Exercise and the Endocannabinoid Network

Waking up at 3.15am and realising trying to get back to sleep is a dream I wake up and decide to see if I can wake up the brain. It woke me up with this strange idea: exercise elevates the endocannabinoid network which is one avenue by which exercise inhibits inflammation. So off to pubmed and the available data supports my intuition but the data is very limited. Only in recent years has there been renewed interest in the endocannabinoid network. Because of government prohibitions and the typical knee jerk response to anything associated with marijuana until recently the research community has been prevented from deeper investigations; the result being we have neglected one of most important networks in modulating inflammation associated with aging and especially in the brain. That is now changing but in my country Australia the government persists with a perspective that based on ignorance and arrogance. Too many stupid politicians in Australia but of course on that matter the country is not exceptional.   

Everybody Must Get Stoned?

This is a startling result and I have to wonder why it isn't being more widely publicised:

In the present study, we observed smaller brain weights and volumes in male macaque monkeys after 1.5–2.3 years of exposure to marijuana at plasma drug levels comparable to those in treated humans. Exposure to marijuana was associated with a similar reduction in mean fresh brain weight, as well as mean fresh weight and volume of the left cerebrum, compared to matched, placebo-exposed animals. For both drugs, the magnitude of these effects was in the range of 8–11%. The reduction seemed to be global (ie including all brain regions), but was most robust in the frontal and parietal lobes. In addition, both gray and white matter volumes appeared to be reduced to a similar degree.

Sunshine, Pathogen Genocide, Vitamin D, Happiness, and Cognition

Immunology has long fascinated me. Somewhere, sometime I read how the immune system was so sensitive it could identify a self from non-self protein in as little as 10 amino acids. "Crap!" I internally exclaimed even though completely ignorant of immunology at that time. As it turns out ...

Sort of true. That is a class of molecular structures known as PAMPS: pathogen associated molecular patterns.  Charles Janeway is the poster boy on that front. Our innate immune system is sensitized to these patterns. When you crunch numbers in a crude off the top sort of way, the immune system does a remarkably good job at fending off pathogens that have certain mathematical advantages. The challenge is so great that evolution came up with(remarkably!) the heavy and light chains which allow a tremendous ongoing creation of antibody types until there is one that "fits". It is a numbers game and while there are good odds with microbes the odds are bad with viruses because their replication and mutation rates are, relatively speaking, much higher. Two modern viruses are excellent examples of this. Hepatitis C and HIV exist in a variety of variants that will keep expanding. So when you think of mass extinctions remember one viable cause is a tiny molecular structure of only two key components which can wipe out a species very quickly and leave no trace. It dies with the species. That is an unsuccessful virus and not our concern. We are concerned with all the bugs that manage to live on and in us.

The Bright Side of the Fish Oil Component - DHA

This news release from ScienceDaily directly contradicts the findings of just a a few weeks ago. In my earlier post I was addressing research which indicated DHA can induce a "Th 1 type mediated inflammatory response". In relation to Stroke the conventional wisdom quite literally screams that such a response is the very last thing one would want to treat stroke yet now we have a report asserting remarkable efficacy of DHA in ameliorating damage from stroke.

ScienceDaily (2010-11-08) -- A new study shows that a component of fish oil is a powerful therapeutic agent that can protect brain tissue in a model of stroke, even when treatment is delayed by five hours. These findings not only target a new stroke treatment approach, but also provide vital information about the length of the therapeutic window.

For those so interested you can download the full article at this link. Bit of surprise, Springerlink usually doesn't give stuff away and I suspect this is a website error so be quick!

The findings of this study are remarkable:

Longevity(Exceptional) - the genes have it

This recent press release has caused a world wide stir, with critics pointing out flaws in the analyses, though with the caveat that the identified flaws did not disprove the conclusions but raised questions that needed further investigation. In that link the researcher states his own research also identifies 150 specific markers in the exceptionally long lived. This more critical analysis though suggests the whole methodological approach is up the creek with one scientist quoted as saying the paper should not have been published because all the conclusions are suspect. The question is: Do we now know enough to enable people to realistically aim at extending their healthy lifespan? Not with studies like the above, but when the current centenarians were born people were only just becoming interested in the work of the quiet monk, Gregor Mendel, who pioneered modern genetics. Today we know so much more, and there is sufficient information to suggest it is possible to increase our lifespan and avoid illness. It is still a numbers game but we can play with the odds. First, some more of these genetic studies ... .

New Targets for Anti-Depressants?

This post is very long (3850 words) and very difficult. It is a preliminary investigation of the idea that depression arises from chronic sustained arousal leading to amine depletion and various other physiological changes.

This news release from Science Daily highlights a new pharmacological approach to treating depression. The nutshell is this: there is a class of proteins in our brains called RGS proteins which inhibit the signalling of various neurotransmitters. By manipulating the RGS protein that inhibits serotonin signalling we can treat depression. Most current anti-depressant drugs attempt to increase the levels of serotonin or norepinephrine. Unfortunately there are now some studies emerging which indicate these current anti-depressants can increase the risk to develop a range of disorders, from kidney problems to cataracts. Generally the risk profiles are low but given the very widespread use of anti-depressants it could constitute a considerable public health cost. Which raises an interesting question: if we place our faith in these statistical analyses then is the government entitled to extract an "pharmaceutical externality tax" to address the health risks and subsequent costs associated with drug side effectss? Yeah, like that'll ever happen. We'll develop a new class of anti-depressants, and wait 30 years before we know about the associated risks ... .



My unalloyed cynicism aside, what caught my interest about this research is the reference to RGS proteins. It reminded me I read in 1999:

Article: 

Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function

Journal: NATURE MEDICINE • VOLUME 5 • NUMBER 8 • AUGUST 1999

Inflammation and Alzheimers

For a long time it was believed that inflammation played a critical role in the development of Alzheimer's. This can be true but needs to be carefully qualified because as the below abstract demonstrates "massive gliosis" induced by interleukin 6 actually prevented amyloid deposition. Look at the gliosis link for the wikipedia entry, it is a good example of when not to trust Wiki. Wiki is very useful for a quick overview of relatively mundane and simple concepts but can be very misleading when dealing with cutting edge research. In the abstract overleaf the bods found that inducing gliosis, which is typically associated with inflammation, is actually leading to clearance of amyloid. Clearance of amyloid is the great interest in current Alzheimer's research and this for the simple reason that amyloid aggregation appears to be a key driving factor in Alzheimer's disease. As usual, with more research, what once looked obvious becomes blurred. Inflammation is found in many pathologies but it is a mistake to assume that inflammation is the cause of that pathology. As this study indicates it can play a vital protective role.

Diabetes and Pollution

To yet again highlight the ever increasing dangers of pollution, this article puts forward a very worrying hypothesis that is cause for concern. This is not the first study to find a link between diabetes and pollution and it will not be the last.

Inflammation, Cancer, Targets of Ginseng

A word of warning about using Ginseng:

If you are diabetic it is ill advised. Ginseng has a remarkable affect on the adrenal glands and this may impact on sugar regulation. Always consult your doctor before using Ginseng.

Ginseng is known to interfere with the actions of various pharmaceutical drugs.

Ginseng should not be used on a continual basis, it can induce adrenal exhaustion.


Article: Inflammation, Cancer, and Targets of Ginseng
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Authors: Lorne J. Hofseth and Michael J. Wargovich
Journal: J. Nutr. 137: 183S–185S, 2007.
Location: Life\Nutrition\Title
Date obtained: 18/10/2008
Date Read: 21/10/2008
Date to Review:
Web Page:
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Notes:
Abstract
Chronic inflammation is associated with a high cancer risk. At the molecular level, free radicals and aldehydes, produced during chronic inflammation, can induce deleterious gene mutation and posttranslational modifications of key cancerrelated proteins. Other products of inflammation, including cytokines, growth factors, and transcription factors such as nuclear factor kB, control the expression of cancer genes (e.g., suppressor genes and oncogenes) and key inflammatory enzymes such as inducible nitric oxide synthase and cyclooxygenase-2. These enzymes in turn directly influence reactive oxygen species and eicosanoid levels. The procancerous outcome of chronic inflammation is increased DNA damage, increased DNA synthesis, cellular proliferation, disruption of DNA repair pathways and cellular milieu, inhibition of apoptosis, and promotion of angiogenesis and invasion. Chronic inflammation is also associated with immunosuppression, which is a risk factor for cancer. Current treatment strategies for reactive species overload diseases are frequently aimed at treating or preventing the cause of inflammation. Although these strategies have led to some progress in combating reactive species overload diseases and associated cancers, exposure often occurs again after eradication, treatment to eradicate the cause fails, or the treatment has long-term side effects. Therefore, the identification of molecules and pathways involved in chronic inflammation and cancer is critical to the design of agents that may help in preventing the progression of reactive species overload disease and cancer associated with disease progression. Here, we use ginseng as an example of an antiinflammatory molecule that targets many of the key players in the inflammation-to-cancer sequence. J. Nutr. 137: 183S–185S, 2007.

TABLE 1 Key players in the inflammation-to-cancer sequence1
The inflammatory player: Examples of mechanisms toward carcinogenesis
RONS, COX, and NOS Damage DNA, modify cancer protein, alter proliferation and
apoptosis (depending on concentration, microenvironment, and genetic background
of target cells), inactivate tumor suppressor pathways (e.g., pRb and p53).
NF-kB Activate proliferation and inhibit apoptosis by activating modulators of these
event: cytokines (e.g., TNF-a), growth factors, survival genes (e.g., Bcl-XL),
angiogenic factors (e.g., VEGF), inflammatory genes (e.g., COX and NOS). Recent
high profile studies indicate this molecule is a key molecular node in the
inflammation-to-cancer sequence (2).
TLRs Activate MAP kinase and NF-kB pathways.
Cytokines Activate or deactive many inflammation and cancer pathways (1). Example:
The proinflammatory cytokine, IL-6 can antagonize p53, inactivate pRb, and activate
survival genes (Bcl-2 and Bcl-XL); The antiinflammatory cytokine, IL-10, can inhibit
proliferation and ras signaling.
Growth factors Transforming growth factor-b, at high concentrations, activates
p21/p27-mediated growth arrest and smad- and p53-mediated apoptosis.
MMPs MMP-2 promotes proliferation by activation of the discoidin domain tyrosine
kinase receptor 2. MMPs also are immunomodulators and stimulate angiogenesis,
inhibit cell adhesion, and inhibit apoptosis.
PPARs PPAR-g ligands are mostly protective to the inflammation- to-cancer sequence.
They inhibit iNOS, COX-2, NF-kB, MMPs, and E2Fs; they activate p53, p27, and p21.
Kinase pathways p38 stimulates proliferation and inhibits apoptosis. An inhibitor of
MAP kinase signaling (CNI-1493) has shown promise in ameliorating Crohn disease
in humans (3).
p53 and pRb pathways Both pathways are inactivated in reactive species overload
diseases (4,5).

Studies indicate that ginseng has potential as a chemopreventive agent or adjuvant treatment. Some of the cancers shown to decrease significantly with ginseng use include cancersof the pharynx, stomach, liver, pancreas, and colon (22,23). Mechanisms include inhibition of DNA damage (24), induction of apoptosis (25), and inhibition of cell proliferation (26). It is also becoming increasingly clear that ginseng has potent effects on the inflammatory cascade and may inhibit the inflammationto- cancer sequence.
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Ginseng targets the inflammatory players There is evidence that ginseng has potent effects on key players in the inflammatory cascade (Fig. 1). For example, ginsan, a polysaccharide extracted from P. ginseng, showed inhibition of s, the p38 MAP kinase pathway, and NF-kB in vitro and inhibition of proinflammatory cytokines in vivo (27). The ginsenoside Rg3 was shown to inhibit phorbol ester–induced COX-2 and NF-kB induction (28). BST204, a fermented ginseng extract, can inhibit inducible NOS (iNOS) expression and subsequent nitric oxide production from lipopolysaccharidestimulated RAW264.7 murine macrophages.

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Ginseng can also inhibit other mediators of the inflammation- to-cancer sequence, such as matrix metalloproteases and kinase pathways (31).
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