<Doing my very best Groucho imitation> ...have I ever told you how lovely you look in this light? That I just love the way that you type your "w's"? That I admire your mind as much as your body?

It sounds like a unique opportunity and I will do some work on it BUT (and please forgive me Ron) I think it is too limited as currently presented. There is a lot at stake here and, if you are going to have the ear of someone who has some weight in Fox;s group, I would be a darned fool and a traitor to Parkiedom if I didn't speak plainly.

I think that the BBB issue is indeed important but that it is just one effect of the bigger problem of inflammation and the resulting activation of the brain's microglial defenders resulting in neuronal loss in the substantia nigra. Inflammation also opens the BBB and toxins do indeed make things worse for some of us (an explanation for differing rates of progression, but the hyperactive response of the microglia is what wipes out your substantia nigra, which coincidentally has one of the highest density microglia populations in the entire brain.

For this reason, inflammation has to be considered one of the two most critical factors in PD. The other is sress induced cortisol elevation, but that is getting into heavier territory and I wouldn't want to dilute the opportunity by taking on too much.

I'm going to tack on a couple of abstracts but I can make a concise case for this with everything footnoted to peer reviewed publications and keep it to a couple of pages. If you are willing to consider it, I will put it up here and defend it for a week before it leaves so that we can polish it as a group. That, in turn, might get us a little attention itself.

Like i said, I would be betraying us all if I didn't pipe up here. The reason is that treatments for this already exist and more targeted ones are easily within reach. Just see the last abstract below. <What is that cologne you are wearing my dear? Could I rub your feet? Could you rub mine then? )



1: Ann N Y Acad Sci. 2003 Jun;991:214-28.

The role of glial reaction and inflammation in Parkinson's disease.

Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP.

INSERM U289, Experimental Neurology and Therapeutics, Hopital de la Salpetriere,
75651 Paris Cedex 13, France. hirsch@ccr.jussieu.fr

The glial reaction is generally considered to be a consequence of neuronal death
in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease,
and Parkinson's disease. In Parkinson's disease, postmortem examination reveals
a loss of dopaminergic neurons in the substantia nigra associated with a massive
astrogliosis and the presence of activated microglial cells. Recent evidence
suggests that the disease may progress even when the initial cause of neuronal
degeneration has disappeared, suggesting that toxic substances released by the
glial cells may be involved in the propagation and perpetuation of neuronal
degeneration. Glial cells can release deleterious compounds such as
proinflammatory cytokines (TNF-alpha, Il-1beta, IFN-gamma), which may act by
stimulating nitric oxide production in glial cells, or which may exert a more
direct deleterious effect on dopaminergic neurons by activating receptors that
contain intracytoplasmic death domains involved in apoptosis. In line with this
possibility, an activation of proteases such as caspase-3 and caspase-8, which
are known effectors of apoptosis, has been reported in Parkinson's disease. Yet,
caspase inhibitors or invalidation of TNF-alpha receptors does not protect
dopaminergic neurons against degeneration in experimental models of the disease,
suggesting that manipulation of a single signaling pathway may not be sufficient
to protect dopaminergic neurons. In contrast, the antiinflammatory drugs
pioglitazone, a PPAR-gamma agonist, and the tetracycline derivative minocycline
have been shown to reduce glial activation and protect the substantia nigra in
an animal model of the disease. Inhibition of the glial reaction and the
inflammatory processes may thus represent a therapeutic target to reduce
neuronal degeneration in Parkinson's disease.

Publication Types:
Review

PMID: 12846989 [PubMed - indexed for MEDLINE]


1: Neurobiol Dis. 2000 Aug;7(4):429-47.

The single intranigral injection of LPS as a new model for studying the
selective effects of inflammatory reactions on dopaminergic system.

Herrera AJ, Castano A, Venero JL, Cano J, Machado A.

Departamento de Bioquimica, Bromatologia, Toxicologia, y Medicina Legal,
Universidad de Sevilla, Calle Prof., Garcia Gonzalez s/n, Sevilla, 41012, Spain.

We have injected lipopolysaccharide (LPS) into the nigrostriatal pathway of rats
in order to address the role of inflammation in Parkinson's disease (PD). LPS
induced a strong macrophage/microglial reaction in Substantia nigra (SN), with a
characteristic clustering of macrophage cells around blood-vessels. The SN was
far more sensitive than the striatum to the inflammatory stimulus. Moreover,
only the dopaminergic neurons of the SN were affected, with no detectable damage
to either the GABAergic or the serotoninergic neurons. The damage to the DA
neurons in the SN was permanent, as observed 1 year postinjection. Unlike the
direct death of dopaminergic neurons caused by agents as MPP(+) or 6-OHDA, LPS
seems to cause indirect death due to inflammatory reaction. Therefore, we
suggest that the injection of a single dose of LPS within the SN is an
interesting model for studying the selective effects of inflammatory reaction on
dopaminergic system and also potentially useful for studying PD. Copyright 2000
Academic Press.

PMID: 10964613 [PubMed - indexed for MEDLINE]

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]


But as I said I will work on the BBB angle as well regardless of your decision.