Stickies – Jump to Our Best

Those posts that we consider to be of particular importance:

Chronic inflammatory stress.

<The immune and endocrine systems interact through the HPA axis.>

1: Baillieres Best Pract Res Clin Endocrinol Metab. 1999 Dec;13(4):555-65.
Chronic inflammatory stress.

Harbuz MS.
University Research Centre for Neuroendocrinology, University of Bristol, UK.

A major mechanism involved in maintaining homeostasis in response to chronic inflammation is the hypothalamo-pituitary-adrenal (HPA) axis, resulting in the release of anti-inflammatory glucocorticoids from the adrenal cortex. An inadequate HPA axis response may result in the development of a pathology or an increase in susceptibility and/or severity of disease. Other neuroendocrine systems are also implicated. Increasingly considered important are circadian rhythms, not only of hormones, but also of components of the immune system. Recent evidence concerning changes in hypothalamic control of the HPA axis following development of disease, the implication of these for the response to stress and the use of the HPA axis as a predictor of susceptibility to disease will also be considered. Finally, the influence of stress on autoimmune disease will be discussed. This chapter will concentrate principally on rheumatoid arthritis, although other autoimmune diseases and animal models will be discussed.
PMID: 10903814 [PubMed - indexed for MEDLINE]

Involvement of innate immunity in the development of inflammatory and autoimmune diseases.

<Note: The nature of wheat changed greatly with the Industrial Revolution as local varieties were replaced by standardized ones.>

1: Ann N Y Acad Sci. 2005 Jun;1051:787-98.
Involvement of innate immunity in the development of inflammatory and autoimmune  diseases.

Tlaskalová-Hogenová H, Tucková L, Stepánková R, Hudcovic T, Palová-Jelínková L, Kozáková H, Rossmann P, Sanchez D, Cinová J, Hrncír T, Kverka M, Frolová L, Uhlig H, Powrie F, Bland P.  Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of  Sciences of the Czech Republic, 1st Faculty of Medicine, Charles University, Víde-ská 1083, Prague 4, Czech Republic. tlaskalo@biomed.cas.cz

Initial events and effector mechanisms of most inflammatory and autoimmune diseases remain largely unknown. Dysfunction of the innate and adaptive immune systems associated with mucosae (the major interface between the organism and its environment, e.g., microbiota, food) can conceivably cause impairment of mucosal  barrier function and development of localized or systemic inflammatory and autoimmune processes. Animal models help in elucidating the etiology and pathogenetic mechanisms of human diseases, such as the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, severe chronic diseases affecting the gut. To study the role of innate immunity and gut microbiota in intestinal inflammation, colitis was induced by dextran sulfate sodium (DSS) in mice with severe combined immunodeficiency (SCID). Conventionally reared (microflora-colonized) SCID mice displayed severe inflammation like that seen in  immunocompetent Balb/c mice, whereas only minor changes appeared in the intestinal mucosa of DSS-fed gnotobiotic germ-free SCID mice. The presence of microflora facilitates the inflammation in DSS-induced colitis that develops in immunodeficient SCID mice, that is, in the absence of T and B lymphocytes. Celiac disease, a chronic autoimmune small bowel disorder, afflicts genetically susceptible individuals with wheat gluten intolerance. We showed that, in contrast with any other food proteins, wheat gliadin and its peptic fragments activate mouse macrophages and human monocytes to produce proinflammatory cytokines through the nuclear factor-kappaB signaling pathway. Activation of innate immunity cells by food proteins or components from gut microbiota thus could participate in the impairment of intestinal mucosa and the development of intestinal and/or systemic inflammation.

PMID: 16127016 [PubMed - indexed for MEDLINE]

Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease.

<Note: Iron triggers aggregation of alpha-synuclein.>

1. FASEB J. 2005 Apr;19(6):533-42.  Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease.

Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J.  Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA.

A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson’s disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the  potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial  enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of  etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.  PMID: 15791003 [PubMed - indexed for MEDLINE]

And What a Long, Strange Trip It’s Been

<Subsonics are inaudible, extremely low frequency, yet very powerful sound waves. In nature they almost always are linked to danger and thus trigger the fight or flight response. They are also quite rare. However, in the world of the Industrial Revolution they became steadily more common. Today, millions of us live with them. Only a fool would say that there is no effect on our health.>

I have not posted for a bit but am very much alive with a great deal still to be said. I have been on an involuntary voyage of exploration and discovery that has included stops at stress, periodic paralysis, potassium, vitamin D, hyperthyroidism, and various other ports of call.

While I will have to allow the details to filter in with time, I will try to begin the process with this post. Do remember, however, that the experience is still being processed and research is ongoing.

The story begins with stress, the least appreciated of the foundations of Parkinson’s Disease. Between the Thanksgiving and Christmas holidays a “perfect storm” began to build as currents from life, money, health, family, etc. all converged on Ground Zero – yours truly.

As the new year advanced the pressures increased until by early Spring cognition began to slip. At least, that is the only explanation that I can offer for the final actions that sent me spiraling away for a few weeks. For any Tolkien fans out there, I held my breath and jumped into the Abyss with the Balrog and have returned clad in white. For those who need an interpreter, I made a major mistake, recovered, and have figured some things out that I will share as they develop.

The mistake lay in deciding that it was time to have a patch of pine trees removed from around my home. They had gotten to a stage where they were falling more and more and were increasingly dangerous. And so, a local contractor began to remove them, one by one. There were about three acres of them and my house was near the center. The job was expected to take two weeks but weather stretched it to seven. Seven weeks of hell.

The crew of four, in addition to chainsaws and other mundane tools, depended very much on a sort of modified bulldozer called a “skidder”. The skidder was what moved the logs around. It emitted a deep, low rumble of a sound that, because of the weight and solid contact with the ground, penetrated deep into the bones which seemed to then vibrate as well.

This rich spectrum of sound frequencies dropped below the levels that the human can normally hear and into the range called “subsonic”. Subsonic sound is very powerful and not normally encountered in nature. One of the few places that our ancestor’s would encounter it is in the roar of a big cat, such as a tiger, as it sprang. The subsonic portion of the roar triggers a brief paralysis and the tiger dines.

So, my inner reptile found itself trapped in my house as the roar of predators came from all directions. Fight or flight triggers were pulled again and again until one evening I found myself curled like a fetus in the floor unable to move even enough to open my eyes. And, while this state passed in about an hour’s time, I had an opportunity to think. In fact, I had several such opportunities.  I will take up my tale again from this point.

But I would like to point out something here. In nature, subsonics are rare and are always a sign of great danger. In modern society, they are common. But the primitive part of our brain has no reason to see them as benign.

In fact, they can be deadly as studies of populations living near airports, for example, have shown. Is it possible that there is a role for this in the maladies of our modern society? (to be continued)

Spotlight: Botanical Phenolics and Brain Health

<Spotlights are mini-reviews of resources that are worth drawing your attention to.>

Botanical Phenolics and Brain Health ; Sun et al, 2009

This is a review of the research on treating PD and similar disorders by means of the use of the complex chemicals produced by plants. It provides numerous links to specific studies and deserves a bookmark.

Factsheet: Green Tea Extract

Green tea is one of the primary botanicals for the PWP.

Note- If links have not carried over properly, the original post complete with working links is at

http://parkinsonsonline.org/blog1/?p=666

_____________________________________________

…its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders.  (Mandel 2008) PMID: 18641210

The results of the study demonstrated that GTE significantly attenuated LPS-induced sickness behavior as well as hepatic damage either by its antioxidant activity or by inhibiting LPS induced cytokine production in rats.  (Singal 2006) PMID: 16444665

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)  (Li 2004) PMID: 15478178

tea drinking may decrease the incidence of dementia, AD and Parkinson’s disease. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders.  (Mandel 2008) PMID: 18953110

The neuronal activity of dopaminergic neurons is closely linked to dopamine release. When neurons switch from a single-spike firing to bursts of action potentials, the release of dopamine increases. The above experimental results suggest that EGCG increases the neuronal activity…  (Park 2007) PMID: 17174286

…pretreatment with L-theanine significantly attenuated the down-regulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) production in SH-SY5Y cells. These results suggest that L-theanine directly provide neuroprotection against PD-related neurotoxicants….  (Cho 2008) PMID: 18452993

Factsheet: B Vitamins and PD

The B vitamins have a special place in PD. They are directly linked to motor and cognitive issues and their effectiveness is compromised by the most common medications.

The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer’s disease. (Morris 2006) PMID: 16917152

Raised plasma total homocysteine is a strong prognostic marker of future cognitive decline, and is common in world populations. Low-normal concentrations of the B vitamins, the main determinant of homocysteine concentrations, are also common and occur in particularly vulnerable sections of the population, such as infants and elderly.  (Smith 2008) PMID: 18709889

Elevated plasma homocysteine (Hcy) concentrations have been reported in L-dopa treated Parkinson’s disease (PD) patients, suggesting that L-dopa treatment is an acquired cause of hyperhomocysteinemia.  (Zoccolella 2005) PMID: 15734674

Analysis of data revealed that Hcy levels were higher in L-dopa treated PD patients when compared with age- and sex-matched controls and that supplementation of the diet with cobalamin and folate is effective in reducing Hcy concentrations  (Lamberti 2005) PMID: 15804266

Elevated concentration of total homocysteine (Hcy) in plasma (> 12 micromol/l) is a risk factor for several diseases of the central nervous system. Epidemiological studies have shown a dose-dependent relationship between concentrations of Hcy and the risk for neurodegenerative diseases. Hcy is a marker for B-vitamin deficiency (folate, B12, B6).  (Herrmann 2007) PMID: 17729191

Vitamin B12 deficiency is an important nutritional disorder causing neurological manifestations of myelopathy, neuropathy and dementia. Sub-acute combined degeneration (SCD) with involvement of the posterior columns in the cervical and thoracic cord is a common presentation of this disorder.  (Puntambekkar 2009)  PMID: 19720386

PubMed Search: “Parkinson’s” + “Vitamin B”

Factsheet: Helicobacter pylori

Why H. pylori? What is it, anyway? H. pylori is the most common human infection on the planet with an infection rate of fifty percent. It lives  in only one place, the human stomach. And it is the only thing able to live there. Once established, it is extremely hard to rid oneself of as it mutates rapidly. It produces a variety of toxins, some of them quite nasty. Killing it off improves PD symptoms but attempting to do so but failing can be fatal.

In addition to the various toxins, problems arise over nutrient competition and absorption issues, B-vitamins in particular. And, of particular interest to me, it produces ammonia in its neutralizing of stomach acid. Ammonia goes to the liver which can get overloaded. When that happens, the ammonia can make it to the brain and that is very bad news, as we shall see.

We propose that IP is a systemic disorder resulting from a ubiquitous peripheral infection, and that only the tip of the iceberg comes to diagnosis. There is evidence for inflammatory/immune activation peripherally and in the brain.

The apparent importance of H. pylori in the etiology/pathogenesis of idiopathic parkinsonism is not confined to those with evidence of current infection.

Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow-up being > or = 3.5 years.

We challenge the concept of idiopathic parkinsonism (IP) as inevitably progressive neurodegeneration, proposing a natural history of sequential microbial insults with predisposing host response.

Chronic hepatic encephalopathy is a neuropsychiatric disorder with protean manifestations, the pathogenesis of which is poorly understood.2 It is generally under-diagnosed because, in most patients, the condition is subclinical….

Hepatic encephalopathy has been linked to H. pylori infection because of the ammonia produced by the organism in the stomach.

Among the plants that killed H. pylori, turmeric was the most efficient, followed by cumin, ginger, chilli, borage, black caraway, oregano and liquorice. Moreover, extracts of turmeric, borage and parsley were able to inhibit the adhesion of H. pylori strains to the stomach sections.

In particular, green tea extract (GTE) showed the strongest inhibition of H. pylori urease

EGCG pretreatment showed significant cytoprotective effects against H. pylori-induced gastric cytotoxicity via interference of the TLR-4 signaling induced by H. pylori. Thus, our result implies that continuous intakes of green tea could prevent the deleterious consequences of H. pylori infection.

“Fact” Sheets

A ton of accumulated snippets that may someday become posts but, in the meantime, are being organized here for your review, education, and comment.

B Vitamins and PD

Green Tea Extract

Helicobacter pylori

Wheat, Intolerance, and PD

I want to speculate a little more than I normally would, mainly because I haven’t finished researching this topic yet. I have been thinking about wheat, of course, and that has led to some interesting questions.

What if our food is trying to kill us? I don’t mean that our poor choices of fatty snacks are plugging our arteries. We already know that. I mean, what if our food is actively and purposefully attempting to knock us off? What if we are in a war and are under attack and don’t even know it? What if there is an intelligence out there in the garden that “hates” us enough to wish us dead? Far fetched? Perhaps. But let’s think about this a little more before we turn our backs on that seemingly innocent radish. And keep your eye on that green bean – he may not really be your friend.

For just a moment, put yourself in the position of a plant.  Your goal in life is to make more of your kind. That poses a problem in that you are essentially defenseless as well as anchored to one spot. You can’t run away. And if it comes to blows, that rabbit will claim the championship very quickly.

Your only option is to use your intelligence.  Now, before we sneer let’s keep in mind that we are trying to outwit a bunny rabbit.  And “intelligence” has several definitions, some of them quite broad.

So you stand there in the sunlight pondering your problem and it occurs to you that you really don’t need to eliminate the bunny and, in fact, he is actually useful at times. You just need to manipulate him so that he doesn’t wipe out your offspring – your seeds. You link together some stray molecules lying about the place and store it in the seed.  You are happy to offer up a leaf now and then in order to assure yourself a supply of bunnies. But that new version of your seeds is going to make a sick rabbit. If he doesn’t get the message, he may become a former rabbit.

This strategy is very effective and common in the plant world.  Seeds often are laden with poisonous proteins called “lectins”.  They can be deadly.

Much of our diet come from seeds. We have managed over time to minimize the amounts of lectins involved, but they remain. And a genome is a fickle beast that occasionally produces surprises.  Lectins are toxins. Some are neurotoxins. Some affect the enteric (GI) nervous system with chronic constipation as a possible outcome.

Constipation is, of course, common in Parkinson’s Disease. So is inflammation of the GI tract. Inflammation increases the permeability of the gut. Constipation increases the opportunities for a given molecule to find its way through the intestinal wall into areas closely watched by the immune system.

Lectins are complex proteins.  Partly digested, they yield a multitude of smaller proteins. Some of those are similar to those of our own tissues. Our immune system rightly sees them as invaders, but then mistakes our own to be so as well.  A classic autoimmune reaction produces tissue damage and inflammation. And, iin a final step, inflammation anywhere in the body can fan the flames in the brain.

Maybe our food is killing us.