Estrogen
and brain aging in men and women: Depression, energy, stress
Although the incidence of
Alzheimer's disease is 2 or 3 times as high among women as among men, there is
a major campaign under way to convince the public that taking estrogen
supplements will prevent the disease. Estrogen is now mainly promoted to prevent
osteoporosis (another problem that is more common in women) and heart disease
(which is more common in men).
This substance, which came into medical use as
"the female hormone" for the treatment of "female
problems," especially for improving fertility, and then for preventing
fertility as the oral contraceptive, is now being aimed primarily at the
post-reproductive population, for problems that are essentially unrelated to
femininity. It is, in fact, being presented to the public as something to
prevent major age-related conditions.
Brain degeneration, like osteoporosis, takes
years to develop. Analysis of letters written by young women, for example,
showed limited mental functioning in those who many years later developed
Alzheimer's disease, and young women who have small bones are the ones most
likely to develop osteoporosis later. It seems clear that the course of
degenerative aging processes is set in young adulthood (or even earlier), and
that it is never too early to be concerned with correcting processes that are
going in the wrong direction.(See Walker, et al., 1988, and Smith, et al.,
1992.)
In "The Biological Generality of
Progesterone" (1979) I proposed that the life-long trajectory of energy
production and longevity was strongly influenced by prenatal nutrition and
progesterone. This idea was based on work by people such as Marion Diamond, who
showed that prenatal progesterone enlarges the cortex of the brain, and that
estrogen makes it smaller, and Leonell Strong, who showed that a treatment that
lowered the estrogen function in a young mouse could produce cancer-free
offspring for several generations. Strong's work was very encouraging, because
it showed that biological problems that had been "bred in" over many
generations could be corrected by some simple metabolic treatments.
Seeing these profoundly toxic long-range effects
of estrogen, which shaped the animal's growth, development, function, and even
its heredity, made it important to learn how estrogen works, because such
fundamental changes covering the whole range of biology, produced by a simple
little molecule, promised to reveal interesting things about the nature of
life.
Aging is an energy problem, and in the brain,
which has extremely high energy requirements, interference with the energy
supply quickly causes cells to die.
I believe that estrogen's "principle,"
in all of its actions, is to interfere with the respiratory mode of energy
production. This is an integrating principle that explains estrogen's
immediate, direct effects on cells and organisms, which aren't explained by the
idea that it acts on the genes through a specific "estrogen
receptor." (It's hard to imagine, for example, how the "estrogen
receptor" doctrine could explain the fact that a single injection of
estrogen can kill a large portion of brain cells.) It explains why estrogen
causes cells to take up water, allowing calcium to enter, activating various
enzymes and cell division. On the organismic level, it explains why estrogen
mimics "shock," releasing histamine and activating the nervous and
glandular stress response system. The inefficiency of metabolism which doesn't
use oxygen in the normal way causes glucose to be used rapidly, and this in
itself is enough to trigger the release of pituitary ACTH and adrenal cortisol.
The ACTH, and related hormones, liberate free fatty acids, which cells take up
instead of glucose, and this (in the so-called Randall cycle) further limits
the body's ability to oxidize glucose.
People have spoken of "cascades" in
relation to the adrenal glucocorticoids (e.g., cortisol) and estrogen, leading
to cell damage, but really both of these hormonal cascades have to be seen as
part of a more general collapse of adaptive systems, as a result of both
chronic and immediate inadequacies of energy production.
Estrogen activates the adrenal stress reaction by
way of the hypothalamus and pituitary, by direct actions on the adrenal glands,
and by a variety of indirect effects, such as the increase of free fatty acids.
It activates the excitotoxic glutamic acid pathway, and interferes with
protective adenosine inhibition of nerves. It has both direct and indirect ways
of promoting the formation of nitric oxide and carbon monoxide. These, and
other estrogen-promoted factors, quickly and seriously interfere with
mitochondrial respiration. Many of these effects contribute to increased
intracellular calcium and free radical production, contributing to both the
excitatory excess and the energy deficit.
The biochemical details of these cascades are
mainly interesting because they show how many different kinds of stress
converge on a few physiological processess--mitochondrial energy production,
cellular excitation, and intercellular communication--which, when damaged
thousands of times, lead to the familiar states of old age. These few
functions, damaged by an infinite variety of stresses, have their own complexly
adaptive ways of deteriorating, producing the various degenerative diseases.
This perspective brings dementia, heart failure,
autoimmunity, immunodeficiency and other diseases of aging together, in ways
that allow generalized therapeutic and preventive approaches.
The antistress, antiestrogen approaches become
fundamental to prevention of aging.
The pro-estrogenic nature of the unsaturated
fatty acids is probably the biggest barrier to the radical elimination of
degenerative diseases. Various saturated fatty acids, including butyric,
octanoic, and palmitic, have protective effects on mitochondrial respiration.
Progesterone is the basic brain-protective
antiestrogen. It works to protect the brain at many levels (preventing lipid
peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.)
and it promotes repair and recovery.
Progesterone in most cases has effects opposite
to estrogen's, improving mitochondrial energy production while preventing
excessive excitation. Along with pregnenolone, progesterone is recognized as a
neurosteroid with anti-excitotoxic actions, with the ability to promote repair
and regeneration of the nervous system. (Roof, Stein, Faden; Schumacher, et
al.; Baulieu.)
The use of aspirin, which reduces inflammation
and inhibits the formation of neurotoxic prostaglandins, is known to be
associated with a lower incidence of Alzheimer's disease, and in other
contexts, it offers protection against estrogen. Naloxone, the antiendorphin,
has been found to reverse some of the cumulative effects of stress, restoring
some pituitary and ovarian function, and it promotes recovery after brain
injury; in a variety of ways, it corrects some of estrogen's toxic
effects.
Adenosine helps to maintain brain glycogen
stores, which are lost in stress and aging. Vitamin B12 protects against nitric
oxide, and improves alertness.
Pyruvic acid has brain-protective effects,
apparently through its decarboxylation (producing carbon dioxide) rather than
through its use as an energy source, since other ketoacids are similarly
protective. (The ketoacids occur in some natural foods.) The directly
brain-protective effect of carbon dioxide offers many clues that should be
interpreted in relation to estrogen's toxicity, since many of their effects on
nerves are opposite. Estrogen blocks the production of energy while it
stimulates nerve cells to use energy more rapidly, and carbon dioxide promotes
the production of energy, while restraining the excitation which expends
energy. The presence of carbon dioxide is an indicator of proper
mitochondrial respiratory functioning.
Pharmaceutical blockers of glutamic acid
transmission, and of calcium and sodium uptake, prevent some deterioration
following brain injury, but the most physiological way to protect against those
toxic processes is to maintain metabolic energy at a high level. Magnesium,
which is protective against excitatory damage and is a calcium antagonist,
tends to be retained in proportion to the activity of thyroid hormone.
As I have discussed previously, progesterone
alone has brought people out of post-epileptic dementia and senile dementia,
but it is reasonable to use a combined physiological approach, including
thyroid.
Besides providing new insights into biological
energy and aging, the recognition that estrogen activates the stress hormone
system--the pituitary-adrenal system--also provides clear insights into other
problems, such as the polycystic ovary syndrome, hirsutism, adrenal
hyperplasia, Cushing's disease, etc.
REFERENCES
[The references are clustered into groups,
showing estrogen's indirect toxicity through its activation of the adrenal
hormones, its direct brain-toxicity, and some of the interactions between these
and fats, nitric oxide, etc.]
.
Stress 1996 Jul;1(1):1-19 Stress,
Glucocorticoids, and Damage to the Nervous System: The Current State of
Confusion. Sapolsky RM Department of Biological Sciences, Stanford
University, Stanford, CA 94305. An extensive literature demonstrates
that glucocorticoids (GCs), the adrenal steroids secreted during stress, can
have a broad range of deleterious effects in the brain. The actions occur
predominately, but not exclusively, in the hippocampus, a structure rich in
corticosteroid receptors and particularly sensitive to GCs. The first half of
this review considers three types of GC effects: a) GC-induced atrophy, in
which a few weeks' exposure to high GC concentrations or to stress causes
reversible atrophy of dendritic processes in the hippocampus; b) GC
neurotoxicity where, over the course of months, GC exposure kills hippocampal
neurons; c) GC neuroendangerment, in which elevated GC concentrations at the
time of a neurological insult such as a stroke or seizure impairs the ability
of neurons to survive the insult. The second half considers the rather
confusing literature as to the possible mechanisms underlying these
deleterious GC actions. Five broad themes are discerned: a) that GCs induce a
metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that
GCs exacerbate various steps in a damaging cascade of glutamate excess,
calcium mobilization and oxygen radical generation. In a review a number of
years ago, I concluded that these two components accounted for the deleterious
GC effects. Specifically, the energetic vulnerability induced by GCs left
neurons metabolically compromised, and less able to carry out the costly task
of containing glutamate, calcium and oxygen radicals. More recent work has
shown this conclusion to be simplistic, and GC actions are shown to probably
involve at least three additional components: c) that GCs impair a variety of
neuronal defenses against neurologic insults; d) that GCs disrupt the
mobilization of neurotrophins; e) that GCs have a variety of
electrophysiological effects which can damage neurons. The relevance
of each of those mechanisms to GC-induced atrophy, neurotoxicity and
neuroendangerment is considered, as are the likely interactions among them.
J Clin Endocrinol Metab 1996 Oct;81(10):3639-43 Short-term
estradiol treatment enhances pituitary-adrenal axis and sympathetic responses
to psychosocial stress in healthy young men. Kirschbaum C, Schommer N,
Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J,
Pirke KM, Hellhammer DH Center for Psychobiological, University of Trier,
Germany.Evidence from animal studies and clinical observations suggest that
the activity of the pituitary-adrenal axis is under significant influence of
sex steroids. The present study investigated how a short term elevation of
estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate
responses to mental stress in healthy men. In a double blind study, 16
men received a patch delivering 0.1 mg estradiol/day transdermally, and age-
and body mass index-matched control subjects received a placebo patch.
Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor
(free speech and mental arithmetic in front of an audience). In response to the
psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were
increased in both experimental groups (all P < 0.0001). However, the estradiol-treated
subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P <
0.002) responses compared to the placebo group. Also, the norepinephrine area
under the response curve was greater in the estradiol group (P <
0.05). Although heart rate responses differences failed to reach statistical
significance, they, too, tended to be larger in the estradiol group. Neither
mood ratings before or after the stressor, nor ratings of the perception of the
stressor could explain the observed endocrine response differences. In
conclusion, short term estradiol administration resulted in
hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial
stress in healthy young men independent of psychological effects, as
assessed in this study.
J Appl Physiol 1996 Mar;80(3):931-9 Treadmill
exercise training and estradiol increase plasma ACTH and prolactin after novel
footshock. White-Welkley JE, Warren GL, Bunnell BN, Mougey EH,
Meyerhoff JL, Dishman RK "We examined whether rats that were treadmill
exercise trained (Tr) or chronically immobilized (CI) had similar responses by
the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and
whether the HPA responses interacted with the hypothalamic-pituitary-gonadal
(HPG) axis." "[ACTH] and [prolactin] after footshock
were higher in Tr rats with E2 compared with CI and sedentary rats without E2; recovery
levels for sedentary animals were higher after Run compared with Im. The
elevation in [corticosterone] from minute 1 to 15 of recovery was higher after
the familiar Run and Im conditions. Our findings are consistent with an
increased responsiveness of the HPA axis to novel footshock after treadmill
exercise training that is additionally modulated by the HPG axis."
Endocrinology 1992 Sep;131(3):1261-9. Chronic
estrogen-induced alterations in adrenocorticotropin and corticosterone
secretion, and glucocorticoid receptor-mediated functions in female rats. Burgess
LH, Handa RJ "The effect of estrogen (E) on the
hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley
rats." "...the ACTH and CORT secretory responses to ether stress could
be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor
agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but
not in E-treated animals. These data suggest that E can impair
glucocorticoid receptor-mediated delayed or slow negative feedback."
"Thus, E treatment results in a loss of the glucocorticoid
receptor's ability to autoregulate; this suggests that E may cause a functional
impairment of the glucocorticoid receptor even though receptor binding appears
normal. These findings suggest that hyperactivation of the
hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in
part to impaired glucocorticoid receptor-mediated slow negative feedback."
Am J Physiol 1994 Jul;267(1 Pt 1):E32-8 Lesions
of hypothalamic paraventricular nuclei do not prevent the effect of estradiol
on energy and fat balance. Dagnault A, Richard D. "Plasma
levels of corticosterone and ACTH were higher in E2-treated rats than in
animals receiving the placebo treatment. The present results provide evidence
that the hypothalamic PVH is not an essential neuroanatomical structure in the
effects of E2 on energy and fat balances."
Fertil Steril 1994 Oct;62(4):738-43 Ovarian
suppression reduces clinical and endocrine expression of late-onset congenital
adrenal hyperplasia due to 21-hydroxylase deficiency. Carmina E, Lobo
RA "OBJECTIVE: To determine the effectiveness of GnRH-agonist (GnRH-a)
treatment in women with late onset congenital adrenal hyperplasia."
"CONCLUSIONS: Suppression of the ovary with GnRH-a treatment was
beneficial in these patients with late-onset congenital adrenal hyperplasia. An
ovarian influence on the clinical and biochemical findings of the disorder is
suggested."
Life Sci 1995;57(9):833-7. Effects of sex
hormones on the steroidogenic activity of dispersed adrenocortical cells of the
rat adrenal cortex. Nowak KW, Neri G, Nussdorfer GG, Malendowicz LK
"The effect of 17 beta-estradiol and testosterone on glucocorticoid
secretion were studied in vitro by using dispersed inner adrenocortical cells
obtained from gonadectomized female and male rats. Independently of the sex of
animals, estradiol enhanced basal, but not ACTH-stimulated corticosterone (B)
secretion; conversely, testosterone inhibited ACTH-stimulated, but not basal B
output." "Testosterone inhibited by about 30% ACTH-stimulated PREG
production and by about 54% total post-PREG secretion (B was decreased to 56%
of the control value, and other steroid hormones were below the limit of sensitivity
of our assay system). These findings indicate that sex hormones directly affect
rat adrenocortical secretion, mainly by acting on the rate-limiting
step of steroidogenesis (i.e. the conversion of cholesterol to PREG); moreover,
they suggest that testosterone is also able depress the activity of the enzymes
operating distally to cholesterol side-chain cleavage."
J Endocrinol 1995 Feb;144(2):311-21 The
influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in
the female rat. Carey MP, Deterd CH, de Koning J, Helmerhorst F, de
Kloet ER "The present study examined the association between hypothalamic-
pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity
determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone
(B) was assessed in intact female rats as a function of oestrous cycle stage
under resting conditions and after exposure to a 20 min restraint stress. To
delineate the roles of oestradiol and progesterone in HPA axis modulation,
plasma concentrations of ACTH and B were determined in ovariectomised (OVX)
animals treated with oestradiol and/or progesterone under resting conditions
and during exposure to the stress of a novel environment. The effects of these
steroid treatments on the transcription and/or binding properties of the two
corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR)
receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal
and stress-induced plasma ACTH and B concentrations were found during
the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX
steroid-replaced animals, basal and stress-induced activity was enhanced in
oestradiol and oestradiol plus progesterone-treated animals compared with OVX
controls." "In conclusion, we find that sex steroids
modulate HPA activity and suggest that the observed effects of these
steroids on hippocampal MR may underlie their concerted mechanism of action in
inducing an enhanced activity at the period of late pro-oestrus."
J Clin Endocrinol Metab 1995 Feb;80(2):603-7 The
impact of estrogen on adrenal androgen sensitivity and secretion in polycystic
ovary syndrome. Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo RA "Adrenal
hyperandrogenism is a common feature of patients with polycystic ovary syndrome
(PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because
enhanced ovarian androgen secretion does not appear to explain this phenomenon,
we explored the role of estrogen in inducing enhanced adrenal sensitivity, in
that a state of relative hyperestrogenism exists in PCO." "Steroid
ratio responses to oCRH suggested that 17,20-desmolase activity (delta
maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with
estrogen suppression and increased again after transdermal E2
administration." "In conclusion, these data provide evidence
that estrogen is at least one factor that influences adrenal androgen
sensitivity in PCO and may help explain the frequent finding of adrenal
hyperandrogenism in this syndrome."
Endocrinology 1993 Nov;133(5):2284-91 Estrogen
and hydroxysteroid sulfotransferases in guinea pig adrenal cortex: cellular and
subcellular distributions. Whitnall MH, Driscoll WJ, Lee YC, Strott CA
"The high concentration of EST immunoreactivity in nuclei suggests that
EST may play a role in modulating the ability of active estrogens to
regulate gene expression in ACTH-responsive cells. The distribution of HST
labeling suggests that sulfonation of adrenocortical 3-hydroxysteroids takes
place largely within smooth endoplasmic reticulum in the zona reticularis in
adult guinea pigs."
J Clin Endocrinol Metab 1993 Sep;77(3):754-8. Interaction
of insulin-like growth factor-II and estradiol directs steroidogenesis in the
human fetal adrenal toward dehydroepiandrosterone sulfate production. Mesiano
S, Jaffe RB
J Clin Endocrinol Metab 1993 Aug;77(2):494-7. Estradiol
stimulates cortisol production by adrenal cells in estrogen-dependent primary
adrenocortical nodular dysplasia. 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."
Endocrinology 1992 Nov;131(5):2430-6 Effects
of gonadectomy and sex hormone therapy on the endotoxin-stimulated
hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological
sexual dimorphism. 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. 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." "Our results
indicate that 1) randomly cycling female mice have significantly more
pronounced corticosterone secretion than males 2 h after endotoxin injection,
although the tumor necrosis factor responses were similar....".
J Neurosci Res 1995 Oct 1;42(2):228-35 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. Kerdelhue
B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik Parsadaniantz S, Williams RF,
Hodgen GD. "These results suggest that there 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."
Biol Reprod 1995 Nov;53(5):996-1002 Activation
of the baboon fetal pituitary-adrenocortical axis at midgestation by estrogen:
responsivity of the fetal adrenal gland to adrenocorticotropic hormone in
vitro. Berghorn KA, Albrecht ED, Pepe G.J.
Fertil Steril 1996 May;65(5):950-3 Ovarian
hyperstimulation augments adrenal dehydro- epiandrosterone sulfate secretion.Casson
PR, Kristiansen SB, Umstot E, Carson SA, Buster JE.
Hinyokika Kiyo 1997 Apr;43(4):275-8 [A
case of concurrent bilateral adrenocortical adenoma causing Cushing's
syndrome].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 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."
Endocrinology 1991 Nov;129(5):2503-11 Variations
in the hypothalamic-pituitary-adrenal response to stress during the estrous
cycle in the rat. Viau V, Meaney MJ. "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 compared to the estrous and
diestrous phases." "In response to stress, ACTH levels were
higher (P less than 0.01) in the E' group compared to the EP' and O' groups. 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, 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' (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, as
progesterone appears to inhibit the facilitatory effects of estrogen on ACTH
release during stress. Taken together, these results suggest an
ovarian influence on both activational and inhibitory components of HPA
activity."
Semin Reprod Endocrinol 1997 May;15(2):137-57 Adrenal
involvement in polycystic ovary syndrome. Gonzalez F. "Whereas
17,20 lyase hyperactivity diagnosed by defined criteria in response to
pharmacological ACTH may be an intrinsic genetic defect, 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. The latest in vitro data suggest
the estrogen may elicit its effect on the adrenal cortex through a receptor
mediated mechanism."
Metabolism 1997 Aug;46(8):902-7. Mild
adrenal and ovarian steroidogenic abnormalities in hirsute women without
hyperandrogenemia: does idiopathic hirsutism exist? Escobar-Morreale HF,
Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C "Basal
and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations
were reduced with ovarian suppression, but their net increment and
ratio to the increase of F in response to ACTH remained unchanged, reflecting
the ovarian contribution to the secretion of these steroids.".
Am J Physiol 1997 Apr;272(4 Pt 2):R1128-34. Modulation
of ovine fetal adrenocorticotropin secretion by androstenedione and
17beta-estradiol. Saoud CJ, Wood CE "Parturition in sheep is
initiated by increases in activity of the fetal hypothalamic-pituitary-adrenal
axis. We have previously reported that cortisol negative feedback
efficacy is decreased at the end of gestation. The present study was
designed to test the hypothesis that 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 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 estradiol
increases basal plasma ACTH secretion while androstenedione reduces cortisol
negative feedback efficacy."
J Clin Endocrinol Metab 1998 Sep;83(9):3083-8. Menstrual
abnormalities in women with Cushing's disease are correlated with
hypercortisolemia rather than raised circulating androgen levels. Lado-Abeal
J, Rodriguez-Arnao J, Newell-Price JD, Perry LA, Grossman AB, Besser GM,
Trainer PJ.
Eur J Endocrinol 1998 Apr;138(4):430-5. Hypothalamo-pituitary-adrenal
axis and adrenal function before and after ovariectomy in premenopausal women. De
Leo V, la Marca A, Talluri B, D'Antona D, Morgante G 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). 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. A
significant reduction in ACTH and adrenal steroids but not in cortisol response
to CRH was observed after ovariectomy.The ratio of deltamax
androstenedione/17-OHP after CRH stimulation was substantially the same before
and after ovariectomy, whereasdeltamax 17-OHP/cortisol was significantly
lower in ovariectomized women showing increased 21- and
11beta-hydroxylase activity. The results show that the acute estrogen deficit
induces changes in the HPA xis characterized by reduced stimulated
secretion of ACTH and steroids but normal stimulated cortisol
production.
Biokhimiia 1987 Sep;52(9):1501-11 [Activation
of lipolysis and ketogenesis in tumor-bearing animals as a reflection of
chronic stress states]. [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 lipolysis and ketogenesis reflect the
tumour-induced chronic stress. Absorption of beta-HB and release of
Ac-Ac by brain were observed at all stages of malignant growth. This is
probably due to a partial switch-over of brain metabolism to non-carbohydrate
energy sources. Besides, certain stages of tumour growth are
associated with active assimilation of NEFA by brain. 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.
R. Sanchez Olea, et al., "Inhibition
by polyunsaturated fatty acids of cell volume regulation and osmolyte fluxes in
astrocytes," Amer. J. of Physiology--cell physiology 38(1),
C96-C102, 1995. "...potent blockers of regulatory volume decrease
and of the swelling-activated efflux of taurine, D-aspartate, inositol,
and I-125 (used as marker of Cl). ...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."
P. H. Chan and R. A. Fishman, "Brain
edema: Induction in cortical slices by polyunsaturated fatty acids,"
Science 201, 358-369, 1978. "This cellular edema was specific, since neither
saturated fatty acids nor a fatty acid containing a single double bond had such
effect."
Endocrinology 1992 Aug;131(2):662-8 Estradiol
selectively regulates agonist binding sites on the N-methyl-D-aspartate
receptor complex in the CA1 region of the hippocampus. Weiland NG.
Laboratory of Neuroendocrinology, Rockefeller University."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...." "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." "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."
J Neurochem 1994 Sep;63(3):953-62 Corticosterone
regulates heme oxygenase-2 and NO synthase transcription and protein expression
in rat brain. Weber CM, Eke BC, Maines MD."We suggest that
glucocorticoid-mediated deficits in hippocampal functions may reflect their
negative effect on messenger-generating systems."
Gen Pharmacol 1993 Nov;24(6):1383-6 Changes
in microtubular tau protein after estrogen in a cultured human neuroblastoma
cell line. Lew GM. "4. The estrogen (10(-7) M) also
caused a 31% reduction in the total number of cells."
Rodriguez, P; Fernandez-Galaz, C; Tejero, A. Controlled
neonatal exposure to estrogens: A suitable tool for reproductive aging studies
in the female rat. Biology of Reproduction, v.49, n.2, (1993):
387-392.
O'Rourke, M T; Lipson, S F; Ellison, P T. Ovarian
function in the latter half of the reproductive lifespan. American
Journal of Human Biology, v.8, n.6, (1996): 751-759.
Schumacher, M; Robel, P; Baulieu, E-E. Development
and regeneration of the nervous system: A role for neurosteroids.Developmental
Neuroscience, v.18, n.1-2, (1996): 6-21.
Life Sci 1996;58(17):1461-7 The
endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic neuronal
cell death in vitro. 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. Cell death was induced by 2-methoxyestradiol in a
concentration- dependent manner." [Provides evidence] "...for
an endogenous neuroactive steroid metabolite in the etiology of some
neurodegenerative diseases."
Recent Prog Horm Res 1997;52:279-303 Aging
of the female reproductive system: a window into brain aging. Wise PM,
Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney JP, McShane T,
Lloyd JM, Weiland NG "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 contribute to the timing of the menopause."
Neuroendocrinology 1989 Nov;50(5):605-612 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. 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." "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." This new model will be useful in analyzing the
contributions of neuroendocrine changes in the arcuate nucleus to reproductive
senescence."
Pathologic effect of estradiol on the
hypothalamus. 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."
Vitamin E protects hypothalamic beta-endorphin
neurons from estradiol neurotoxicity.
Desjardins GC; Beaudet A; Schipper HM; Brawer JR. Endocrinology, 1992 Nov,
131:5, 2482-4 "Estradiol valerate (EV) treatment has been shown to
result in the destruction of 60% of beta-endorphin neurons in the hypothalamic
arcuate nucleus."
Estrogen-induced hypothalamic beta-endorphin
neuron loss: a possible model of hypothalamic aging. 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. 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. 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 destruction of greater than 60% of
all beta-endorphin neurons in the arcuate nucleus while leaving other
neuronal populations spared. This loss of opioid neurons is prevented by
treatment with antioxidants indicating that it results from 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. 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 suppression of the pattern of LHRH release,
and subsequently that of LH. Indeed, prevention of the neuroendocrine
effects of estradiol by antioxidant treatment also prevents the cascade
of neuroendocrine aberrations resulting in anovulatory acyclicity. 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.
The 21-aminosteroid antioxidant, U74389F,
prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult
female rats. Schipper HM; Desjardins GC; Beaudet A;
Brawer JR. Brain Res, 1994 Jul 25, 652:1, 161-3 "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."
J Neurochem 1998 Sep;71(3):1187-93 Energy
dependency of glucocorticoid exacerbation of gp120 neurotoxicity. 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. Furthermore, energy supplementation
blocked the ability of GCs to worsen gp120's effects on neuronal survival and
calcium mobilization. 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."
Acta Otolaryngol Suppl (Stockh) 1990;476:32-6. Glutamate
neurotoxicity in the cochlea: a possible consequence of ischaemic or anoxic
conditions occurring in ageing. Pujol R, Rebillard G, Puel JL, Lenoir
M, Eybalin M, Recasens M.
Br J Pharmacol 1996 Jan;117(1):189-95. Metabotropic
glutamate receptors, transmitter output and fatty acids: studies in rat brain
slices. 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."
Adv Exp Med Biol 1992;318:147-58 A role
for the arachidonic acid cascade in fast synaptic modulation: ion channels and
transmitter uptake systems as target proteins. 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 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."
J Neurochem 1999 Jan;72(1):129-38. Transient
inhibition of glutamate uptake in vivo induces neurodegeneration when energy
metabolism is impaired. Sanchez-Carbente MR, Massieu L. "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." "Our
results show that glutamate uptake inhibition leads to marked neuronal damage
in energy-deficient rats but not in intact animals...."
J Neurochem 1998 Nov;71(5):1993-2005. Glia
modulate NMDA-mediated signaling in primary cultures of cerebellar granule
cells. 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 that
glia effectively reduce the accumulation of highly diffusible and toxic
arachidonic acid metabolites in neurons. Alternatively, glia may alter
neuronal development/phenotype in a manner that selectively reduces
susceptibility to NR-mediated toxicity."
J Neurosci 1997 Dec 1;17(23):9060-7. Pyruvate
protects neurons against hydrogen peroxide-induced toxicity. Desagher
S, Glowinski J, Premont J. "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." "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."
J Neurosci 1998 Jan 1;18(1):156-63.
Neuroprotective effects of creatine and cyclocreatine in animal models of
Huntington's disease. Matthews RT, Yang L, Jenkins BG, Ferrante RJ,
Rosen BR, Kaddurah-Daouk R, Beal MF .
M. C. Diamond, Enriching Heredity: The
Importance of the Environment on the Anatomy of the Brain. Free
Press, N.Y., 1988.
C. Finch and L. Hayflick, Handbook of
the Biology of Aging. Van Nostrand Reinhold, N.Y., 1977.
Swanson RA Physiologic coupling of glial
glycogen metabolism to neuronal activity in brain. 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. Conversely, decreased neuronal activity
during hibernation and anesthesia is accompanied by a marked increase in brain
glycogen content. 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 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.
"Free fatty acids activate the
hypothalamic-pituitary-adrenocortical axis in rats." Widmaier EP; Rosen K; Abbott B.Endocrinology, 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. This
dose of Intralipid increased corticosterone levels by nearly 20-fold at 120
min. At 180 min, corticosterone levels were still significantly greater 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 increases FFA levels due to
lipolysis, it is possible that FFA and the HPA axis constitute a previously
unrecognized positive feedback loop."
"Impairment of glucose disposal by infusion
of triglycerides in humans: role of glycemia," Felley CP; Felley EM; van Melle GD; Frascarolo P; Jéquier E;
Felber JP, Am J Physiol, 1989 Jun, 256:6 Pt 1, E747-52. "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."
Nature 1998 Jan 15;391(6664):281-5.
Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Bezzi
P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A. 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. 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. 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. 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.
Prog Neurobiol 1998 Jan;54(1):99-125.
Microglia as effector cells in brain damage and repair: focus on prostanoids
and nitric oxide. Minghetti L, Levi G. "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."
In Vitro Cell Dev Biol Anim 1998 Mar;34(3):265-74.
Prostaglandins act as neurotoxin for differentiated neuroblastoma cells in
culture and increase levels of ubiquitin and beta-amyloid. Prasad KN,
La Rosa FG, Prasad JE. "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 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. 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. These data suggest that PGs act as external neurotoxic
signals which increase levels of ubiquitin and beta-amyloid that
represent one of the intracellular signals for initiating degeneration of nerve
cells."
Brain Res Bull 1998 Apr;45(6):637-40. The
fatty acid composition of maternal diet affects the response to excitotoxic
neural injury in neonatal rat pups.Valencia P, Carver JD, Wyble LE, Benford
VJ, Gilbert-Barness E, Wiener DA, Phelps C Fatty acids and their
derivatives play a role in the response to neural injury. The effects
of prenatal and postnatal dietary fatty acid composition on excitotoxic neural
injury were investigated in neonatal rat pups."
Proc Soc Exp Biol Med 1998 Nov;219(2):120-5.
Prostaglandins as putative neurotoxins in Alzheimer's disease. Prasad
KN, Hovland AR, La Rosa FG, Hovland PG. "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."
Mol Chem Neuropathol 1998 May;34(1):79-101.
Effects of EGb 761 on fatty acid reincorporation during reperfusion following
ischemia in the brain of the awake gerbil. Rabin O, Drieu K, Grange E,
Chang MC, Rapoport SI, Purdon AD.
Regulation of arcuate nucleus synaptology by
estrogen. 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 males,
testosterone of gonadal origin is converted to estrogen in the brain 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 which does not support an estrogen-induced gonadotrophin
surge in the adult. In female rats, hypothalamic development occurs
with permissively low levels 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. The most physiological example of
this is the 30-50% loss of axosomatic synapses following the preovulatory
estrogen surge on diestrus-proestrus. Studies on post-synaptic
membranes of the arcuate nucleus reveal sex differences in membrane
organization and protein content which are estrogen-dependent. 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. 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. This
loss of function may result from a cumulative estrogen effect during the
repeated ovarian cycles which results in a reorganization of the synaptology 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."
17 beta Estradiol-induced increase in brain
dopamine D-2 receptor: antagonism by MIF-1. Rajakumar
G; Chiu P; Chiu S; Johnson RL; Mishra RK 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 in the neurological sequelae
induced by estrogen. 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 thedensity of
dopamine D-2 receptor 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 extrapyramidal motor disorders
caused by estrogen imbalance in humans.
Eur J Clin Invest 1984 Dec;14(6):431-4 Effect
of ovulation on haem metabolism in rabbits. Lindahl J, Werner B,
Lerner R. "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 bone-marrow haem turnover,
respectively." ". . . 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."
J Neurotrauma 1993 Winter;10(4):373-84. 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. McIntosh
TK, Fernyak S, Hayes RL, Faden AI
J Neurosci 1990 Nov;10(11):3524-30. Opiate
antagonist nalmefene improves intracellular free Mg2+, bioenergetic state, and
neurologic outcome following traumatic brain injury in rats. 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."
Brain Res 1989 Mar 20;482(2):252-60. Magnesium
protects against neurological deficit after brain injury. McIntosh TK,
Vink R, Yamakami I, Faden AI.
Adv Neurol 1988;47:531-46. Role of
thyrotropin-releasing hormone and opiate receptor antagonists in limiting
central nervous system injury. 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."
Exp Neurol 1994 Sep;129(1):64-9.Progesterone
facilitates cognitive recovery and reduces secondary neuronal loss caused by
cortical contusion injury in male rats. Roof RL, Duvdevani R, Braswell
L, Stein DG.
Exp Neurol 1996 Apr;138(2):246-51. Progesterone
rapidly decreases brain edema: treatment delayed up to 24 hours is still
effective. Roof RL, Duvdevani R, Heyburn JW, Stein DG.
Mol Chem Neuropathol 1997 May;31(1):1-11. Progesterone
protects against lipid peroxidation following traumatic brain injury in rats. Roof
RL, Hoffman SW, Stein DG.
Jiang N, et al. Progesterone is
neuroprotective after transient middle cerebral artery occlusion in male rats. Brain
Res. 1996 Sep 30;735(1):101-7.
Roof RL, et al. Progesterone rapidly
decreases brain edema: treatment delayed up to 24 hours is still effective. Exp
Neurol. 1996 Apr;138(2):246-51.
Duvdevani R, et al. Blood-brain barrier
breakdown and edema formation following frontal cortical contusion: does
hormonal status play a role? J Neurotrauma. 1995 Feb;12(1):65-75.
Exp Neurol 1997 Dec;148(2):453-63. Endogenous
repair after spinal cord contusion injuries in the rat. Beattie MS,
Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK, Faden AI, Hsu CY,
Noble LJ, Salzman S, Young W. "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."
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