There is one point about the BBB theory that poses a problem: If the increased permeability is the cause of our problem, why is damage limited to the substantia nigra? The same question in another form might be why is the BBB just leaking in the area of the SN? In other words why would the damage be localized there?

There is an answer if we cast a slightly wider net. First, is there something special about the SN compared to the rest of the brain? Yes, at least one thing. The SN has an unusually high number of the immune system defenders called microglia. Possibly the highest density in the entire brain, in fact.

One thing about microglia is that in certain circumstances they attack the neurons they are supposed to defend. If that happened in the high density SN there would be a problem.

The circumstances where this malfunction occurs is in an adult who was exposed to bacterial toxins during critical stages of development as a fetus. That exposure has three effects of relevance. First is a lower number of neurons in the SN at birth. We start out with one strike against us.

Second is the over reactive microglia in the adult. This self destructive reaction occurs when the "primed" microglia detect further traces of the bacterial toxin that started the problem years before. We are born with a loaded gun in our brain.

Third effect is an alteration in the part of our brain that controls our stress response. The result is that our cortisol levels are chronically elevated. This stress response has an important effect. It triggers chronic inflammation.

Chronic inflammation, among other things, opens the BBB, allowing toxins to enter.

And one of the most common of those toxins is the bacterial one that started the whole chain. The BBB leaks from inflammation, the toxin enters the brain, the microglia go berserk, and neurons begin to die.

That is one of the pillars of the multiple hit hypothesis that we are going to be hearing a lot about over the coming years. of course the leaky BBB lets in other toxins as well, but the bacterial one is the one that turns our own defenders into madmen.

One caveat is that the above has all been demonstrated on animal models and part on humans thus far. But many teams are working on the various parts and a lot of things are faling into place.

That's all well and good, of course, but we need help today, not tomorrow.


These three studies show that green tea extracts not only calm down the microglia but also protect the BBB and the counterpart in the GI tract.


1: J Neurosci Res. 2004 Dec 1;78(5):723-31.

(-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial
activation and protects against inflammation-mediated dopaminergic neuronal
injury.

Li R, Huang YG, Fang D, Le WD.

Health Science Center, Shanghai Institute for Biological Science, Chinese
Academy of Science, Shanghai Second Medical University, Shanghai, Peoples
Republic of China.

Microglial activation is believed to play a pivotal role in the selective
neuronal injury associated with several neurodegenerative disorders, including
Parkinson's disease (PD) and Alzheimer's disease. We provide evidence that
(-)-epigallocatechin gallate (EGCG), a major monomer of green tea polyphenols,
potently inhibits lipopolysaccharide (LPS)-activated microglial secretion of
nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) through the
down-regulation of inducible NO synthase and TNF-alpha expression. In addition,
EGCG exerted significant protection against microglial activation-induced
neuronal injury both in the human dopaminergic cell line SH-SY5Y and in primary
rat mesencephalic cultures. Our study demonstrates that EGCG is a potent
inhibitor of microglial activation and thus is a useful candidate for a
therapeutic approach to alleviating microglia-mediated dopaminergic neuronal
injury in PD.

PMID: 15478178 [PubMed - indexed for MEDLINE]

1: World J Gastroenterol. 2007 Jan 21;13(3):349-54.

Red wine and green tea reduce H pylori- or VacA-induced gastritis in a mouse
model.

Ruggiero P, Rossi G, Tombola F, Pancotto L, Lauretti L, Del Giudice G, Zoratti
M.

Novartis Vaccines & Diagnostics s.r.l., Research Center, Via Fiorentina 1, Siena
I-53100, Italy. paolo.ruggiero@novartis.com

AIM: To investigate whether red wine and green tea could exert anti-H pylori or
anti-VacA activity in vivo in a mouse model of experimental infection. METHODS:
Ethanol-free red wine and green tea concentrates were administered orally as a
mixture of the two beverages to H pylori infected mice, or separately to
VacA-treated mice. Gastric colonization and gastric inflammation were quantified
by microbiological, histopathological, and immunohistochemical analyses.
RESULTS: In H pylori-infected mice, the red wine and green tea mixture
significantly prevented gastritis and limited the localization of bacteria and
VacA to the surface of the gastric epithelium. Similarly, both beverages
significantly prevented gastric epithelium damage in VacA-treated mice; green
tea, but not red wine, also altered the VacA localization in the gastric
epithelium. CONCLUSION: Red wine and green tea are able to prevent H
pylori-induced gastric epithelium damage, possibly involving VacA inhibition.
This observation supports the possible relevance of diet on the pathological
outcome of H pylori infection.

PMID: 17230601 [PubMed - in process]


1: Wien Klin Wochenschr. 1999 Apr 9;111(7):278-82.

The green tea extract epigallocatechin gallate is able to reduce neutrophil
transmigration through monolayers of endothelial cells.

Hofbauer R, Frass M, Gmeiner B, Handler S, Speiser W, Kapiotis S.

Department of Medical and Chemical Laboratory Diagnostics, University of Vienna,
Austria. roland.hofbauer@akh-wien.ac.at

Green tea is widely used in Asia and has also become popular in Western
countries. The influence of green tea extracts on leukocytes is not well
understood. Leukocytes play a crucial role in the process of inflammation. They
migrate from the intravascular space into the tissue to attack micro-organisms.
The aim of the current study was to investigate the influence of
epigallocatechin gallate on leukocyte transmigration through endothelial cell
monolayers and thereby evaluate its potential role in the inflammatory process.
Human umbilical vein endothelial cells were cultured on microporous membranes to
achieve a monolayer. Freshly isolated neutrophils from healthy subjects were
measured with a migration assay. The amount of untreated neutrophils migrating
through untreated endothelial cell monolayers was used as control and set as
100%. Neutrophils and/or endothelial cell monolayers were pre-treated with
epigallocatechin gallate using relevant, as well as higher and lower
concentrations. The relevant plasma concentration of epigallocatechin gallate
was able to significantly inhibit neutrophil migration through endothelial cell
monolayers (69 +/- 6.4% SD; p < 0.05 compared to control), when both cell types
(leukocytes and endothelial cell monolayer) were treated. This is similar to the
situation after resorption in-vivo. Treating either neutrophils or endothelial
cell monolayers alone led to significant reductions in migratory response (only
neutrophils treated: 86 +/- 8.1% SD, p < 0.05; only endothelial cell monolayers:
77 +/- 6.1%, p < 0.05). In conclusion, epigallocatechin gallate was identified
as a potent inhibitor of leukocyte migration through endothelial cell
monolayers. The treatment of both cell types showed an additive effect.
Endothelial cells seem to be more affected than neutrophils. Further clinical
investigations are necessary to understand the potential clinical consequences.

PMID: 10355038 [PubMed - indexed for MEDLINE]