[olsen]

Rick--interesting comments in light of your theory that PD may be caused by a "prenatal event" to be activated/triggered later in life:

http://www.nature.com/bjp/journal/va.../0707167a.html

British Journal of Pharmacology advance online publication 5 March 2007; doi: 10.1038/sj.bjp.0707167

Inflammation as a causative factor in the aetiology of Parkinson's disease

P S Whitton1



conclusion from above linked article:

"PD is a relatively common neurodegenerative disease with a well-characterized group of symptoms. Although a number of different mechanisms have been proposed in the aetiology of PD, none have been considered to have absolute predominance. In part, this has been due to the difficulty in establishing any clear epidemiology for idiopathic PD, which is responsible for some 95% of cases. Indeed, on the face of it, idiopathic PD appears to strike at random with no apparent pattern either geographically or among patient groups. The observations in patients and experimental models of PD that neuroinflammation appears to be one of the, if not the, most consistant pathological change, opens new possibilities in understanding this illness. The CNS had been considered to be a relatively immunologically quiescent organ but this is now undergoing a considerable re-evaluation. It has become apparent from a number of lines of research, including a substantial volume relating to PD, that microglial cells can become activated by a wide range of stimuli. Critically, these include infections of peripheral origin. The findings by Ling et al. (2002, 2006) that prenatal infection of female rats leads to progressive neuroinflammatory and degenerative PD-like changes in the offspring, following a subsequent LPS challenge, are of great interest. The implication is that a predisposition to SN neurodegeneration may be established before birth or possibly by infections afterwards. That these could in part underlie a disease that might not emerge until decades later could indeed account for the difficulty in 'predicting' PD, as the events would be highly unlikely to be connected. The potential use of anti-inflammatory drugs in PD is interesting but it is hard to envisage great benefit unless the intervention is made with a very early diagnosis leading to the possibility that calming the neuroinflammatory crisis in the SN might at least slow disease progression."

(I include only the 2 references the author cites in this conclusion-- the rest are obtainable from the article

Ling Z, Gayle DA, Ma SY, Lipton JW, Tong CW, Hong JS (2002). In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. Movement Dis 17: 116–124. | PubMed |

Ling Z, Zhu Y, Tong CW, Snyder JA, Lipoton JW, Carvey PM (2006). Progressive dopamine neuron loss following supra-nigral lipopolysaccharide (LPS) infusion into rats exposed to LPS prenatally. Exp Neurol 199: 499–512. | Article | PubMed | ChemPort |


(there's that smiley face again--I could not even edit it out! Madelyn)

[reverett123]

Yes, it looks more and more like the prenatal environment is the key. The bacterial toxins at the right time lay one of the cornerstones. The cited works by the PM Carvey team are very important as are those of another team led by Bin Liu. If anyone wants to really start to get an understanding of this, a little time spent on Medline reading those two groups will do it.

Another and similar cornerstone that is being largely overlooked but which Anne Frobert and I have been following up on is the role of maternal stress during pregnancy and stress in general through life.

In a nutshell, the basic process is that prenatal toxin (LPS) sensitizes the adult immune system so that the brain's defenders over react when future encounters occur. Prenatal stress hormones disrupt our response to further stressors such that we have, among other things, chronic inflammation. That, in turn, compromises the BBB and lets toxins into the brain, including good old LPS. Our microglial defenders give a tiny yell of "Ancient, my enemy!" and go berserk.

There's a lot more and we will soon have up a website to pull these threads together and try to make it understandable. In the meantime, there are at least two things shown to stop the microglial reaction - green tea extract and dextromethorphan! We are on the cutting edge here folks.

[Teretxu]

Yep, we had a long thread last year on the old Braintalk forum about being born with PD. I have photos of myself as a little tyke in a clearly parkinsonian postures (arms bent at elbow, head poking forward), and although I was always good at sports, I do remember episodes of stress-related tremors in my teens.

Like Redd Foxx used to say: The fungus is among us! (and, tragically, we might be infecting our babies in the womb)

[ashleyk]

The BJP report above confirms research done at the NIH that neuroinflammation is one of, or the cause, of PD and other like diseases. The NIH goes further and shows that they have seen a significant? slowing of disease progression in rodents using low doses of opioid receptor antagonists like naloxone (naltrexone) and dextromethorphan. That's why, I believe, some of us are treating ourselves with low doses of these substances in the hope that we will not get much worse.
Ashley

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
We recently reported that dextromethorphan (DM), a widely used anti-tussive agent, attenuated endotoxin-induced dopaminergic neurodegeneration in vitro. In the current study, we investigated the potential neuroprotective effect of DM and the underlying mechanism of action in the MPTP rodent PD model. Mice (C57BL/6J) that received daily MPTP injections (15 mg free base/kg body weight, s.c.) for 6 consecutive days exhibited significant degeneration of the nigrostriatal dopaminergic pathway. However, the MPTP-induced loss of nigral dopaminergic neurons was significantly attenuated in those mice receiving DM (10 mg/kg body weight, s.c.). In mesencephalic neuron-glia cultures, DM significantly reduced the MPTP-induced production of both extracellular superoxide free radicals and intracellular reactive oxygen species (ROS). Because NADPH oxidase is the primary source of extracellular superoxide and intracellular ROS, we investigated the involvement of NADPH oxidase in the neuroprotective effect of DM. Indeed, the neuroprotective effect of DM was only observed in the wild-type but not in the NADPH oxidase-deficient mice, indicating that NADPH oxidase is a critical mediator of the neuroprotective activity of DM. More importantly, due to its proven safety record of long-term clinical use in humans, DM may be a promising agent for the treatment of degenerative neurological disorders such as PD.
PMID: 14734632 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Inflammation has been increasingly recognized to contribute to the pathogenesis of Parkinson's disease. Several compounds are neuroprotective at femtomolar concentrations through the inhibition of inflammation. However, the mechanisms mediating femtomolar-acting compounds are poorly understood. Here we show that both gly-gly-phe (GGF), a tri-peptide contained in the dynorphin opioid peptide, and naloxone are neuroprotective at femtomolar concentrations against LPS-induced dopaminergic neurotoxicity through the reduction of microglial activation. Mechanistic studies demonstrated the critical role of NADPH oxidase in the GGF and naloxone inhibition of microglial activation and associated DA neurotoxicity. Pharmacophore analysis of the neuroprotective dynorphin peptides and naloxone revealed common chemical properties (hydrogen bond acceptor, hydrogen bond donor, positive ionizable, hydrophobic) of these femtomolar-acting compounds. These results support a common high-affinity site of action for several femtomolar-acting compounds, where NADPH oxidase is the critical mechanism governing neuroprotection, suggesting a novel avenue of anti-inflammatory and neuroprotective therapy.
Publication Types: PMID: 15791005 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

[paula_w]

One culprit is probably water. I don't have a source for this other than my memory but at the only environmental conference I ever attended they compared irrigation watered populations to natural watered food (this was an ideal set up because this rural tribe or group [Mexico I believe] split up over the issue of wanting irrigation). The irrigated group's children started showing learning disabilities. Pollution often effects reproduction.

[reverett123]

The emerging picture is one of an ongoing, life-long process that begins in the womb with time-critical exposures to disruptive chemicals. Toxins in our outer environment are one class. Toxins from gram-negative bacteria are a second. And maternal stress chemicals are a third. Any and all of these, if encountered at the proper time, alter our nervous system, our endocrine system, our immune system, and our GI system. All these things interact over the course of our lives with other factors such as methylmercury in vaccines or mercury amalgams, further encounters with LPS, and chronic stress from modern life. This is what I have spent the last year working on with the French MD Anne Frobert. (She has put four years into it herself and I keep mentioning her name in hopes she will get credit someday.)

This is incredibly complex, but I am about to (hopefully 30 days) have a website up and going to encourage discussion of the many facets of this by researchers across the disciplinary boundaries using the same forum software we use here. If any are lurking or if anyone knows any researchers who might be interested, send me a private message and I will keep them informed.

In the meantime, don't drink the water...



1: Neurotoxicology. 2005 Aug;26(4):633-40. Epub 2004 Dec 18.

Neurological impairment in fetal mouse brain by drinking water disinfectant
byproducts.

Ahmed AE, Campbell GA, Jacob S.

Molecular Toxicology Laboratory of the Department of Pathology, 06-09,
University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
aahmed@utmb.edu

Developmental exposure to environmental chemicals may have detrimental effects
on embryonic brains that could play a major role in the etio-pathology of fetal
and adult neurological diseases. The exact mechanism by which prenatal exposures
to environmental agents, such as drinking water disinfectant byproducts (DBP),
cause neurological impairment in fetus is not known. Our objective is to examine
the impact of prenatal exposure to DBP on fetal brain development. Pregnant CD-1
mice, at the sixth day of gestation (GD-6), received a daily (GD-6-GD-18) oral
dose of chloroacetonitrile (CAN, 25 ppm), a member of DBP. To assess fetal brain
uptake of CAN, several animals were injected with a tracer dose of 2-[(14)C]-CAN
(333 microCi/kg, i.v.), at GD-12 and processed for quantitative in situ micro
whole-body autoradiography (QIMWBA) at 1 and 24 h after treatment. The remaining
animals continued receiving CAN until GD-18 when fetal brains were processed for
biochemical determination of oxidative stress (OS) or prepared for histological
examinations. The results indicate a rapid placental transfer and fetal brain
uptake of 2-[(14)C]-CAN/metabolites in cortical areas and hippocampus. In
treated animals 3-fold decrease in glutathione (GSH), 1.3-fold increase in lipid
peroxidation and 1.4-fold increase in DNA oxidation were detected as compared to
control. DeOlmos cupric silver staining of fetal brains indicated significant
increase in cortical neurodegeneration in treated animals. Immunohistochemical
labeling (TUNEL) of apoptotic nuclei in the cortices and choroid plexuses were
also increased in treated animals as compared to control. In conclusion, CAN
crosses the placental and fetal blood-brain barriers and induces OS that
triggered apoptotic neurodegenration in fetal brain. Future studies will examine
the molecular mechanisms of these events and its impact on neural development of
offspring.

PMID: 16112326 [PubMed - indexed for MEDLINE]