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http://www.bio.net/bionet/mm/neur-sci/2004-August/058929.html
Allopregnenolone (synthesized from 5AR) may prevent neurodegeneration
Kofi kofi at anon.un
Wed Aug 11 19:26:31 EST 2004
The latest research in mice raises a disturbing question about the
safety of FDA approved 5AR inhibitors like finasteride
(Proscar/Propecia) and especially dutasteride (Avodart) when it comes to
managing long-term risk for neurodegenerative diseases like Alzheimer's.
This is because these drugs not only reduce levels of DHT but also wound
allopregnanolone production in the process.
To summarize the new findings on allopregnanolone (see attached below),
Niemann-Pick type C is a rare lysosomal storage disorder/childhood
neurodegenerative disease in which brain cells accumulate fat and die
due in part to severely disrupted neurosteroidogenesis. A mutant gene
for lysosomal acid sphingomyelinase disturbs cholesterol synthesis
throughout the body and results in the accumulation of sphingomyelin.
Progressive loss of neurosteroid synthesis may contribute to
neurodegeneration. Replacing lost allopregnanolone substantially
increases the survival of mice with this type of disease by mitigating
the damage and delaying the onset of symptoms. Results were best when
administered as early as possible in the animals life.
Allopregnanolone may be effective with managing other neurodegenerative
disorders. Other important neurosteroids like pregnenolone are also
diminished in Niemann-Pick type C but what's interesting here is how
valuable allopregnanolone is by itself.
<http://www.sciencedaily.com/releases/2004/07/040713082347.htm>. NPC
model mice may have amyloid-beta accumulations similar to those in
Alzheimer's [PMID 14982851, 14982829] and may represent a good model for
studying general aspects of neurodegeneration.
5 alpha reductase (5AR) is an enzyme which comes in two forms, type I
and type II. It not only converts testosterone (T) to
dihydrotestosterone (DHT, a ketone), it also converts progesterone to
allopregnanolone and deoxycorticosterone (DOC) to tetrahydroDOC (THDOC),
both allosteric enhancers of the GABA(a) receptor (e.g., they increase
the effectiveness of inhibition signals relayed along GABA channels in
nerves). The second stage of this conversion is performed by
3alpha-hydroxysteroid oxidoreductase.
This pathway has widespread influence in the body. Progesterone is the
precursor to allopregnanolone. Monthly drops in womens progesterone
prior to their periods is a factor in PMS and epileptic seizure.
Progesterone lozenges ameliorate seizures. Both estrogen and
progesterone are important for TMJ remodeling [PMID 10670598]. Men with
epilepsy can benefit from aromatase inhibitors which block the
conversion of testosterone to estrogen via aromatase [PMID 15123030].
Allopregnanolone can block cocaine induced seizures [PMID 12921865].
Complete 5AR inhibition shortens inhibitory currents in GABA(A) channels
both via allopregnanolone [PMID 12559121] and
5alpha-dihydrocoticosterone (THDOC) [PMID 11978855].
SSRIs (antidepressants like Zoloft) have been shown to upregulate levels
of progesterone and allopregnanolone (THP) [PMID 12957330] as well as
neurogenesis [PMID 14872203, 15001810, 14512209]. In animal models its
the hippocampal neurogenesis that accounts for the behavioral effects of
SSRIs [PMID 12907793]. Conversely, inescapable stress which reduces
hippocampal neurogenesis also causes depression [PMID 12838272].
Levels of allopregnanolone can also be regulated by 3alpha-HSDs
(3alpha-hydroxysteroid dehydrogenase) - enzymes which are identical in
function to 5AR, except they convert T back from DHT instead of the
other way around. 3alpha-HSDs are responsible for downregulating levels
of DHT in the prostate and unusual inhibition of 3alpha-HSD would
increase DHT levels, decrease allopregnanolone and incline a male toward
impaired GABA functioning, acne, baldness, BHP and prostate cancer.
Stimulating 3alpha-HSD might be more effective than 5AR inhibition for
treating androgen disorders (although elevated exposure to either
progesterone or allopregnanolone can become anxiety-provoking instead of
calming; there are gender differences to this effect [PMID 12606703]).
Certain synthetic progesterones may interfere with allopregnanolone
synthesis. Medroxyprogesterone acetate (MPA), an ingredient in some
birth control pills and hormone replacement therapies, doesnt convert
into allopregnanolone and causes anxiety, aggression and depressed sex
drive in mice compared to combinations of natural hormones
<http://www.sciencedaily.com/releases/2004/06/040608065645.htm>.
This overview should drive home just how important allopregnanolone may
be to human health. Finasteride is a 5AR type II inhibitor which
reduces DHT levels by up to 70%. Dutasteride inhibits both type I and
type II 5AR achieving a reduction of up to 94% of DHT. Type I is the
only 5AR expressed in the brain. Its long term inhibition was never
studied when dutasteride was approved by the FDA. Blocking DHT
synthesis in the brain like this also blocks allopregnanolone production
there. While other tissues like bone also express 5AR, finasteride has
been specifically studied on bone growth and has had no effect. Will
this also be true for neurodegenerative disorders which take decades to
develop? Will 5AR inhibitors be safe for individuals with epilepsy,
TMJ, neuropathy, alcoholism, tinnitus, metals poisoning or other
GABAergic illnesses?
If it's true that dramatic 5AR inhibition contributes to long term
neurodegeneration then what other therapeutic agents are available for
dealing with excessive DHT?
Understanding why male hormonal disorders like BHP, prostate cancer and
baldness have become common in "advanced" economies is important to
answering this question. One contributing factor is the bad mix of fats
consumed in the American diet (high in trans-fats, hydrogenated oils,
bad omega-6 and -9's and low in omega-3). Another factor is high
glycemic index diets which contribute to insulin resistance and androgen
signaling disorders like polycystic ovarian syndrome. High levels of
insulin lower levels of sex hormone-binding globulin, a substance which
binds to testosterone and lowers the amount of "free" androgens
available to bind to the receptor (see [PMID 14527633],
<http://www.thepaleodiet.com/articles/acne vulgaris.pdf>). These
androgen driven disorders are all complex genetic disorders which can
develop from many different angles. For instance, in a small study,
prematurely balding men could be divided into two groups: the first
group (about a third of the men) had a hormonal/insulin profile similar
to women with polycycstic ovarian syndrome (low SHBG, hyperinsulemia,
high free androgens and insulin resistance) whereas the second group had
no similarities or only lower SHBG [PMID 15209536]. How you react to
pathologically elevated levels of DHT is determined by your genetic risk
and your environment.
While dietary factors like fat and sugar consumption are important , the
major actor on DHT throughout our evolutionary history has been a
substance called equol. Equol is a derivative of the soy metabolite
daidzein produced by bifidus bacteria in the gut. It directly binds to
dihydrotestosterone and deactivates it [PMID 14681200]. Most male
mammals produce ample amounts of equol to regulate excessive DHT
production. High levels of equol in men lowers the risk for prostate
cancer [PMID 14681200, 14720329] and improves blood cholesterol [PMID
14679315].
By taking antibiotics, you usually increase your risk for chronic
inflammatory disorders. In this case, killing your gut bacteria leaves
abnormally high levels of free DHT floating around in your blood
stimulating your androgen receptors beyond what your body is used to.
Over a lifetime, this brings out your genetic risk for androgen-driven
disorders like the ones I keep mentioning. Destroying your gut bacteria
with antibiotics probably also increases the risk for allergies, asthma,
arthritis and other inflammatory disorders (see
<http://www.sciencedaily.com/releases/2004/07/040723091648.htm>,
<http://www.newscientist.com/news/news.jsp?id=ns99995047>, PMID
15120189) - not to mention it can give you a bad yeast infection like
you see in chronic sinusitis.
How can you obtain equol if you no longer make your own?
That's the problem. You can't. The only versions manufactured and sold
today are racemic - meaning both the left and right isomers of the
molecule are produced in a mixture. Only one form is naturally made and
used in the human body. The other is not well studied. Another
limiting factor is that finasteride and dutasteride are patented while
equol can't be - it's a natural product which has been around too long.
Contact manufacturers and let them know there is a market for this
therapeutic substance and that it's worth conducting clinical trials.
If 5AR inhibitors do pose long term risks and you absolutely have to
take them, it may be possible to lessen the neurological damage with
things like acetyl-l-carnitine, minocycline, l-theanine, taurine,
curcumin, green tea (EGCG), CoQ10, nicotinamide/niacinamide, creatine,
ketogenic diets, so on and so forth (each of which carries with it its
own complicating factors).
If this information has in any way improved your medical care, please
consider voting for John Kerry.
- Your amazing one and only crime-fighting/medical-spelunking UN
secretary general Kofi Anon
(Relevant NIH abstracts are denoted by PMID ### reference. To look it
up, type
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&lis
t_uids=###&dopt=Abstract> in your browser or simply type the abstract ID
into the NIH search engine.)
http://www.sciencedaily.com/releases/2004/07/040713082347.htm
Source:
University Of California, San Francisco
Date:
2004-07-13
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Neurodegenerative Disease In Children Might Respond To Neurosteroids
Scientists studying mice have identified a possible strategy for slowing
a rare, fatal childhood neurodegenerative disease known as Niemann-Pick
type C, in which brain cells accumulate fat and die. The finding could
also have implications for treating other neurodegenerative disease,
they say.
In their study, published in the July issue of Nature Medicine, the team
discovered that the synthesis of neurosteroid hormones in the brain -- a
process known as neurosteroidogenesis -- is severely disrupted in mice
that naturally develop the disease. They then determined that
replenishing the depleted neurosteroid hormone allopregnanolone, the
prime casualty of the disruption, significantly delayed the onset of
some of the animals' neurological deficits, and doubled their lifespan.
The treatment was particularly potent when administered early in the
animals' life.
"The results were astounding," says senior author Synthia Mellon, PhD,
professor of obstetrics, gynecology and reproductive sciences at
University of California, San Francisco.
While the treatment did not target the cause of the disease -- a
mutation in one of two genes that disrupts the transport of cholesterol
within all cells of the body -- nor cure it, the therapy substantially
delayed the onset of weight loss, motor coordination, mobility -- and
death. It also significantly delayed the accumulation of fats in
cortical cells, and the death of some neurons in the cortex and
cerebellum. The study was not designed to test intellectual function,
another component of the disease.
LOSS OF NEUROSTEROIDS IN NEURODEGENERATION
"The finding suggests that the progressive loss of neurosteroids
contributes to neuronal degeneration in NP-C mice," says Mellon. "We
didn't cure the problem. There's still a big clog in the cell, but we've
circumvented it. We've treated downstream consequences of that clog."
Scientists do not know if neurosteroid synthesis is disrupted in
children with the disease, so the potential efficacy of allopregnanolone
in children with NP-C cannot be predicted, says Mellon. However,
allopregnanolone is produced naturally in humans, and provoked no
evident side effects when administered to the NP-C mice. Thus, if the
neurosteroid hormone is depleted in patients, it could prove a tactic
for delaying the onset or progression of some symptoms of the disease.
To determine neurosteroidogenesis activity in children with NP-C,
scientists could compare brain tissue from autopsied NP-C patients with
that from children who died from unrelated causes. Mellon says she and
colleagues hope to be able to initiate pre-clinical studies aimed at
determining safety, safe dosage and any possible side effects of
allopregnanolone, with an eye to optimizing dosage and carrying out a
clinical trial.
If the therapy worked, it would signify a major advance, as scientists
have not made headway in repairing the culprit gene, discovered in 1997,
or the protein it synthesizes. Although clinical manifestations are
varied and can present at any time from intrauterine life to adulthood,
patients often begin demonstrating motor and intellectual decline during
late childhood, and die between the ages of eight and eighteen. The
disease, which also causes enlargement of the liver, occurs in about 1
in 150,000 children.
ILLUMINATING THE ROLE OF NEUROSTEROIDS
The finding, in broader terms, provides some of the strongest evidence
to date that neurosteroids may play an important role in neurological
function in humans, says Mellon. If synthesis of these steroid hormones
is found to be disrupted in other neurodegenerative diseases -- a
question that has just begun to be investigated -- neurosteroid therapy
could prove effective in stalling them, she says.
Like most other steroid hormones, neurosteroids are derived from
cholesterol, a lipid that plays an important role in the formation of
cell membranes. But while much is known about the role of other steroid
hormones, such as testosterone, scientists are only beginning to
understand the role of those that function in the brain. Neurosteroids
are known to affect neuronal growth and differentiation and to modulate
various moods and reactions via neurotransmitter receptors, including
GABA. However, says Mellon, scientists generally have presumed that
neurosteroids play a supportive, rather than an essential, role in
neurological function.
The research team, whose scientific interest is illuminating the role of
neurosteroids, suspected that neurosteroid synthesis would be disturbed
in NP-C, due to disruption of cholesterol transport within cells, which
leads to the accumulation of cholesterol and other lipids in cellular
compartments. Their theory was bolstered by the fact that mice with NP-C
have below normal concentrations of testosterone and underdeveloped
reproductive organs, suggesting that, at least, the synthesis of sex
steroid hormones in the testes is disrupted in the disease.
To test their hypothesis, the scientists compared the brains of normal,
so-called "wild type," mice, with those of animals with NP-C. The
results were dramatic. While neurosteroidogenesis was not affected in
NP-C mice prenatally, the impact began at birth and increased over time.
The quantity of pregnenolone, the first steroid produced from
cholesterol, was significantly decreased. The quantity of
allopregnanolone, which is converted from pregnenolone, was diminished
even further.
Supporting this finding, the two enzymes that synthesize
allopregnanolone, 3a-hydroxysteroid dehydrogenase and 5a-reductase, were
significantly depleted in all principal brain regions (the cortex, the
midbrain and the hindbrain) by birth, and were reduced to irrelevant
quantities by 10 weeks.
The team then examined the impact of administering allopregnanolone to
the brains of NP-C mice. The effect was equally pronounced. In a series
of experiments, the drug was given progressively early in the animals'
lives, at 21 to 23 days of age in the first mice examined, at 7 days of
age in the last mice evaluated. The response, in terms of stalled
neurological deficits, cellular damage and death, was greater the
earlier the administration of the neurosteroid.
DRAMATIC RESULTS
The most dramatic results reported were in mice treated with a single
injection at seven days of age. They gained weight steadily until age 86
days, and lived to a mean age of 124 days. In contrast, untreated NP-C
mice had a mean survival of 67 days.
In still more notable results, the researchers cited, but did not
report, in their published paper that several treatments beginning at
day seven in the animals' lives extended their lifespan and delayed the
onset of neurological impairment even further.
"The finding suggests that allopregnanolone may be involved in a
neurodevelopmental process that occurs within or before the first week
of life," says Mellon.
NP-C is an autosomal recessive disease, meaning both parents must
contribute a copy of the mutated gene to cause the disease, and that
there is a 25 percent chance their offspring will develop it. As infants
suspected of having the disease can be tested to see if they carry the
mutated gene, the disease can be detected early. Thus, if
allopregnanolone proves effective in humans, it could be used to stall
the disease from the outset.
The obvious next challenge for the researchers, however, will be
determining how brain development of the mouse compares to that of the
human.
Co-authors of the study were Lisa D. Griffin, MD, PhD, formerly UCSF
assistant professor of neurology, Wenhui Gong, MD, PhD, a postdoctoral
fellow in the Mellon lab, and Lucie Verot, PhD, graduate student in the
laboratory of Marie T. Vanier, MD, PhD, of INSERM, U189 and Laboratoire
Foundation Gillet-Merieux, Lyon-Sud Medical School and Hospital,
Pierre-Benite, France.
The study was funded by the National Institutes of Health, the National
Niemann Pick Disease Foundation, the March of Dimes Birth Defects
Foundation, the Ara Parsaeghian Medical Research Foundation and Vaincre
les Maladies Lyosomales.
Editor's Note: The original news release can be found here.
Semin Cell Dev Biol. 2004 Aug;15(4):445-54. Related Articles, Links
Click here to read
Cellular pathology of Niemann-Pick type C disease.
Ikonen E, Holtta-Vuori M.
Institute of Biotechnology, University of Helsinki, Helsinki,
Finland.
Niemann-Pick type C (NPC) is a lysosomal storage disorder that
results in the accumulation of cholesterol and sphingolipids. Mutations
in the NPC1 or NPC2 gene are responsible for the disease but the precise
functions of the encoded proteins remain unresolved. Recent observations
have challenged the traditional concept of NPC as a primary cholesterol
transport defect. This review updates the recent NPC literature,
summarizing the increasing insight into the cholesterol trafficking
circuits and also addressing the contribution of other lipids in the
cellular pathogenesis. The importance of NPC as a model for subcellular
lipid imbalance in studying more common diseases, such as Alzheimer's
and cardiovascular diseases, is discussed.
PMID: 15207834 [PubMed - in process]
Am J Respir Cell Mol Biol. 2004 Jul 15 [Epub ahead of print] Related
Articles, Links
Click here to read
Mechanistic similarities between cultured cell models of cystic
fibrosis and Niemann-Pick type C.
White NM, Corey DA, Kelley TJ.
Recent data demonstrate that inhibition of
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase restores normal
signal transducer and activator of transcription-1 (STAT1) and inducible
nitric oxide synthase expression (NOS2) regulation in CF cells through
the modulation of RhoA function. These findings lead to the hypothesis
that alterations in the cholesterol synthesis pathway may be an
initiating factor in CF-related cell signaling regulation. A disease
with a known lesion in the cholesterol synthesis pathway is Niemann-Pick
type C (NPC). The hypothesis of this study is that CF cells and NPC
fibroblasts share a common mechanistic lesion and should exhibit similar
cell signaling alterations. NPC fibroblasts exhibit similar alterations
in STAT1, RhoA, SMAD3, and NOS2 protein expression that characterize CF.
Further comparison reveals NPC-like accumulation of free cholesterol in
two cultured models of CF epithelial cells. These data identify novel
signaling changes in NPC, demonstrate the cholesterol-synthesis pathway
is a likely source of CF-related cell signaling changes, and that
cultured CF cells exhibit impaired cholesterol processing.
PMID: 15256387 [PubMed - as supplied by publisher]
Nat Med. 2004 Jul;10(7):704-11. Epub 2004 Jun 20. Related Articles, Links
Click here to read
Niemann-Pick type C disease involves disrupted neurosteroidogenesis
and responds to allopregnanolone.
Griffin LD, Gong W, Verot L, Mellon SH.
Department of Neurology, Center for Reproductive Sciences,
University of California, San Francisco, 513 Parnassus Avenue, San
Francisco, California 94143-0556, USA.
Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive,
childhood neurodegenerative disease. The NP-C mouse recapitulates the
cholesterol and sphingolipid storage, onset of neurological deficits,
histopathological lesions, Purkinje cell loss and early death typical of
the most severe form of human NP-C. Neurosteroids, steroids made in the
brain, affect neuronal growth and differentiation, and modulate
neurotransmitter receptors. Disordered cholesterol trafficking might
disrupt neurosteroidogenesis, thereby contributing to the NP-C
phenotype. Here we show that NP-C mouse brain contains substantially
less neurosteroid than wild-type brain and has an age-related decrease
in the ability to synthesize 5alpha-dihydroprogesterone and
allopregnanolone. Immunohistochemical assessment confirms a decrease in
expression of 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase,
especially in cerebellum. Neonatal administration of allopregnanolone
delays the onset of neurological symptoms, increases Purkinje and
granule cell survival, reduces cortical GM2 and GM3 ganglioside
accumulation and doubles the lifespan of NP-C mice. Earlier
administration increases effectiveness of treatment. Decreased
production of allopregnanolone apparently contributes to the pathology
of NP-C; thus, neurosteroid treatment may be useful in ameliorating
progression of the disease.
PMID: 15208706 [PubMed - in process]
Biochem Biophys Res Commun. 2004 Mar 5;315(2):408-17. Related Articles,
Links
Click here to read
Chronic exposure to U18666A induces apoptosis in cultured murine
cortical neurons.
Cheung NS, Koh CH, Bay BH, Qi RZ, Choy MS, Li QT, Wong KP, Whiteman
M.
Department of Biochemistry, Faculty of Medicine, National University
of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
Niemann-Pick disease type C (NPC) is a juvenile neurodegenerative
disorder characterized by premature neuronal loss and altered
cholesterol metabolism. Previous reports applying an 8-h exposure of
U18666A, a cholesterol transport-inhibiting agent, demonstrated a
dose-dependent reduction in beta-amyloid (Abeta) deposition and
secretion in cortical neurons, with no significant cell injury. In the
current study, we examined the chronic effect of 24-72h of U18666A
treatment on primary cortical neurons and several cell lines. Our
results showed caspase-3 activation and cellular injury in
U18666A-treated cortical neurons but not in the cell lines, suggesting
cell death by apoptosis only occurred in cortical neurons after chronic
exposure to U18666A. We also demonstrated through filipin staining the
accumulation of intracellular cholesterol in cortical neurons treated
with U18666A, indicating the phenotypic mimic of NPC by U18666A.
However, additions of 10 and 25microM pravastatin with 0.5microg/ml
U18666A significantly attenuated toxicity. Taken together, these data
showed for the first time that U18666A induces cell death by apoptosis
and suggested an important in vitro model system to study NPC.
PMID: 14766223 [PubMed - indexed for MEDLINE]
Exp Neurol. 2003 Dec;184(2):887-903. Related Articles, Links
Click here to read
Postnatal development of inflammation in a murine model of
Niemann-Pick type C disease: immunohistochemical observations of
microglia and astroglia.
Baudry M, Yao Y, Simmons D, Liu J, Bi X.
Department of Psychiatry & Human Behavior, University of California
Irvine, Irvine, CA 92612, USA.
Niemann-Pick type C (NPC) is a rare and fatal neurovisceral storage
disorder that is currently untreatable. In most cases, NPC is caused by
mutations of the NPC1 gene, which encodes a glycoprotein playing an
important role in cholesterol transport. Mice lacking the NPC1 gene
exhibit several pathological features of NPC patients and have been
widely used to provide insights into the mechanisms of the disease. In
the present study, we analyzed the postnatal development of pathological
manifestations of inflammation in several brain regions of NPC1-/- mice.
Brain sections from NPC1-/- and wild-type (NPC1+/+) mice were
immunostained with the MAC1 antibody, which recognizes microglia, with
antibodies against glial fibrillary acidic protein (GFAP), which
recognize astrocytes, and with antibodies against the cytokine
interleukin-1beta (IL-1beta). Numbers of MAC1 immunopositive cells were
markedly increased in several brain regions of NPC1-/- mice as early as
2 weeks of age. This effect was particularly evident in globus pallidus,
ventral lateral thalamus, medial geniculate nucleus, and cerebellum.
MAC1-immunopositive cells had enlarged cell bodies and shorter
processes, suggesting they were in an active state. By 4 weeks, most
brain structures exhibited enhanced microglial activation in NPC1-/-
mice, and this was maintained at 12 weeks. At 2 weeks, reactive
astrocytes were only observed in the ventral lateral thalamus while they
were present throughout the brain of NPC1-/- mice at 4 weeks of age.
Moreover, the astroglial reaction coincided with up-regulation of the
cytokine, interleukin-1beta, in most, but not all brain regions. In
particular, no interleukin-1beta up-regulation was observed in regions
devoid of neuronal degeneration. These results suggest that microglial
activation precedes and might be causally related to neuronal
degeneration, while astrocyte activation might be a consequence of
neuronal degeneration.
PMID: 14769381 [PubMed - indexed for MEDLINE]
Allopregnenolone (synthesized from 5AR) may prevent neurodegeneration
Kofi kofi at anon.un
Wed Aug 11 19:26:31 EST 2004
The latest research in mice raises a disturbing question about the
safety of FDA approved 5AR inhibitors like finasteride
(Proscar/Propecia) and especially dutasteride (Avodart) when it comes to
managing long-term risk for neurodegenerative diseases like Alzheimer's.
This is because these drugs not only reduce levels of DHT but also wound
allopregnanolone production in the process.
To summarize the new findings on allopregnanolone (see attached below),
Niemann-Pick type C is a rare lysosomal storage disorder/childhood
neurodegenerative disease in which brain cells accumulate fat and die
due in part to severely disrupted neurosteroidogenesis. A mutant gene
for lysosomal acid sphingomyelinase disturbs cholesterol synthesis
throughout the body and results in the accumulation of sphingomyelin.
Progressive loss of neurosteroid synthesis may contribute to
neurodegeneration. Replacing lost allopregnanolone substantially
increases the survival of mice with this type of disease by mitigating
the damage and delaying the onset of symptoms. Results were best when
administered as early as possible in the animals life.
Allopregnanolone may be effective with managing other neurodegenerative
disorders. Other important neurosteroids like pregnenolone are also
diminished in Niemann-Pick type C but what's interesting here is how
valuable allopregnanolone is by itself.
<http://www.sciencedaily.com/releases/2004/07/040713082347.htm>. NPC
model mice may have amyloid-beta accumulations similar to those in
Alzheimer's [PMID 14982851, 14982829] and may represent a good model for
studying general aspects of neurodegeneration.
5 alpha reductase (5AR) is an enzyme which comes in two forms, type I
and type II. It not only converts testosterone (T) to
dihydrotestosterone (DHT, a ketone), it also converts progesterone to
allopregnanolone and deoxycorticosterone (DOC) to tetrahydroDOC (THDOC),
both allosteric enhancers of the GABA(a) receptor (e.g., they increase
the effectiveness of inhibition signals relayed along GABA channels in
nerves). The second stage of this conversion is performed by
3alpha-hydroxysteroid oxidoreductase.
This pathway has widespread influence in the body. Progesterone is the
precursor to allopregnanolone. Monthly drops in womens progesterone
prior to their periods is a factor in PMS and epileptic seizure.
Progesterone lozenges ameliorate seizures. Both estrogen and
progesterone are important for TMJ remodeling [PMID 10670598]. Men with
epilepsy can benefit from aromatase inhibitors which block the
conversion of testosterone to estrogen via aromatase [PMID 15123030].
Allopregnanolone can block cocaine induced seizures [PMID 12921865].
Complete 5AR inhibition shortens inhibitory currents in GABA(A) channels
both via allopregnanolone [PMID 12559121] and
5alpha-dihydrocoticosterone (THDOC) [PMID 11978855].
SSRIs (antidepressants like Zoloft) have been shown to upregulate levels
of progesterone and allopregnanolone (THP) [PMID 12957330] as well as
neurogenesis [PMID 14872203, 15001810, 14512209]. In animal models its
the hippocampal neurogenesis that accounts for the behavioral effects of
SSRIs [PMID 12907793]. Conversely, inescapable stress which reduces
hippocampal neurogenesis also causes depression [PMID 12838272].
Levels of allopregnanolone can also be regulated by 3alpha-HSDs
(3alpha-hydroxysteroid dehydrogenase) - enzymes which are identical in
function to 5AR, except they convert T back from DHT instead of the
other way around. 3alpha-HSDs are responsible for downregulating levels
of DHT in the prostate and unusual inhibition of 3alpha-HSD would
increase DHT levels, decrease allopregnanolone and incline a male toward
impaired GABA functioning, acne, baldness, BHP and prostate cancer.
Stimulating 3alpha-HSD might be more effective than 5AR inhibition for
treating androgen disorders (although elevated exposure to either
progesterone or allopregnanolone can become anxiety-provoking instead of
calming; there are gender differences to this effect [PMID 12606703]).
Certain synthetic progesterones may interfere with allopregnanolone
synthesis. Medroxyprogesterone acetate (MPA), an ingredient in some
birth control pills and hormone replacement therapies, doesnt convert
into allopregnanolone and causes anxiety, aggression and depressed sex
drive in mice compared to combinations of natural hormones
<http://www.sciencedaily.com/releases/2004/06/040608065645.htm>.
This overview should drive home just how important allopregnanolone may
be to human health. Finasteride is a 5AR type II inhibitor which
reduces DHT levels by up to 70%. Dutasteride inhibits both type I and
type II 5AR achieving a reduction of up to 94% of DHT. Type I is the
only 5AR expressed in the brain. Its long term inhibition was never
studied when dutasteride was approved by the FDA. Blocking DHT
synthesis in the brain like this also blocks allopregnanolone production
there. While other tissues like bone also express 5AR, finasteride has
been specifically studied on bone growth and has had no effect. Will
this also be true for neurodegenerative disorders which take decades to
develop? Will 5AR inhibitors be safe for individuals with epilepsy,
TMJ, neuropathy, alcoholism, tinnitus, metals poisoning or other
GABAergic illnesses?
If it's true that dramatic 5AR inhibition contributes to long term
neurodegeneration then what other therapeutic agents are available for
dealing with excessive DHT?
Understanding why male hormonal disorders like BHP, prostate cancer and
baldness have become common in "advanced" economies is important to
answering this question. One contributing factor is the bad mix of fats
consumed in the American diet (high in trans-fats, hydrogenated oils,
bad omega-6 and -9's and low in omega-3). Another factor is high
glycemic index diets which contribute to insulin resistance and androgen
signaling disorders like polycystic ovarian syndrome. High levels of
insulin lower levels of sex hormone-binding globulin, a substance which
binds to testosterone and lowers the amount of "free" androgens
available to bind to the receptor (see [PMID 14527633],
<http://www.thepaleodiet.com/articles/acne vulgaris.pdf>). These
androgen driven disorders are all complex genetic disorders which can
develop from many different angles. For instance, in a small study,
prematurely balding men could be divided into two groups: the first
group (about a third of the men) had a hormonal/insulin profile similar
to women with polycycstic ovarian syndrome (low SHBG, hyperinsulemia,
high free androgens and insulin resistance) whereas the second group had
no similarities or only lower SHBG [PMID 15209536]. How you react to
pathologically elevated levels of DHT is determined by your genetic risk
and your environment.
While dietary factors like fat and sugar consumption are important , the
major actor on DHT throughout our evolutionary history has been a
substance called equol. Equol is a derivative of the soy metabolite
daidzein produced by bifidus bacteria in the gut. It directly binds to
dihydrotestosterone and deactivates it [PMID 14681200]. Most male
mammals produce ample amounts of equol to regulate excessive DHT
production. High levels of equol in men lowers the risk for prostate
cancer [PMID 14681200, 14720329] and improves blood cholesterol [PMID
14679315].
By taking antibiotics, you usually increase your risk for chronic
inflammatory disorders. In this case, killing your gut bacteria leaves
abnormally high levels of free DHT floating around in your blood
stimulating your androgen receptors beyond what your body is used to.
Over a lifetime, this brings out your genetic risk for androgen-driven
disorders like the ones I keep mentioning. Destroying your gut bacteria
with antibiotics probably also increases the risk for allergies, asthma,
arthritis and other inflammatory disorders (see
<http://www.sciencedaily.com/releases/2004/07/040723091648.htm>,
<http://www.newscientist.com/news/news.jsp?id=ns99995047>, PMID
15120189) - not to mention it can give you a bad yeast infection like
you see in chronic sinusitis.
How can you obtain equol if you no longer make your own?
That's the problem. You can't. The only versions manufactured and sold
today are racemic - meaning both the left and right isomers of the
molecule are produced in a mixture. Only one form is naturally made and
used in the human body. The other is not well studied. Another
limiting factor is that finasteride and dutasteride are patented while
equol can't be - it's a natural product which has been around too long.
Contact manufacturers and let them know there is a market for this
therapeutic substance and that it's worth conducting clinical trials.
If 5AR inhibitors do pose long term risks and you absolutely have to
take them, it may be possible to lessen the neurological damage with
things like acetyl-l-carnitine, minocycline, l-theanine, taurine,
curcumin, green tea (EGCG), CoQ10, nicotinamide/niacinamide, creatine,
ketogenic diets, so on and so forth (each of which carries with it its
own complicating factors).
If this information has in any way improved your medical care, please
consider voting for John Kerry.
- Your amazing one and only crime-fighting/medical-spelunking UN
secretary general Kofi Anon
(Relevant NIH abstracts are denoted by PMID ### reference. To look it
up, type
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&lis
t_uids=###&dopt=Abstract> in your browser or simply type the abstract ID
into the NIH search engine.)
http://www.sciencedaily.com/releases/2004/07/040713082347.htm
Source:
University Of California, San Francisco
Date:
2004-07-13
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Neurodegenerative Disease In Children Might Respond To Neurosteroids
Scientists studying mice have identified a possible strategy for slowing
a rare, fatal childhood neurodegenerative disease known as Niemann-Pick
type C, in which brain cells accumulate fat and die. The finding could
also have implications for treating other neurodegenerative disease,
they say.
In their study, published in the July issue of Nature Medicine, the team
discovered that the synthesis of neurosteroid hormones in the brain -- a
process known as neurosteroidogenesis -- is severely disrupted in mice
that naturally develop the disease. They then determined that
replenishing the depleted neurosteroid hormone allopregnanolone, the
prime casualty of the disruption, significantly delayed the onset of
some of the animals' neurological deficits, and doubled their lifespan.
The treatment was particularly potent when administered early in the
animals' life.
"The results were astounding," says senior author Synthia Mellon, PhD,
professor of obstetrics, gynecology and reproductive sciences at
University of California, San Francisco.
While the treatment did not target the cause of the disease -- a
mutation in one of two genes that disrupts the transport of cholesterol
within all cells of the body -- nor cure it, the therapy substantially
delayed the onset of weight loss, motor coordination, mobility -- and
death. It also significantly delayed the accumulation of fats in
cortical cells, and the death of some neurons in the cortex and
cerebellum. The study was not designed to test intellectual function,
another component of the disease.
LOSS OF NEUROSTEROIDS IN NEURODEGENERATION
"The finding suggests that the progressive loss of neurosteroids
contributes to neuronal degeneration in NP-C mice," says Mellon. "We
didn't cure the problem. There's still a big clog in the cell, but we've
circumvented it. We've treated downstream consequences of that clog."
Scientists do not know if neurosteroid synthesis is disrupted in
children with the disease, so the potential efficacy of allopregnanolone
in children with NP-C cannot be predicted, says Mellon. However,
allopregnanolone is produced naturally in humans, and provoked no
evident side effects when administered to the NP-C mice. Thus, if the
neurosteroid hormone is depleted in patients, it could prove a tactic
for delaying the onset or progression of some symptoms of the disease.
To determine neurosteroidogenesis activity in children with NP-C,
scientists could compare brain tissue from autopsied NP-C patients with
that from children who died from unrelated causes. Mellon says she and
colleagues hope to be able to initiate pre-clinical studies aimed at
determining safety, safe dosage and any possible side effects of
allopregnanolone, with an eye to optimizing dosage and carrying out a
clinical trial.
If the therapy worked, it would signify a major advance, as scientists
have not made headway in repairing the culprit gene, discovered in 1997,
or the protein it synthesizes. Although clinical manifestations are
varied and can present at any time from intrauterine life to adulthood,
patients often begin demonstrating motor and intellectual decline during
late childhood, and die between the ages of eight and eighteen. The
disease, which also causes enlargement of the liver, occurs in about 1
in 150,000 children.
ILLUMINATING THE ROLE OF NEUROSTEROIDS
The finding, in broader terms, provides some of the strongest evidence
to date that neurosteroids may play an important role in neurological
function in humans, says Mellon. If synthesis of these steroid hormones
is found to be disrupted in other neurodegenerative diseases -- a
question that has just begun to be investigated -- neurosteroid therapy
could prove effective in stalling them, she says.
Like most other steroid hormones, neurosteroids are derived from
cholesterol, a lipid that plays an important role in the formation of
cell membranes. But while much is known about the role of other steroid
hormones, such as testosterone, scientists are only beginning to
understand the role of those that function in the brain. Neurosteroids
are known to affect neuronal growth and differentiation and to modulate
various moods and reactions via neurotransmitter receptors, including
GABA. However, says Mellon, scientists generally have presumed that
neurosteroids play a supportive, rather than an essential, role in
neurological function.
The research team, whose scientific interest is illuminating the role of
neurosteroids, suspected that neurosteroid synthesis would be disturbed
in NP-C, due to disruption of cholesterol transport within cells, which
leads to the accumulation of cholesterol and other lipids in cellular
compartments. Their theory was bolstered by the fact that mice with NP-C
have below normal concentrations of testosterone and underdeveloped
reproductive organs, suggesting that, at least, the synthesis of sex
steroid hormones in the testes is disrupted in the disease.
To test their hypothesis, the scientists compared the brains of normal,
so-called "wild type," mice, with those of animals with NP-C. The
results were dramatic. While neurosteroidogenesis was not affected in
NP-C mice prenatally, the impact began at birth and increased over time.
The quantity of pregnenolone, the first steroid produced from
cholesterol, was significantly decreased. The quantity of
allopregnanolone, which is converted from pregnenolone, was diminished
even further.
Supporting this finding, the two enzymes that synthesize
allopregnanolone, 3a-hydroxysteroid dehydrogenase and 5a-reductase, were
significantly depleted in all principal brain regions (the cortex, the
midbrain and the hindbrain) by birth, and were reduced to irrelevant
quantities by 10 weeks.
The team then examined the impact of administering allopregnanolone to
the brains of NP-C mice. The effect was equally pronounced. In a series
of experiments, the drug was given progressively early in the animals'
lives, at 21 to 23 days of age in the first mice examined, at 7 days of
age in the last mice evaluated. The response, in terms of stalled
neurological deficits, cellular damage and death, was greater the
earlier the administration of the neurosteroid.
DRAMATIC RESULTS
The most dramatic results reported were in mice treated with a single
injection at seven days of age. They gained weight steadily until age 86
days, and lived to a mean age of 124 days. In contrast, untreated NP-C
mice had a mean survival of 67 days.
In still more notable results, the researchers cited, but did not
report, in their published paper that several treatments beginning at
day seven in the animals' lives extended their lifespan and delayed the
onset of neurological impairment even further.
"The finding suggests that allopregnanolone may be involved in a
neurodevelopmental process that occurs within or before the first week
of life," says Mellon.
NP-C is an autosomal recessive disease, meaning both parents must
contribute a copy of the mutated gene to cause the disease, and that
there is a 25 percent chance their offspring will develop it. As infants
suspected of having the disease can be tested to see if they carry the
mutated gene, the disease can be detected early. Thus, if
allopregnanolone proves effective in humans, it could be used to stall
the disease from the outset.
The obvious next challenge for the researchers, however, will be
determining how brain development of the mouse compares to that of the
human.
Co-authors of the study were Lisa D. Griffin, MD, PhD, formerly UCSF
assistant professor of neurology, Wenhui Gong, MD, PhD, a postdoctoral
fellow in the Mellon lab, and Lucie Verot, PhD, graduate student in the
laboratory of Marie T. Vanier, MD, PhD, of INSERM, U189 and Laboratoire
Foundation Gillet-Merieux, Lyon-Sud Medical School and Hospital,
Pierre-Benite, France.
The study was funded by the National Institutes of Health, the National
Niemann Pick Disease Foundation, the March of Dimes Birth Defects
Foundation, the Ara Parsaeghian Medical Research Foundation and Vaincre
les Maladies Lyosomales.
Editor's Note: The original news release can be found here.
Semin Cell Dev Biol. 2004 Aug;15(4):445-54. Related Articles, Links
Click here to read
Cellular pathology of Niemann-Pick type C disease.
Ikonen E, Holtta-Vuori M.
Institute of Biotechnology, University of Helsinki, Helsinki,
Finland.
Niemann-Pick type C (NPC) is a lysosomal storage disorder that
results in the accumulation of cholesterol and sphingolipids. Mutations
in the NPC1 or NPC2 gene are responsible for the disease but the precise
functions of the encoded proteins remain unresolved. Recent observations
have challenged the traditional concept of NPC as a primary cholesterol
transport defect. This review updates the recent NPC literature,
summarizing the increasing insight into the cholesterol trafficking
circuits and also addressing the contribution of other lipids in the
cellular pathogenesis. The importance of NPC as a model for subcellular
lipid imbalance in studying more common diseases, such as Alzheimer's
and cardiovascular diseases, is discussed.
PMID: 15207834 [PubMed - in process]
Am J Respir Cell Mol Biol. 2004 Jul 15 [Epub ahead of print] Related
Articles, Links
Click here to read
Mechanistic similarities between cultured cell models of cystic
fibrosis and Niemann-Pick type C.
White NM, Corey DA, Kelley TJ.
Recent data demonstrate that inhibition of
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase restores normal
signal transducer and activator of transcription-1 (STAT1) and inducible
nitric oxide synthase expression (NOS2) regulation in CF cells through
the modulation of RhoA function. These findings lead to the hypothesis
that alterations in the cholesterol synthesis pathway may be an
initiating factor in CF-related cell signaling regulation. A disease
with a known lesion in the cholesterol synthesis pathway is Niemann-Pick
type C (NPC). The hypothesis of this study is that CF cells and NPC
fibroblasts share a common mechanistic lesion and should exhibit similar
cell signaling alterations. NPC fibroblasts exhibit similar alterations
in STAT1, RhoA, SMAD3, and NOS2 protein expression that characterize CF.
Further comparison reveals NPC-like accumulation of free cholesterol in
two cultured models of CF epithelial cells. These data identify novel
signaling changes in NPC, demonstrate the cholesterol-synthesis pathway
is a likely source of CF-related cell signaling changes, and that
cultured CF cells exhibit impaired cholesterol processing.
PMID: 15256387 [PubMed - as supplied by publisher]
Nat Med. 2004 Jul;10(7):704-11. Epub 2004 Jun 20. Related Articles, Links
Click here to read
Niemann-Pick type C disease involves disrupted neurosteroidogenesis
and responds to allopregnanolone.
Griffin LD, Gong W, Verot L, Mellon SH.
Department of Neurology, Center for Reproductive Sciences,
University of California, San Francisco, 513 Parnassus Avenue, San
Francisco, California 94143-0556, USA.
Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive,
childhood neurodegenerative disease. The NP-C mouse recapitulates the
cholesterol and sphingolipid storage, onset of neurological deficits,
histopathological lesions, Purkinje cell loss and early death typical of
the most severe form of human NP-C. Neurosteroids, steroids made in the
brain, affect neuronal growth and differentiation, and modulate
neurotransmitter receptors. Disordered cholesterol trafficking might
disrupt neurosteroidogenesis, thereby contributing to the NP-C
phenotype. Here we show that NP-C mouse brain contains substantially
less neurosteroid than wild-type brain and has an age-related decrease
in the ability to synthesize 5alpha-dihydroprogesterone and
allopregnanolone. Immunohistochemical assessment confirms a decrease in
expression of 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase,
especially in cerebellum. Neonatal administration of allopregnanolone
delays the onset of neurological symptoms, increases Purkinje and
granule cell survival, reduces cortical GM2 and GM3 ganglioside
accumulation and doubles the lifespan of NP-C mice. Earlier
administration increases effectiveness of treatment. Decreased
production of allopregnanolone apparently contributes to the pathology
of NP-C; thus, neurosteroid treatment may be useful in ameliorating
progression of the disease.
PMID: 15208706 [PubMed - in process]
Biochem Biophys Res Commun. 2004 Mar 5;315(2):408-17. Related Articles,
Links
Click here to read
Chronic exposure to U18666A induces apoptosis in cultured murine
cortical neurons.
Cheung NS, Koh CH, Bay BH, Qi RZ, Choy MS, Li QT, Wong KP, Whiteman
M.
Department of Biochemistry, Faculty of Medicine, National University
of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
Niemann-Pick disease type C (NPC) is a juvenile neurodegenerative
disorder characterized by premature neuronal loss and altered
cholesterol metabolism. Previous reports applying an 8-h exposure of
U18666A, a cholesterol transport-inhibiting agent, demonstrated a
dose-dependent reduction in beta-amyloid (Abeta) deposition and
secretion in cortical neurons, with no significant cell injury. In the
current study, we examined the chronic effect of 24-72h of U18666A
treatment on primary cortical neurons and several cell lines. Our
results showed caspase-3 activation and cellular injury in
U18666A-treated cortical neurons but not in the cell lines, suggesting
cell death by apoptosis only occurred in cortical neurons after chronic
exposure to U18666A. We also demonstrated through filipin staining the
accumulation of intracellular cholesterol in cortical neurons treated
with U18666A, indicating the phenotypic mimic of NPC by U18666A.
However, additions of 10 and 25microM pravastatin with 0.5microg/ml
U18666A significantly attenuated toxicity. Taken together, these data
showed for the first time that U18666A induces cell death by apoptosis
and suggested an important in vitro model system to study NPC.
PMID: 14766223 [PubMed - indexed for MEDLINE]
Exp Neurol. 2003 Dec;184(2):887-903. Related Articles, Links
Click here to read
Postnatal development of inflammation in a murine model of
Niemann-Pick type C disease: immunohistochemical observations of
microglia and astroglia.
Baudry M, Yao Y, Simmons D, Liu J, Bi X.
Department of Psychiatry & Human Behavior, University of California
Irvine, Irvine, CA 92612, USA.
Niemann-Pick type C (NPC) is a rare and fatal neurovisceral storage
disorder that is currently untreatable. In most cases, NPC is caused by
mutations of the NPC1 gene, which encodes a glycoprotein playing an
important role in cholesterol transport. Mice lacking the NPC1 gene
exhibit several pathological features of NPC patients and have been
widely used to provide insights into the mechanisms of the disease. In
the present study, we analyzed the postnatal development of pathological
manifestations of inflammation in several brain regions of NPC1-/- mice.
Brain sections from NPC1-/- and wild-type (NPC1+/+) mice were
immunostained with the MAC1 antibody, which recognizes microglia, with
antibodies against glial fibrillary acidic protein (GFAP), which
recognize astrocytes, and with antibodies against the cytokine
interleukin-1beta (IL-1beta). Numbers of MAC1 immunopositive cells were
markedly increased in several brain regions of NPC1-/- mice as early as
2 weeks of age. This effect was particularly evident in globus pallidus,
ventral lateral thalamus, medial geniculate nucleus, and cerebellum.
MAC1-immunopositive cells had enlarged cell bodies and shorter
processes, suggesting they were in an active state. By 4 weeks, most
brain structures exhibited enhanced microglial activation in NPC1-/-
mice, and this was maintained at 12 weeks. At 2 weeks, reactive
astrocytes were only observed in the ventral lateral thalamus while they
were present throughout the brain of NPC1-/- mice at 4 weeks of age.
Moreover, the astroglial reaction coincided with up-regulation of the
cytokine, interleukin-1beta, in most, but not all brain regions. In
particular, no interleukin-1beta up-regulation was observed in regions
devoid of neuronal degeneration. These results suggest that microglial
activation precedes and might be causally related to neuronal
degeneration, while astrocyte activation might be a consequence of
neuronal degeneration.
PMID: 14769381 [PubMed - indexed for MEDLINE]
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