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to jim chinnis re: cholesterol synthesis within CNS
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eml
medicine forum Guru Wannabe


Joined: 12 Jun 2005
Posts: 135

PostPosted: Wed Jun 21, 2006 6:16 pm    Post subject: to jim chinnis re: cholesterol synthesis within CNS Reply with quote

reference/abstract: Locatelli S., Lutjohann, D, Von Bergman, K.
Effect of simvastatin (40 and 80 mgm/day) on plasma cholesterol and
extrahepatic synthesized 24S and 27-hydroxycholesterol.
Ataherosclerosis 2000;151:43.
report shows concentration of 24S hydroxycholesterol is significantly
reduced in patients receiving inhibitors of cholesterol synthesis,
indicating that these inhibitors penetrate the blood-brain barrier and
inhibit synthesis within the CNS.
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Jim Chinnis
medicine forum Guru


Joined: 30 Apr 2005
Posts: 1030

PostPosted: Wed Jun 21, 2006 6:45 pm    Post subject: Re: to jim chinnis re: cholesterol synthesis within CNS Reply with quote

"eml" <mmlevy46@hotmail.com> wrote in part:

Quote:
reference/abstract: Locatelli S., Lutjohann, D, Von Bergman, K.
Effect of simvastatin (40 and 80 mgm/day) on plasma cholesterol and
extrahepatic synthesized 24S and 27-hydroxycholesterol.
Ataherosclerosis 2000;151:43.
report shows concentration of 24S hydroxycholesterol is significantly
reduced in patients receiving inhibitors of cholesterol synthesis,
indicating that these inhibitors penetrate the blood-brain barrier and
inhibit synthesis within the CNS.

Interesting. Following up on this, I found some more recent papers,
including the following (full text is free, also):

Arch Neurol. 2002 Feb;59(2):213-6.

Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using
high-dosage simvastatin in patients with hypercholesterolemia: evidence that
simvastatin affects cholesterol metabolism in the human brain.

Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K.

Department of Clinical Pharmacology, Universitatsklinikum, University of
Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.

BACKGROUND: Previous studies have shown that patients with early onset of
Alzheimer disease and vascular dementia have higher levels of circulating
brain-derived 24S-hydroxycholesterol (cerebrosterol).Two recent
epidemiological studies indicated that treatment with inhibitors of
cholesterol synthesis (statins) reduces the incidence of Alzheimer disease.
OBJECTIVE: To test the hypothesis that treatment with high-dosage
simvastatin reduces circulating levels of 24S-hydroxycholesterol. DESIGN:
Prospective, 24-week treatment trial for lowering of cholesterol levels. We
conducted assessments at baseline, week 6, and week 24. SETTING: An academic
outpatient clinical study. PATIENTS: Eighteen patients who met the criteria
for hypercholesterolemia. INTERVENTION: Treatment with 80 mg/d of
simvastatin at night. MAIN OUTCOME MEASURES: Plasma lipoprotein levels were
measured enzymatically; lathosterol, by means of gas chromatography; and
24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry.
RESULTS: Simvastatin reduced total plasma cholesterol levels by 36% and 35%
after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced
by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol,
an indicator of whole-body cholesterol synthesis, was reduced by 60% and
61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were
lowered by 45% and 53%, respectively (P<.001). The ratio of
24S-hydroxycholesterol to cholesterol also decreased significantly (-12%
[P=.01] and -23% [P<.002], respectively). The further reduction of
24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to
24 was also significant (P=.02 for both). CONCLUSIONS: The greater reduction
of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol
indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol
turnover in the brain. The present results might describe a possible
mechanism of how long-term treatment with statins could reduce the incidence
of Alzheimer disease.
--
Jim Chinnis Warrenton, Virginia, USA
Back to top
Sharon Hope
medicine forum Guru


Joined: 30 Apr 2005
Posts: 752

PostPosted: Thu Jun 22, 2006 2:42 am    Post subject: Re: to jim chinnis re: cholesterol synthesis within CNS Reply with quote

Good cite. Unfortunately, the conclusion is off. Statins blocking the
brain's ability to replenish the substance that makes up 2/3 of its dry
weight is not a good thing, in fact, it is associated with the inability to
learn. (AKA Memory Loss)

See:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16505352&query_hl=3&itool=pubmed_docsum
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3869-74. Epub 2006 Feb 27.

Brain cholesterol turnover required for geranylgeraniol production and
learning in mice.

Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW.

Department of Molecular Genetics, University of Texas Southwestern Medical
Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such
as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized
in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion
activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase
excrete cholesterol more slowly, and the tissue compensates by suppressing
the mevalonate pathway. Here we report that this suppression causes a defect
in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in
spatial, associative, and motor learning, and in hippocampal long-term
potentiation (LTP). Acute treatment of wild-type hippocampal slices with an
inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects
of statin treatment and genetic elimination of 24-hydroxylase on LTP are
reversed by a 20-min treatment with geranylgeraniol but not by cholesterol.
We conclude that cholesterol turnover in brain activates the mevalonate
pathway and that a constant production of geranylgeraniol in a small subset
of neurons is required for LTP and learning.

PMID: 16505352 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------



"Jim Chinnis" <jchinnis@SPAMalum.mit.edu> wrote in message
news:qr4j92p2250tscd44dfveccgk3jhngds2m@4ax.com...
Quote:
"eml" <mmlevy46@hotmail.com> wrote in part:

reference/abstract: Locatelli S., Lutjohann, D, Von Bergman, K.
Effect of simvastatin (40 and 80 mgm/day) on plasma cholesterol and
extrahepatic synthesized 24S and 27-hydroxycholesterol.
Ataherosclerosis 2000;151:43.
report shows concentration of 24S hydroxycholesterol is significantly
reduced in patients receiving inhibitors of cholesterol synthesis,
indicating that these inhibitors penetrate the blood-brain barrier and
inhibit synthesis within the CNS.

Interesting. Following up on this, I found some more recent papers,
including the following (full text is free, also):

Arch Neurol. 2002 Feb;59(2):213-6.

Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using
high-dosage simvastatin in patients with hypercholesterolemia: evidence
that
simvastatin affects cholesterol metabolism in the human brain.

Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K.

Department of Clinical Pharmacology, Universitatsklinikum, University of
Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.

BACKGROUND: Previous studies have shown that patients with early onset of
Alzheimer disease and vascular dementia have higher levels of circulating
brain-derived 24S-hydroxycholesterol (cerebrosterol).Two recent
epidemiological studies indicated that treatment with inhibitors of
cholesterol synthesis (statins) reduces the incidence of Alzheimer
disease.
OBJECTIVE: To test the hypothesis that treatment with high-dosage
simvastatin reduces circulating levels of 24S-hydroxycholesterol. DESIGN:
Prospective, 24-week treatment trial for lowering of cholesterol levels.
We
conducted assessments at baseline, week 6, and week 24. SETTING: An
academic
outpatient clinical study. PATIENTS: Eighteen patients who met the
criteria
for hypercholesterolemia. INTERVENTION: Treatment with 80 mg/d of
simvastatin at night. MAIN OUTCOME MEASURES: Plasma lipoprotein levels
were
measured enzymatically; lathosterol, by means of gas chromatography; and
24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry.
RESULTS: Simvastatin reduced total plasma cholesterol levels by 36% and
35%
after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were
reduced
by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol,
an indicator of whole-body cholesterol synthesis, was reduced by 60% and
61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were
lowered by 45% and 53%, respectively (P<.001). The ratio of
24S-hydroxycholesterol to cholesterol also decreased significantly (-12%
[P=.01] and -23% [P<.002], respectively). The further reduction of
24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to
24 was also significant (P=.02 for both). CONCLUSIONS: The greater
reduction
of plasma concentrations of 24S-hydroxycholesterol compared with
cholesterol
indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol
turnover in the brain. The present results might describe a possible
mechanism of how long-term treatment with statins could reduce the
incidence
of Alzheimer disease.
--
Jim Chinnis Warrenton, Virginia, USA
Back to top
Sharon Hope
medicine forum Guru


Joined: 30 Apr 2005
Posts: 752

PostPosted: Thu Jun 22, 2006 2:48 am    Post subject: Re: to jim chinnis re: cholesterol synthesis within CNS Reply with quote

Also in conflict with the conclusion of the cite Jim offers (see especially
their second and third points):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15649137&query_hl=3&itool=pubmed_DocSum

Biochem Soc Symp. 2005;(72):129-38.



The conflicting role of brain cholesterol in Alzheimer's disease: lessons
from the brain plasminogen system.

Ledesma MD, Dotti CG.

Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino,
A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.

Retrospective clinical studies indicate that individuals chronically treated
with cholesterol synthesis inhibitors, statins, are at lower risk of
developing AD (Alzheimer's disease). Moreover, treatment of guinea pigs with
high doses of simvastatin or drastic reduction of cholesterol in cultured
cells decrease Abeta (beta-amyloid peptide) production. These data sustain
the concept that high brain cholesterol is responsible for Abeta
accumulation in AD, providing the scientific support for the proposed use of
statins to prevent this disease. However, a number of unresolved issues
raise doubts that high brain cholesterol is to blame. First, it has not been
shown that higher neuronal cholesterol increases Abeta production. Secondly,
it has not been demonstrated that neurons in AD have more cholesterol than
control neurons. On the contrary, the brains of AD patients show a specific
down-regulation of seladin-1, a protein involved in cholesterol synthesis,
and low membrane cholesterol was observed in hippocampal membranes of ApoE4
(apolipoprotein E4) AD cases. This effect was also evidenced by altered
cholesterol-rich membrane domains (rafts) and raft-mediated functions, such
as diminished generation of the Abeta-degrading enzyme plasmin. Thirdly,
numerous genetic defects that cause neurodegeneration are due to defective
cholesterol metabolism. Fourthly, in female mice, the most brain-permeant
statin induces neurodegeneration and high amyloid production. Altogether,
this evidence makes it difficult to accept that statins are beneficial
through acting as brain cholesterol-synthesis inhibitors. It appears more
likely that their advantageous role arises from improved brain oxygenation.

Publication Types:
a.. Review

PMID: 15649137 [PubMed - indexed for MEDLINE]


"Jim Chinnis" <jchinnis@SPAMalum.mit.edu> wrote in message
news:qr4j92p2250tscd44dfveccgk3jhngds2m@4ax.com...
Quote:
"eml" <mmlevy46@hotmail.com> wrote in part:

reference/abstract: Locatelli S., Lutjohann, D, Von Bergman, K.
Effect of simvastatin (40 and 80 mgm/day) on plasma cholesterol and
extrahepatic synthesized 24S and 27-hydroxycholesterol.
Ataherosclerosis 2000;151:43.
report shows concentration of 24S hydroxycholesterol is significantly
reduced in patients receiving inhibitors of cholesterol synthesis,
indicating that these inhibitors penetrate the blood-brain barrier and
inhibit synthesis within the CNS.

Interesting. Following up on this, I found some more recent papers,
including the following (full text is free, also):

Arch Neurol. 2002 Feb;59(2):213-6.

Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using
high-dosage simvastatin in patients with hypercholesterolemia: evidence
that
simvastatin affects cholesterol metabolism in the human brain.

Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K.

Department of Clinical Pharmacology, Universitatsklinikum, University of
Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.

BACKGROUND: Previous studies have shown that patients with early onset of
Alzheimer disease and vascular dementia have higher levels of circulating
brain-derived 24S-hydroxycholesterol (cerebrosterol).Two recent
epidemiological studies indicated that treatment with inhibitors of
cholesterol synthesis (statins) reduces the incidence of Alzheimer
disease.
OBJECTIVE: To test the hypothesis that treatment with high-dosage
simvastatin reduces circulating levels of 24S-hydroxycholesterol. DESIGN:
Prospective, 24-week treatment trial for lowering of cholesterol levels.
We
conducted assessments at baseline, week 6, and week 24. SETTING: An
academic
outpatient clinical study. PATIENTS: Eighteen patients who met the
criteria
for hypercholesterolemia. INTERVENTION: Treatment with 80 mg/d of
simvastatin at night. MAIN OUTCOME MEASURES: Plasma lipoprotein levels
were
measured enzymatically; lathosterol, by means of gas chromatography; and
24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry.
RESULTS: Simvastatin reduced total plasma cholesterol levels by 36% and
35%
after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were
reduced
by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol,
an indicator of whole-body cholesterol synthesis, was reduced by 60% and
61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were
lowered by 45% and 53%, respectively (P<.001). The ratio of
24S-hydroxycholesterol to cholesterol also decreased significantly (-12%
[P=.01] and -23% [P<.002], respectively). The further reduction of
24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to
24 was also significant (P=.02 for both). CONCLUSIONS: The greater
reduction
of plasma concentrations of 24S-hydroxycholesterol compared with
cholesterol
indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol
turnover in the brain. The present results might describe a possible
mechanism of how long-term treatment with statins could reduce the
incidence
of Alzheimer disease.
--
Jim Chinnis Warrenton, Virginia, USA
Back to top
Jim Chinnis
medicine forum Guru


Joined: 30 Apr 2005
Posts: 1030

PostPosted: Thu Jun 22, 2006 3:29 am    Post subject: Re: to jim chinnis re: cholesterol synthesis within CNS Reply with quote

"Sharon Hope" <shope@anet.net> wrote in part:

Quote:
Also in conflict with the conclusion of the cite Jim offers

I have no dog in this hunt, FWIW.
--
Jim Chinnis Warrenton, Virginia, USA
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Sharon Hope
medicine forum Guru


Joined: 30 Apr 2005
Posts: 752

PostPosted: Thu Jun 22, 2006 3:39 am    Post subject: Re: to jim chinnis re: cholesterol synthesis within CNS Reply with quote

Understand, just trying to differentiate the cites.

Thanks, and take care

"Jim Chinnis" <jchinnis@SPAMalum.mit.edu> wrote in message
news:ck3k92dsf0b3mjdt8cuc0dm815n7qmmkpm@4ax.com...
Quote:
"Sharon Hope" <shope@anet.net> wrote in part:

Also in conflict with the conclusion of the cite Jim offers

I have no dog in this hunt, FWIW.
--
Jim Chinnis Warrenton, Virginia, USA
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