Re: to jim chinnis re: cholesterol synthesis within CNS

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@xxxxxxxxxxxxxxxx> wrote in message
news:qr4j92p2250tscd44dfveccgk3jhngds2m@xxxxxxxxxx
"eml" <mmlevy46@xxxxxxxxxxx> 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


.

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