Zonulin is also involved in the barrier function of the gut, especially
in celiac disease. However, caffeine may block regulatory T-cells via
its elevation of neutral endopeptidase. NEP blocks vasoactive
intestinal polypeptide and VIP is an on signal for Tregs. Caffeine can
also adversely affect circadian rhythms and GABA production.
On another note, cobalt and iron chelators like green tea extract can
switch on HIF-1a and this improves barrier function - at least in the
gut. This may indicate another route through which green tea protects
against neurodegeneration.
<http://www.sciencedaily.com/releases/2008/04/080402194407.htm>
Cup Of Coffee A Day Could Help Protect Against Alzheimer's Disease,
Study Suggests
ScienceDaily (Apr. 3, 2008) ‹ A daily dose of caffeine blocks the
disruptive effects of high cholesterol that scientists have linked to
Alzheimer's disease. A study in the open access publication, Journal of
Neuroinflammation revealed that caffeine equivalent to just one cup of
coffee a day could protect the blood-brain barrier (BBB) from damage
that occurred with a high-fat diet.
The BBB protects the central nervous system from the rest of the body's
circulation, providing the brain with its own regulated
microenvironment. Previous studies have shown that high levels of
cholesterol break down the BBB which can then no longer protect the
central nervous system from the damage caused by blood borne
contamination. BBB leakage occurs in a variety of neurological disorders
such as Alzheimer's disease.
In this study, researchers from the University of North Dakota School of
Medicine and Health Sciences gave rabbits 3 mg caffeine each day -- the
equivalent of a daily cup of coffee for an average-sized person. The
rabbits were fed a cholesterol-enriched diet during this time.
After 12 weeks a number of laboratory tests showed that the BBB was
significantly more intact in rabbits receiving a daily dose of caffeine.
"Caffeine appears to block several of the disruptive effects of
cholesterol that make the blood-brain barrier leaky," says Jonathan
Geiger, University of North Dakota School of Medicine and Health
Sciences. "High levels of cholesterol are a risk factor for Alzheimer's
disease, perhaps by compromising the protective nature of the
blood-brain barrier. For the first time we have shown that chronic
ingestion of caffeine protects the BBB from cholesterol-induced leakage."
Caffeine appears to protect BBB breakdown by maintaining the expression
levels of tight junction proteins. These proteins bind the cells of the
BBB tightly to each other to stop unwanted molecules crossing into the
central nervous system.
The findings confirm and extend results from other studies showing that
caffeine intake protects against memory loss in aging and in Alzheimer's
disease.
"Caffeine is a safe and readily available drug and its ability to
stabilise the blood-brain barrier means it could have an im****tant part
to play in therapies against neurological disorders," says Geiger.
Journal reference: Caffeine blocks disruption of blood brain barrier in
a rabbit model of Alzheimer's disease Xuesong Chen, Jeremy W. Gawryluk,
John F. Wagener, Othman Ghribi and Jonathan D. Geiger Journal of
Neuroinflammation (in press)
Adapted from materials provided by BioMed Central/Journal of
Neuroinflammation, via EurekAlert!, a service of AAAS.
J Neuroinflammation. 2008 Apr 3;5(1):12 [Epub ahead of print] LinkOut
Caffeine blocks disruption of blood brain barrier in a rabbit model of
Alzheimer's disease.
* Chen X,
* Gawryluk JW,
* Wagener JF,
* Ghribi O,
* Geiger JD.
ABSTRACT: High levels of serum cholesterol and disruptions of the blood
brain barrier (BBB) have all been implicated as underlying mechanisms in
the pathogenesis of Alzheimer's disease. Results from studies conducted
in animals and humans suggest that caffeine might be protective against
Alzheimer's disease but by poorly understood mechanisms. Using rabbits
fed a cholesterol-enriched diet, we tested our hypothesis that chronic
ingestion of caffeine protects against high cholesterol diet-induced
disruptions of the BBB. New Zealand rabbits were fed a 2%
cholesterol-enriched diet, and 3 mg caffeine was administered daily in
drinking water for 12 weeks. Total cholesterol and caffeine
concentrations from blood were measured. Olfactory bulbs (and for some
studies hippocampus and cerebral cortex as well) were evaluated for BBB
leakage, BBB tight junction protein expression levels, activation of
astrocytes, and microglia density using histological, immunostaining and
immunoblotting techniques. We found that caffeine blocked high
cholesterol diet-induced increases in extravasation of IgG and
fibrinogen, increases in leakage of Evan's blue dye, decreases in levels
of the tight junction proteins occludin and ZO-1, increases in
astrocytes activation and microglia density where IgG extravasation was
present. Chronic ingestion of caffeine protects against high cholesterol
diet-induced increases in disruptions of the BBB, and caffeine and drugs
similar to caffeine might be useful in the treatment of Alzheimer's
disease.
PMID: 18387175
Another interesting paper in the same vein:
Reproductive hormones regulate the selective permeability of the
blood-brain barrier.
Wilson AC, Clemente L, Liu T, Bowen RL, Meethal SV, Atwood
CS.
Department of Medicine, University of Wisconsin-Madison and Geriatric
Research, Education and Clinical Center, Veterans Administration
Hospital, 2500 Overlook Terrace, Madison, WI, 53705 USA.
Reproductive hormones have been demonstrated to modulate both gap- and
tight-junction protein expression in reproductive tissues and
endometrium, however the effects of changes in reproductive hormones on
the selective permeability of the blood-brain barrier (BBB) remain
unclear. Age-related declines in BBB integrity correlate with the loss
of serum *** steroids and increase in gonadotropins with
menopause/andropause. To examine the effect of reproductive senescence
on gap- and tight-junction protein expression/localization and BBB
permeability, female mice at 3 months of age were either sham operated
(normal serum E(2) and gonadotropins), ovariectomized (low serum E(2)
and high serum gonadotropins) or ovariectomized and treated with the
GnRH agonist leuprolide acetate (low serum E(2) and gonadotropins).
Ovariectomy induced a 2.2-fold increase in Evan's blue dye extravasation
into the brain. The expression and localization of the cytoplasmic
membrane-associated tight-junction protein zona occludens 1 (ZO-1) in
microvessels was not altered among groups indicating that the increased
paracellular permeability was not due to changes in this tight-junction
protein. However, ovariectomy induced a redistribution of the
gap-junction protein connexin-43 (Cx43) such that immunoreactivity
relocalized from along the extracellular microvascular endothelium to
become associated with endothelial cells. An increase in Cx43 expression
in the mouse brain following ovariectomy was suppressed in
ovariectomized animals treated with leuprolide acetate, indicating that
serum gonadotropins rather than *** steroids were modulating Cx43
expression. These results suggest that elevated serum gonadotropins
following reproductive senescence may be one possible cause of the loss
of selective permeability of the BBB at this time. Furthermore, these
findings implicate Cx43 in mediating changes in BBB permeability, and
serum gonadotropins in the cerebropathophysiology of age-related
neurodegenerative diseases such as stroke and Alzheimer's disease.
PMID: 18381207
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