
|
cycling rats, we found significantly higher peak ACTH (P less than 0.01)
|
|
and B (P less than 0.05) responses to stress during proestrus </strong>
|
|
compared to the estrous and diestrous phases." "In response
|
|
to<strong> stress, ACTH levels were higher (P less than 0.01) in the E' group
|
|
compared to the EP' and O' groups. </strong>
|
|
Although the peak B response was similar in all groups, the E' and EP'
|
|
groups secreted more B after the termination of stress than did the
|
|
O' group. Within the 20 min stress period,<strong> ACTH levels in the E'
|
|
group were significantly (P less than 0.05) higher at 5, 10, and 15
|
|
min after the onset of stress, compared to the EP' and O' groups. Plasma
|
|
B levels were significantly higher in the E' group at 5 and 10 min (P
|
|
less than 0.05 and P less than 0.01, respectively) compared to the EP'
|
|
and O' group. beta-endorphin-like immunoreactive responses to restraint
|
|
stress were also significantly higher in the E' group compared to the
|
|
EP' (P less than 0.05) and O'</strong> (P less than 0.01) groups. In contrast
|
|
to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection
|
|
in the E' group were comparable to O' animals. There was no effect of
|
|
E2 on ACTH clearance, whereas B clearance was enhanced in E' treated
|
|
animals vs. O'-treated animals. These results indicate that the HPA
|
|
axis in the female rat is most sensitive to stress during proestrous.
|
|
Such enhanced HPA responses to stress are limited to the early portion
|
|
of proestrous, <strong>as progesterone appears to inhibit the facilitatory
|
|
effects of estrogen on ACTH release during stress. </strong>
|
|
Taken together, these results suggest an ovarian influence on both activational
|
|
and inhibitory components of HPA activity." </p>
|
|
<p>Semin Reprod Endocrinol 1997
|
|
May;15(2):137-57 <strong>Adrenal involvement in polycystic ovary syndrome. </strong>
|
|
Gonzalez F. "Whereas 17,20 lyase hyperactivity diagnosed
|
|
by defined criteria in response to pharmacological ACTH may be an intrinsic
|
|
genetic defect, <strong>increases in 17,20 lyase activity and adrenal androgen
|
|
hyper-responsiveness to ACTH in response to physiological ACTH may be
|
|
promoted by the functional elevation of estrogen of ovarian origin in
|
|
PCOS. </strong>The latest in vitro data suggest the estrogen may elicit its
|
|
effect on the adrenal cortex through a receptor mediated mechanism."</p>
|
|
<p>Metabolism 1997 Aug;46(8):902-7. <strong>
|
|
Mild adrenal and ovarian steroidogenic abnormalities in hirsute women
|
|
without hyperandrogenemia: does idiopathic hirsutism exist?</strong> Escobar-Morreale
|
|
HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C <strong>"Basal
|
|
and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations
|
|
were reduced with ovarian suppression,</strong> but their net increment and
|
|
ratio to the increase of F in response to ACTH remained unchanged, <strong>
|
|
reflecting the ovarian contribution to the secretion of these steroids."</strong>. </p>
|
|
<p>Am J Physiol 1997 Apr;272(4
|
|
Pt 2):R1128-34.<strong> Modulation of ovine fetal adrenocorticotropin
|
|
secretion by androstenedione and 17beta-estradiol.</strong> Saoud CJ, Wood
|
|
CE "Parturition in sheep is initiated by increases in activity
|
|
of the fetal hypothalamic-pituitary-adrenal axis. We<strong> have previously
|
|
reported that cortisol negative feedback efficacy is decreased at the
|
|
end of gestation. </strong>The present study was designed to test the hypothesis
|
|
that<strong> increasing plasma estrogen and/or androgen concentrations in
|
|
the fetus might increase plasma adrenocorticotropic hormone (ACTH) concentration,
|
|
either by stimulating ACTH secretion or by altering the negative feedback</strong>
|
|
effect of cortisol on ACTH." "We conclude that increased fetal
|
|
cortisol and ACTH secretion at the end of gestation may be due to the
|
|
combined effects of the gonadal steroids in that<strong> estradiol increases
|
|
basal plasma ACTH secretion while androstenedione reduces cortisol
|
|
negative feedback efficacy." </strong></p>
|
|
<p>J Clin Endocrinol Metab 1998
|
|
Sep;83(9):3083-8. <strong> Menstrual abnormalities in women with Cushing's
|
|
disease are correlated with hypercortisolemia rather than raised circulating
|
|
androgen levels.</strong> Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD,
|
|
Perry LA, Grossman AB, Besser GM, Trainer PJ.</p>
|
|
<p>Eur J Endocrinol 1998 Apr;138(4):430-5. <strong>
|
|
Hypothalamo-pituitary-adrenal axis and adrenal function before and after
|
|
ovariectomy in premenopausal women.</strong> De Leo V, la Marca A, Talluri
|
|
B, D'Antona D, Morgante G <strong> The hypothalamo-pituitary-adrenal (HPA)
|
|
axis is modulated by sex hormones. Few data exist on the relation between
|
|
acute estrogen deficit and HPA axis response to corticotropin-releasing
|
|
hormone (CRH).</strong> The effects of a sudden drop in estradiol levels
|
|
on basal and CRH-stimulated levels of ACTH, cortisol, testosterone,
|
|
androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in
|
|
nine premenopausal women (44-48 years of age), before and after ovariectomy.
|
|
The CRH test was performed before and 8 days after ovariectomy.<strong> A
|
|
significant reduction in ACTH and adrenal steroids but not in cortisol
|
|
response to CRH was observed after ovariectomy. </strong>
|
|
The ratio of deltamax androstenedione/17-OHP after CRH stimulation was
|
|
substantially the same before and after ovariectomy, whereas <strong>deltamax
|
|
17-OHP/cortisol was significantly lower in ovariectomized</strong> women
|
|
showing increased 21- and 11beta-hydroxylase activity. The results show
|
|
that the acute estrogen deficit induces changes in the HPA xis characterized
|
|
by <strong>reduced stimulated secretion of ACTH and steroids</strong> but normal
|
|
stimulated cortisol production. </p>
|
|
<p>Biokhimiia 1987 Sep;52(9):1501-11 <strong>
|
|
[Activation of lipolysis and ketogenesis in tumor-bearing animals as
|
|
a reflection of chronic stress states].</strong> [Article in Russian] Chekulaev
|
|
VA, Shelepov VP, Pasha-zade GR, Shapot VS In order to elucidate the
|
|
peculiarities of brain metabolism in tumour-bearing organisms, the arterio-venous
|
|
(A-V) content of glucose, acetoacetate (Ac-Ac), beta-hydroxybutyrate
|
|
(beta-HB) and non-esterified fatty acids (NEFA) in growing Zajdela ascite
|
|
hepatoma (ZAH) and solid hepatoma 27 (H-27) was compared. Analysis of
|
|
metabolic patterns of healthy, starving and fed recipients (ZAH and
|
|
H-27) revealed the inadequacy of the concepts on anorexia as being the
|
|
cause of carbohydrate-lipid metabolic disturbances. In tumour-bearing
|
|
organisms <strong>lipolysis and ketogenesis reflect the tumour-induced chronic
|
|
stress.</strong> Absorption of beta-HB and release of Ac-Ac by brain
|
|
were observed at all stages of malignant growth. <strong>This is probably
|
|
due to a partial switch-over of brain metabolism to non-carbohydrate
|
|
energy sources. </strong>Besides, certain stages of tumour growth are associated
|
|
with <strong>active assimilation of NEFA by brain.</strong> A correlation between
|
|
the A-V difference with respect to glucose and Ac-Ac as well as between
|
|
the glucose and NEFA contents was established. It was assumed that the
|
|
A-V difference in glucose is the main regulator of ketone body metabolism. </p>
|
|
<p>R. Sanchez Olea, et al., <strong>
|
|
"Inhibition by polyunsaturated fatty acids of cell volume regulation
|
|
and osmolyte fluxes in astrocytes,"</strong> Amer. J. of Physiology--cell
|
|
physiology 38(1), C96-C102, 1995. <strong>"...potent blockers
|
|
of regulatory volume decrease and of the swelling-activated efflux of
|
|
taurine, D-aspartate,</strong> inositol, and I-125 (used as marker of Cl). <strong>
|
|
...oleic and ricinoleic acids and saturated fatty acids were ineffective."
|
|
"...polyunsaturated fatty acids directly inhibit the permeability
|
|
pathways correcting cell volume after swelling in cultured astrocytes."</strong></p>
|
|
<p> P.
|
|
H. Chan and R. A. Fishman, "<strong>Brain edema: Induction in
|
|
cortical slices by polyunsaturated fatty acids</strong>," Science 201,
|
|
358-369, 1978. "This cellular edema was specific, since <strong>
|
|
neither saturated fatty acids nor a fatty acid containing a single double
|
|
bond had such effect</strong>." </p>
|
|
<p> Endocrinology
|
|
1992 Aug;131(2):662-8 <strong>Estradiol selectively regulates agonist
|
|
binding sites on the N-methyl-D-aspartate receptor complex in the CA1
|
|
region of the hippocampus.</strong> Weiland NG. Laboratory of Neuroendocrinology,
|
|
Rockefeller University. <strong> "Estradiol alters cognitive function
|
|
and lowers the threshold for seizures in women and laboratory animals.
|
|
Both of these activities are modulated by the excitatory neurotransmitter
|
|
glutamate in the hippocampus. To assess the hypothesis that estradiol
|
|
increases the sensitivity of the hippocampus to glutamate activation
|
|
by increasing glutamate binding sites, the densities of N-methyl-D-aspartate
|
|
(NMDA) agonist sites...."</strong> "Two days of estradiol treatment
|
|
increased the density of NMDA agonist, but not of competitive nor noncompetitive
|
|
NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus." <strong>
|
|
"The increase in NMDA agonist sites with ovarian hormone treatment
|
|
should result in an increase in the sensitivity of the hippocampus to
|
|
glutamate activation which may mediate some of the effects of estradiol
|
|
on learning and epileptic seizure activity."</strong></p>
|
|
<p>J Neurochem 1994 Sep;63(3):953-62 <strong>
|
|
Corticosterone regulates heme oxygenase-2 and NO synthase transcription
|
|
and protein expression in rat brain.</strong> Weber CM, Eke BC, Maines MD.<strong>"We
|
|
suggest that glucocorticoid-mediated deficits in hippocampal functions
|
|
may reflect their negative effect on messenger-generating systems." </strong></p>
|
|
<p>
|
|
Gen Pharmacol 1993 Nov;24(6):1383-6 <strong> Changes in microtubular tau
|
|
protein after estrogen in a cultured human neuroblastoma cell line.</strong>
|
|
Lew GM. <strong>"4. The estrogen (10(-7) M) also caused a 31% reduction
|
|
in the total number of cells."</strong></p>
|
|
<p>Rodriguez, P; Fernandez-Galaz,
|
|
C; Tejero, A. <strong>Controlled neonatal exposure to estrogens: A
|
|
suitable tool for reproductive aging studies in the female rat.</strong>
|
|
Biology of Reproduction, v.49, n.2, (1993): 387-392.</p>
|
|
<p> O'Rourke, M T; Lipson, S F;
|
|
Ellison, P T. <strong>Ovarian function in the latter half of the reproductive
|
|
lifespan.</strong> American Journal of Human Biology, v.8, n.6, (1996):
|
|
751-759. </p>
|
|
<p>Schumacher, M; Robel, P; Baulieu,
|
|
E-E. <strong>Development and regeneration of the nervous system: A
|
|
role for neurosteroids.</strong> Developmental Neuroscience, v.18,
|
|
n.1-2, (1996): 6-21. </p>
|
|
<p> Life
|
|
Sci 1996;58(17):1461-7 <strong>The endogenous estrogen metabolite 2-methoxyestradiol
|
|
induces apoptotic neuronal cell death in vitro.</strong> Nakagawa-Yagi Y,
|
|
Ogane N, Inoki Y, Kitoh N. "We examined the effects of 2-methoxyestradiol,
|
|
a metabolite of estradiol, on cell death in retinoic acid (RA)-differentiated
|
|
neuroblastoma SH-SY5Y cell cultures. <strong>Cell death was induced by 2-methoxyestradiol
|
|
in a concentration- dependent manner</strong>."<strong> [</strong>Provides evidence]<strong>
|
|
"...for an endogenous neuroactive steroid metabolite in the etiology
|
|
of some neurodegenerative diseases."</strong></p>
|
|
<p>Recent Prog Horm Res 1997;52:279-303 <strong>
|
|
Aging of the female reproductive system: a window into brain aging.</strong>
|
|
Wise PM, Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney
|
|
JP, McShane T, Lloyd JM, Weiland NG <strong>"The menopause marks the
|
|
permanent end of fertility in women. It was once thought that the exhaustion
|
|
of ovarian follicles was the single, most important explanation for
|
|
the transition to the menopause. Over the past decade, this perception
|
|
has gradually changed with the realization that there are multiple pacemakers
|
|
of reproductive senescence. We will present evidence that lends credence
|
|
to the hypothesis that the central nervous system is a critical pacemaker
|
|
of reproductive aging and that changes at this level</strong> contribute
|
|
to the timing of the menopause." </p>
|
|
<p>Neuroendocrinology 1989 Nov;50(5):605-612 <strong>
|
|
N-methyl-aspartic acid lesions of the arcuate nucleus in adult C57BL/6J
|
|
mice: a new model for age-related lengthening of the estrous cycle.</strong>
|
|
May PC, Kohama SG, Finch CE. "We report a new effect of the excitotoxin
|
|
N-methyl-aspartic acid (NMA) on adult mice. Besides confirming cell
|
|
loss in the arcuate nucleus of animals treated as adults, we also observed
|
|
lengthened estrous cycles. Cycling female C57BL/6J mice were treated
|
|
with subcutaneous injections of NMA and estrous cycles monitored for
|
|
30 days. NMA treatment lengthened average estrous cycle length by 1
|
|
day, to 5.6 days."<strong> "Consistent with the regional pattern
|
|
of cell loss, little specific binding of any glutamatergic ligand was
|
|
observed in the VMN. NMA caused weight gain in all age groups."
|
|
"The transition from 4-day to 5- and 6-day estrous cycles produced
|
|
by NMA treatment mimics the early age-related changes in estrous cycle
|
|
patterns in rodents."</strong> This new model will be useful in analyzing
|
|
the contributions of neuroendocrine changes in the arcuate nucleus to
|
|
reproductive senescence." </p>
|
|
<p><strong>Pathologic effect of estradiol
|
|
on the hypothalamus.</strong> Brawer JR; Beaudet A; Desjardins GC; Schipper
|
|
HM. Biol Reprod, 1993 Oct, 49:4, 647-52. "In addition
|
|
to its multiple physiological actions, we have shown that estradiol
|
|
is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic
|
|
arcuate nucleus. The mechanism underlying this neurotoxic action appears
|
|
to involve the conversion of estradiol to catechol estrogen and subsequent
|
|
oxidation to o-semiquinone free radicals. The estradiol-induced loss
|
|
of beta-endorphin neurons engenders a compensatory increment in mu opioid
|
|
binding in the medial preoptic area rendering this region supersensitive
|
|
to residual beta-endorphin or to other endogenous opioids. The consequent
|
|
persistent opioid inhibition results in a cascade of neuroendocrine
|
|
deficits that are ultimately expressed as a chronically attenuated plasma
|
|
LH pattern to which the ovaries respond by becoming anovulatory and
|
|
polycystic. This neurotoxic action of estradiol may contribute to a
|
|
number of reproductive disorders in humans and in animals in which aberrant
|
|
hypothalamic function is a major component." </p>
|
|
<p><strong>Vitamin E protects hypothalamic
|
|
beta-endorphin neurons from estradiol neurotoxicity</strong>. Desjardins
|
|
GC; Beaudet A; Schipper HM; Brawer JR. Endocrinology, 1992 Nov, 131:5,
|
|
2482-4 <strong>"Estradiol valerate (EV) treatment has been shown to
|
|
result in the destruction of 60% of beta-endorphin neurons in the hypothalamic
|
|
arcuate nucleus."</strong> </p>
|
|
<p><strong>Estrogen-induced hypothalamic
|
|
beta-endorphin neuron loss: a possible model of hypothalamic aging.</strong>
|
|
Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Exp Gerontol,
|
|
1995 May-Aug, 30:3-4, 253-67 Over the course of normal aging,
|
|
all female mammals with regular cycles display an irreversible arrest
|
|
of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis
|
|
until death.<strong> Although it is widely accepted that exposure to estradiol
|
|
throughout life contributes to reproductive aging, a unified hypothesis
|
|
of the role of estradiol in reproductive senescence has yet to emerge.</strong>
|
|
Recent evidence derived from a rodent model of chronic estradiol-mediated
|
|
accelerated reproductive senescence now suggests such a hypothesis.
|
|
It has been shown that chronic estradiol exposure results in the <strong>
|
|
destruction of greater than 60% of all beta-endorphin neurons in the
|
|
arcuate nucleus </strong>while leaving other neuronal populations spared.
|
|
This loss of opioid neurons is prevented by treatment with antioxidants
|
|
indicating that it results from <strong>estradiol-induced formation of free
|
|
radicals. Furthermore, we have shown that this beta-endorphin cell loss
|
|
is followed by a compensatory upregulation of mu opioid receptors in
|
|
the vicinity of LHRH cell bodies.</strong> The increment in mu opioid receptors
|
|
presumably renders the opioid target cells supersensitive to either
|
|
residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin,
|
|
thus resulting in chronic opioid <strong>suppression of the pattern of LHRH
|
|
release, and subsequently that of LH.</strong> Indeed, prevention of the
|
|
neuroendocrine effects of estradiol by antioxidant treatment also <strong>
|
|
prevents the cascade of neuroendocrine aberrations resulting in anovulatory
|
|
acyclicity.</strong> The loss of beta-endorphin neurons along with the paradoxical
|
|
opioid supersensitivity which ensues, provides a unifying framework
|
|
in which to interpret the diverse features that characterize the reproductively
|
|
senescent female. </p>
|
|
<p><strong>The 21-aminosteroid antioxidant,
|
|
U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin
|
|
in adult female rats.</strong> Schipper HM; Desjardins GC; Beaudet A; Brawer
|
|
JR. Brain Res, 1994 Jul 25, 652:1, 161-3 <strong> "A single intramuscular
|
|
injection of 2 mg estradiol valerate (EV) results in neuronal degeneration
|
|
and beta-endorphin depletion in the hypothalamic arcuate nucleus of
|
|
adult female rats."</strong></p>
|
|
<p>J Neurochem 1998 Sep;71(3):1187-93 <strong>
|
|
Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity.</strong>
|
|
Brooke SM, Howard SA, Sapolsky RM "The HIV envelope glycoprotein,
|
|
gp120, a well documented neurotoxin, may be involved in AIDS-related
|
|
dementia complex. gp120 works through an NMDA receptor- and calcium-dependent
|
|
mechanism to damage neurons. We have previously demonstrated that both
|
|
natural and synthetic glucocorticoids (GCs) exacerbate gp120-induced
|
|
neurotoxicity and calcium mobilization in hippocampal mixed cultures.
|
|
GCs, steroid hormones secreted during stress, are now shown to work
|
|
in conjunction with gp120 to decrease ATP levels and to work synergistically
|
|
with gp120 to decrease the mitochondrial potential in hippocampal cultures. <strong>
|
|
Furthermore, energy supplementation blocked the ability of GCs to worsen
|
|
gp120's effects on neuronal survival and calcium mobilization.</strong> A
|
|
GC-induced reduction in glucose transport in hippocampal neurons, as
|
|
previously documented, may contribute to this energetic dependency.
|
|
These results may have clinical significance, considering the common
|
|
treatment of severe cases of Pneumocystis carinii pneumonia, typical
|
|
of HIV infection, with large doses of synthetic GCs." </p>
|
|
<p>Acta Otolaryngol Suppl (Stockh)
|
|
1990;476:32-6. <strong>Glutamate neurotoxicity in the cochlea: a possible
|
|
consequence of ischaemic or anoxic conditions occurring in ageing.</strong>
|
|
Pujol R, Rebillard G, Puel JL, Lenoir M, Eybalin M, Recasens M. </p>
|
|
<p>Br J Pharmacol 1996 Jan;117(1):189-95.<strong>
|
|
Metabotropic glutamate receptors, transmitter output and fatty acids:
|
|
studies in rat brain slices. </strong>Lombardi G, Leonardi P, Moroni F. "The
|
|
requirement of both unsaturated fatty acids and 1S,3R-ACPD in the facilitation
|
|
of transmitter exocytosis may play an important role in the regulation
|
|
of synaptic plasticity." </p>
|
|
<p>Adv Exp Med Biol 1992;318:147-58 <strong>
|
|
A role for the arachidonic acid cascade in fast synaptic modulation:
|
|
ion channels and transmitter uptake systems as target proteins.</strong>
|
|
Volterra A, Trotti D, Cassutti P, Tromba C, Galimberti R, Lecchi P,
|
|
Racagni G. "Recent evidence indicates that arachidonic acid
|
|
(AA) and its metabolites play a fast messenger role in synaptic modulation
|
|
in the CNS." "Other types of K+ channels in vertebrate excitable
|
|
cells have been found to be<strong> sensitive to arachidonic acid, lipoxygenase
|
|
products, and polyunsaturated fatty acids (PUFA). In the mammalian CNS,
|
|
arachidonic acid is released upon stimulation of N-methyl-D-aspartate
|
|
(NMDA)-type glutamate receptors." "Polyunsaturated fatty acids
|
|
mimic arachidonate with a rank of potency parallel to the degree of
|
|
unsaturation. Since the effect of glutamate on the synapses is terminated
|
|
by diffusion and uptake, a slowing of the termination process may potentiate
|
|
glutamate synaptic efficacy. However, excessive extracellular accumulation
|
|
of glutamate may lead to neurotoxicity." </strong></p>
|
|
<p>J Neurochem 1999 Jan;72(1):129-38<strong>.
|
|
Transient inhibition of glutamate uptake in vivo induces neurodegeneration
|
|
when energy metabolism is impaired. </strong>
|
|
Sanchez-Carbente MR, Massieu L<strong>. </strong>
|
|
"Impairment of glutamate transport during ischemia might be related
|
|
to the elevation of the extracellular concentration of glutamate and
|
|
ischemic neuronal damage. Additionally, impairment of energy metabolism
|
|
in vivo leads to neurodegeneration apparently mediated by a secondary
|
|
excitotoxic mechanism. In vitro observations show that glucose deprivation
|
|
and inhibition of energy metabolism exacerbate the toxic effects of
|
|
glutamate." <strong> "Our results show that glutamate uptake inhibition
|
|
leads to marked neuronal damage in energy-deficient rats but not in
|
|
intact animals...."</strong></p>
|
|
<p>J Neurochem 1998 Nov;71(5):1993-2005. <strong>
|
|
Glia modulate NMDA-mediated signaling in primary cultures of cerebellar
|
|
granule cells.</strong> Beaman-Hall CM, Leahy JC, Benmansour S, Vallano ML
|
|
"Nordihydroguaiaretic acid, a lipoxygenase inhibitor, blocked NMDA-mediated
|
|
toxicity in astrocyte-poor cultures, raising the possibility<strong> that
|
|
glia effectively reduce the accumulation of highly diffusible and toxic
|
|
arachidonic acid metabolites in</strong> neurons. Alternatively, glia may
|
|
alter neuronal development/phenotype in a manner that selectively reduces
|
|
susceptibility to NR-mediated toxicity." </p>
|
|
<p>J Neurosci 1997 Dec 1;17(23):9060-7<strong>.
|
|
Pyruvate protects neurons against hydrogen peroxide-induced toxicity. </strong>
|
|
Desagher S, Glowinski J, Premont J<strong>. "Pyruvate strongly protected
|
|
neurons against both H2O2 added to the external medium and H2O2 endogenously
|
|
produced through the redox cycling of the experimental quinone menadione.
|
|
The neuroprotective effect of pyruvate appeared to result rather from
|
|
the ability of alpha-ketoacids to undergo nonenzymatic decarboxylation
|
|
in the presence of H2O2 than from an improvement of energy metabolism.
|
|
Indeed, several other alpha-ketoacids, including alpha-ketobutyrate,
|
|
which is not an energy substrate, reproduced the neuroprotective effect
|
|
of pyruvate. In contrast, lactate, a neuronal energy substrate, did
|
|
not protect neurons from H2O2."</strong> "Together, these results
|
|
indicate that pyruvate efficiently protects neurons against both exogenous
|
|
and endogenous H2O2. Its low toxicity and its capacity to cross the
|
|
blood-brain barrier open a new therapeutic perspective in brain pathologies
|
|
in which H2O2 is involved."<strong> </strong></p>
|
|
<p>J Neurosci 1998 Jan 1;18(1):156-63<strong>.
|
|
Neuroprotective effects of creatine and cyclocreatine in animal models
|
|
of Huntington's disease. </strong>Matthews RT, Yang L, Jenkins BG, Ferrante
|
|
RJ, Rosen BR, Kaddurah-Daouk R, Beal MF<strong> . </strong></p>
|
|
<p> M.
|
|
C. Diamond, <strong><em>Enriching Heredity: The Importance of the Environment
|
|
on the Anatomy of the Brain.</em></strong> Free Press, N.Y., 1988.</p>
|
|
<p> C.
|
|
Finch and L. Hayflick, <strong><em>Handbook of the Biology of Aging.</em></strong>
|
|
Van Nostrand Reinhold, N.Y., 1977.</p>
|
|
<p>Swanson RA <strong>Physiologic
|
|
coupling of glial glycogen metabolism to neuronal activity in brain.</strong>
|
|
Can J Physiol Pharmacol, 1992, 70 Suppl:, S138-44. Brain glycogen
|
|
is localized almost exclusively to glia, where it undergoes continuous
|
|
utilization and resynthesis. We have shown that glycogen utilization
|
|
increases during tactile stimulation of the rat face and vibrissae.<strong>
|
|
Conversely, decreased neuronal activity during hibernation and anesthesia
|
|
is accompanied by a marked increase in brain glycogen content</strong>. These
|
|
observations support a link between neuronal activity and glial glycogen
|
|
metabolism. The energetics of glycogen metabolism suggest that glial
|
|
glycogen is mobilized to meet increased metabolic demands of glia rather
|
|
than to serve as a substrate for neuronal activity. An advantage to
|
|
the use of glycogen may be the potentially faster generation of ATP
|
|
from glycogen than from glucose. Alternatively, glycogen could be utilized
|
|
if glucose supply is transiently insufficient during the onset of increased
|
|
metabolic activity. Brain glycogen may have a <strong>dynamic role as a buffer
|
|
between the abrupt increases in focal metabolic demands that occur during
|
|
normal brain activity and the compensatory changes in focal cerebral
|
|
blood flow or oxidative metabolism.</strong> </p>
|
|
<p><strong>"Free fatty acids activate
|
|
the hypothalamic-pituitary-adrenocortical axis in rats." </strong>
|
|
Widmaier EP; Rosen K; Abbott B. <em>Endocrinology,</em><strong> </strong>
|
|
1992 Nov, 131:5, 2313-8. "Intravenous administration of Intralipid
|
|
10% increases blood levels of essential free fatty acids." "Since
|
|
corticosterone, the final secretory product of the rat hypothalamic-pituitary-adrenocortical
|
|
(HPA) axis, is also lipolytic, we tested the hypothesis that FFA would
|
|
inhibit the HPA axis." "At 60 min, plasma ACTH levels were
|
|
significantly elevated to over 1500 pg/ml in Intralipid-infused rats,
|
|
but were unchanged in saline controls. <strong>This dose of Intralipid increased
|
|
corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone
|
|
levels were still significantly greater</strong> than those in saline controls.
|
|
Lower doses of Intralipid also significantly elevated both FFA and corticosterone
|
|
levels, but by 180 min, levels of both were similar to those in controls."
|
|
"The results suggest that high circulating FFA levels activate,
|
|
rather than inhibit, the HPA axis in rats. Since stress activates glucocorticoid
|
|
production and<strong> increases FFA levels due to lipolysis, it is possible
|
|
that FFA and the HPA axis constitute a previously unrecognized positive
|
|
feedback loop."</strong></p>
|
|
<p><strong>"Impairment of glucose
|
|
disposal by infusion of triglycerides in humans: role of glycemia," </strong>
|
|
Felley CP; Felley EM; van Melle GD; Frascarolo P; Jéquier E; Felber
|
|
JP, Am J Physiol, 1989 Jun, 256:6 Pt 1, E747-52. <strong>"These results
|
|
suggest the existence of physiological regulatory mechanisms by which
|
|
1) the rise in plasma free fatty acid inhibits both oxidative and nonoxidative
|
|
glucose disposal, and 2) the rise in glycemia stimulates predominantly
|
|
nonoxidative glucose disposal."</strong></p>
|
|
<p>Nature 1998 Jan 15;391(6664):281-5<strong>.
|
|
Prostaglandins stimulate calcium-dependent glutamate release in astrocytes.</strong>
|
|
Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan
|
|
T, Volterra A<strong>. </strong>Astrocytes in the brain form an intimately
|
|
associated network with neurons. They respond to neuronal activity and
|
|
synaptically released glutamate by raising intracellular calcium concentration
|
|
([Ca2+]i), which could represent the start of back-signalling to neurons.<strong>
|
|
Here we show that coactivation of the AMPA/kainate and metabotropic
|
|
glutamate receptors (mGluRs) on astrocytes stimulates these cells to
|
|
release glutamate through a Ca2+-dependent process mediated by prostaglandins.
|
|
Pharmacological inhibition of prostaglandin synthesis prevents glutamate
|
|
release, whereas application of prostaglandins (in particular PGE2)
|
|
mimics and occludes the releasing action of GluR agonists. PGE2 promotes
|
|
Ca2+-dependent glutamate release from cultured astrocytes and also from
|
|
acute brain slices under conditions that suppress neuronal exocytotic
|
|
release. </strong>When applied to the CA1 hippocampal region, PGE2 induces
|
|
increases in [Ca2+]i both in astrocytes and in neurons. The [Ca2+]i
|
|
increase in neurons is mediated by glutamate released from astrocytes,
|
|
because it is abolished by GluR antagonists.<strong> Our results reveal a
|
|
new pathway of regulated transmitter release from astrocytes and outline
|
|
the existence of an integrated glutamatergic cross-talk between neurons
|
|
and astrocytes in situ that may play critical roles in synaptic plasticity
|
|
and in neurotoxicity. </strong></p>
|
|
<p>Prog Neurobiol 1998 Jan;54(1):99-125<strong>.
|
|
Microglia as effector cells in brain damage and repair: focus on prostanoids
|
|
and nitric oxide. </strong>Minghetti L, Levi G.<strong> </strong>
|
|
"The present article deals with two classes of compounds that activated
|
|
microglial cells can produce in large amounts: prostanoids (that derive
|
|
from arachidonic acid through the cyclooxygenase pathway), and nitric
|
|
oxide (that is synthesized from arginine by nitric oxide synthase).
|
|
Prostanoids and nitric oxide have a number of common targets, on which
|
|
they may exert similar or opposite actions, and have a crucial role
|
|
in the regulation of inflammation, immune responses and cell viability.
|
|
Their synthesis can massively increase when the inducible isoforms of
|
|
cyclooxygenase and nitric oxide synthase are expressed." </p>
|
|
<p>In Vitro Cell Dev Biol Anim
|
|
1998 Mar;34(3):265-74<strong>. Prostaglandins act as neurotoxin for differentiated
|
|
neuroblastoma cells in culture and increase levels of ubiquitin and
|
|
beta-amyloid. </strong>Prasad KN, La Rosa FG, Prasad JE<strong>. </strong>
|
|
"Although chronic inflammatory reactions have been proposed to
|
|
cause neuronal degeneration associated with Alzheimer's disease (AD),
|
|
the role of prostaglandins (PGs), one of the secretory products of inflammatory
|
|
reactions, in degeneration of nerve cells has not been studied. Our
|
|
initial observation that <strong>PGE1-induced differentiated neuroblastoma
|
|
(NB) cells degenerate in vitro more rapidly than those inducedby RO20-1724,
|
|
an inhibitor of cyclic nucleotide phosphodiesterase, has led us to postulate
|
|
that PGs act as a neurotoxin.</strong> This study has further investigated
|
|
the effects of PGs on differentiated NB cells in culture. Results showed
|
|
that PGA1 was more effective than PGE1 in causing degeneration of differentiated
|
|
NB cells as shown by the cytoplasmic vacuolation and fragmentation of
|
|
soma, nuclei, and neurites. Because increased levels of ubiquitin and
|
|
beta-amyloid have been implicated in causing neuronal degeneration,
|
|
we studied the effects of PGs on the levels of these proteins during
|
|
degeneration of NB cells in vitro...." "Results showed that
|
|
PGs increased the intracellular levels of ubiquitin and beta-amyloid
|
|
prior to degeneration, whereas the degenerated NB cells had negligible
|
|
levels of these proteins. <strong>These data suggest that PGs act as external
|
|
neurotoxic signals</strong> which increase levels of ubiquitin and beta-amyloid
|
|
that represent one of the intracellular signals for initiating degeneration
|
|
of nerve cells." </p>
|
|
<p>Brain Res Bull 1998 Apr;45(6):637-40. <strong>
|
|
The fatty acid composition of maternal diet affects the response to
|
|
excitotoxic neural injury in neonatal rat pups.</strong>Valencia P, Carver
|
|
JD, Wyble LE, Benford VJ, Gilbert-Barness E, Wiener DA, Phelps C<strong>
|
|
Fatty acids and their derivatives play a role in the response to neural
|
|
injury.</strong> The effects of prenatal and postnatal dietary fatty acid
|
|
composition on excitotoxic neural injury were investigated in neonatal
|
|
rat pups."</p>
|
|
<p>Proc Soc Exp Biol Med 1998
|
|
Nov;219(2):120-5<strong>. Prostaglandins as putative neurotoxins in Alzheimer's
|
|
disease.</strong> Prasad KN, Hovland AR, La Rosa FG, Hovland PG<strong>. </strong>
|
|
"Chronic inflammatory reactions in the brain appear to be one
|
|
of the primary etiological factors in the pathogenesis of Alzheimer's
|
|
disease (AD). This is supported by the fact that the secretory products
|
|
of inflammatory reactions, which include cytokines, complement proteins,
|
|
adhesion molecules, and free radicals, are neurotoxic. We have recently
|
|
reported that prostaglandins (PGs), which are also released during inflammatory
|
|
reactions, cause rapid degenerative changes in differentiated murine
|
|
neuroblastoma cells (NB) in culture." "The mechanisms underlying
|
|
Abeta-induced neuronal degeneration have been under intense investigation,
|
|
and several mechanisms of action have been proposed. We postulate that
|
|
PG-induced elevation of Abeta may lead to an increased binding of Abeta
|
|
to the 20S proteasome, resulting in a reduction of 20S proteasome-mediated
|
|
degradation of ubiquitin-conjugated proteins. This is predicted to lead
|
|
to an increase in an accumulation of abnormal proteins, which ultimately
|
|
contribute to neuronal degeneration and death. Based on our hypothesis
|
|
and on studies published by others, we propose that a combination of
|
|
nonsteroidal anti-inflammatory drugs, which inhibit the synthesis of
|
|
PGs, and antioxidant vitamins, which quench free radicals and both of
|
|
which have been recently reported to be of some value in AD treatment
|
|
when used-individually, may be much more effective in the prevention
|
|
and treatment of AD than the individual agents alone." </p>
|
|
<p>Mol Chem Neuropathol 1998 May;34(1):79-101<strong>.
|
|
Effects of EGb 761 on fatty acid reincorporation during reperfusion
|
|
following ischemia in the brain of the awake gerbil. </strong>
|
|
Rabin O, Drieu K, Grange E, Chang MC, Rapoport SI, Purdon AD<strong>. </strong></p>
|
|
<p><strong>Regulation of arcuate nucleus
|
|
synaptology by estrogen.</strong> Leedom L; Lewis C; Garcia-Segura LM; Naftolin
|
|
F. Ann N Y Acad Sci, 1994 Nov 14, 743:, 61-71 "Estrogen
|
|
modulates the synaptology of the hypothalamic arcuate nucleus during
|
|
sexual differentiation of the rat brain in both males and females. In <strong>
|
|
males, testosterone of gonadal origin is converted to estrogen in the
|
|
brain</strong> by an enzyme, aromatase, which is also present in females.
|
|
The exposure of the male's hypothalamus to relatively high levels of
|
|
estrogen (following a perinatal testosterone surge) leads to the development
|
|
of a pattern of synaptogenesis<strong> which does not support an estrogen-induced
|
|
gonadotrophin surge in the adult.</strong> In female rats, hypothalamic
|
|
development <strong>occurs with permissively low levels</strong> of estrogen,
|
|
enabling a midcycle estrogen-induced gonadotrophin surge and ovulation
|
|
in adulthood. During adult reproductive life in female rats, circulating
|
|
estrogen modulates the synaptology of the arcuate nucleus. <strong>The most
|
|
physiological example of this is the 30-50% loss of axosomatic synapses
|
|
following the preovulatory estrogen surge on diestrus-proestrus.</strong>
|
|
Studies on post-synaptic membranes of the arcuate nucleus reveal sex
|
|
differences in membrane organization and protein content which are estrogen-dependent. <strong>
|
|
Estrogen apparently stimulates endocytosis of areas of post-synaptic
|
|
membrane that are dense with small intramembranous protein particles,
|
|
resulting in a reduction in the number of small intramembranous particles.
|
|
This also appears to be the physiologic mechanism of neuronal changes
|
|
in females during the estrus cycle.</strong> Repeated exposure to preovulatory
|
|
levels of estrogen may lead to an age-related decline in reproductive
|
|
capacity in female rats. Aging females lose the estrogen-induced
|
|
gonadotrophin surge responsible for ovulation. <strong>This loss of function
|
|
may result from a cumulative estrogen effect during the repeated ovarian
|
|
cycles which results in a reorganization of the synaptology</strong> on which
|
|
regulates the estrogen-induced gonadotrophin surge." ".
|
|
. .recent research has shown that GABA, the monoamines, and several
|
|
neuropeptides are participants in the estrogen-sensitive network which
|
|
regulates GNRH secretion. In this regard, present work shows estrogen-induced
|
|
changes in GABA and dopamine synapses in the arcuate nucleus."</p>
|
|
<p><strong>17 beta Estradiol-induced
|
|
increase in brain dopamine D-2 receptor: antagonism by MIF-1.</strong> <strong>
|
|
Rajakumar G</strong>; Chiu P; Chiu S; Johnson RL; <strong>Mishra RK</strong> Department
|
|
of Psychiatry, Faculty of Health Sciences, McMaster University, Hamilton,
|
|
Ontario, Canada. Peptides, 1987 Nov-Dec, 8:6, 997-1002 Animal
|
|
behavioral and neurochemical studies implicate dopaminergic systems<strong>
|
|
in the neurological sequelae induced by estrogen.</strong> In the present
|
|
study, we demonstrated for the first time that MIF-1, a neuropeptide
|
|
unrelated to classical dopamine agonists, when given prior to, concurrently
|
|
with, and after 17 beta-estradiol, antagonized significantly the estrogen-induced
|
|
increase in the<strong> density of dopamine D-2 receptor</strong> both in the
|
|
striatum and the mesolimbic area of male rat brain. The current findings
|
|
have implications for the prophylactic and therapeutic potential for
|
|
MIF-1 in <strong>extrapyramidal motor disorders caused by estrogen imbalance
|
|
in humans.</strong></p>
|
|
<p>Eur J Clin Invest 1984 Dec;14(6):431-4 <strong>
|
|
Effect of ovulation on haem metabolism in rabbits.</strong> Lindahl
|
|
J, Werner B, Lerner R<strong>. "To investigate the origin of the cyclic
|
|
changes in the rate of endogenous carbon-monoxide production (nCO) during
|
|
the menstrual cycle, haem turnover was determined before and after chorion
|
|
gonadotropic hormone-induced ovulation in six female rabbits. 14C-labelled
|
|
delta-aminolevulinic acid and glycine were administered and the excretion
|
|
rate of 14CO (A14CO) was measured for determination of hepatic and</strong>
|
|
bone-marrow haem turnover, respectively." <strong> ". . . nCO was
|
|
increased 34% (P less than 0.05) during the post-ovulation period. As
|
|
the increase in 'unassigned' haem turnover was small and may be unaccompanied
|
|
by a contemporary increase in bilirubin/CO production, it was concluded
|
|
that the increase in nCO during the post-ovulation period essentially
|
|
depends on increased destruction of circulating red cells in the rabbit."</strong></p>
|
|
<p>J Neurotrauma 1993 Winter;10(4):373-84. <strong>
|
|
Beneficial effect of the nonselective opiate antagonist naloxone hydrochloride
|
|
and the thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term
|
|
neurobehavioral outcome following experimental brain injury in the rat. </strong>
|
|
McIntosh TK, Fernyak S, Hayes RL, Faden AI</p>
|
|
<p>J Neurosci 1990 Nov;10(11):3524-30. <strong>
|
|
Opiate antagonist nalmefene improves intracellular free Mg2+, bioenergetic
|
|
state, and neurologic outcome following traumatic brain injury in rats. </strong>
|
|
Vink R, McIntosh TK, Rhomhanyi R, Faden AI. "Treatment of CNS trauma
|
|
with the opiate antagonist naloxone improves outcome, though the mechanisms
|
|
of action remain speculative."</p>
|
|
<p>Brain Res 1989 Mar 20;482(2):252-60. <strong>
|
|
Magnesium protects against neurological deficit after brain injury.</strong>
|
|
McIntosh TK, Vink R, Yamakami I, Faden AI.</p>
|
|
<p>Adv Neurol 1988;47:531-46. <strong>
|
|
Role of thyrotropin-releasing hormone and opiate receptor antagonists
|
|
in limiting central nervous system injury.</strong> Faden AI. "Opiate
|
|
antagonists, including receptor antagonists and physiologic antagonists,
|
|
have been shown to produce beneficial effects in a variety of models
|
|
of CNS injury and in a variety of species. Opiate antagonists improve
|
|
spinal cord blood flow, electrical conduction of the spinal cord, pathological
|
|
changes, and motor recovery following traumatic spinal cord injury in
|
|
cats. TRH appears to be superior to naloxone in this regard, although
|
|
direct comparisons between receptor-selective opiate receptor antagonists
|
|
and TRH have not been made." </p>
|
|
<p>Exp Neurol 1994 Sep;129(1):64-9.<strong>Progesterone
|
|
facilitates cognitive recovery and reduces secondary neuronal loss caused
|
|
by cortical contusion injury in male rats.</strong> Roof RL, Duvdevani R,
|
|
Braswell L, Stein DG.</p>
|
|
<p>Exp Neurol 1996 Apr;138(2):246-51. <strong>
|
|
Progesterone rapidly decreases brain edema: treatment delayed up to
|
|
24 hours is still effective.</strong> Roof RL, Duvdevani R, Heyburn JW, Stein
|
|
DG.</p>
|
|
<p>Mol Chem Neuropathol 1997 May;31(1):1-11. <strong>
|
|
Progesterone protects against lipid peroxidation following traumatic
|
|
brain injury in rats.</strong> Roof RL, Hoffman SW, Stein DG.</p>
|
|
<p>Jiang N, et al. <strong>Progesterone
|
|
is neuroprotective after transient middle cerebral artery occlusion
|
|
in male rats.</strong> Brain Res. 1996 Sep 30;735(1):101-7. </p>
|
|
<p>Roof RL, et al. <strong>Progesterone
|
|
rapidly decreases brain edema: treatment delayed up to 24 hours is still
|
|
effective.</strong> Exp Neurol. 1996 Apr;138(2):246-51. </p>
|
|
<p>Duvdevani R, et al. <strong>Blood-brain
|
|
barrier breakdown and edema formation following frontal cortical contusion:
|
|
does hormonal status play a role?</strong> J Neurotrauma. 1995 Feb;12(1):65-75. </p>
|
|
<p>Exp Neurol 1997 Dec;148(2):453-63. <strong>
|
|
Endogenous repair after spinal cord contusion injuries in the rat. </strong>
|
|
Beattie MS, Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK,
|
|
Faden AI, Hsu CY, Noble LJ, Salzman S, Young W.<strong> "In addition
|
|
to signs of regeneration, we noted evidence for the proliferation of
|
|
cells located in the ependymal zone surrounding the central canal at
|
|
early times following contusion injuries."</strong>
|
|
</p>
|
|
</small>
|
|
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