Inflammation/hibernation is a complex story at the foundation of chronic diseases. Inflammation is the common thread -- activation of the inflammation transcription factor NFkB.
Trauma Causes Life-Threatening Trauma
Trauma, everything from a bee sting to a horrific traffic accident that causes head and spine injuries, results in initial tissue damage and subsequent inflammation damage. The inflammatory response to punctures and abrasions is usually appropriate and self-limiting. The immune response to serious injuries is frequently more life-threatening than the initial damage.
Transplanted Organs Suffer from Inflammation
Organs removed for transplantation are subjected to a certain amount of necessary trauma and oxygen deprivation. If the organ was simply popped into a waiting recipient biochemically unaware of the process, the initial damage would be readily repaired in its new home. Unfortunately, some of the organs overreact and become damaged by their own immune/inflammatory reaction to the surgery.
Hibernation Reduces Trauma Inflammation
Organ transplants between animals that are hibernating, are much more successful, because the damaging inflammation is suppressed. Hibernation in animals or in human organs can be induced by the use of opioid peptides, e.g. DADLE, and subsequent surgical procedures are more successful. Hibernation also provides protection against experimental stroke. Apparently, the activation of the opioid receptor suppresses activation of NFkB and avoids inflammation.
Opioids and Steroid Hormones Block NFkB Activation and Inflammation
Steroid hormones can also provide protection against inflammatory damage resulting from head trauma. Thus, the ubiquitous steroid receptors may also block NFkB activation and inflammation.
Trauma Releases ATP that Triggers P2X7 and NFkB
Extracellular ATP can activate NFkB activity and inflammation, and ATP accumulation at trauma sites may be particularly dangerous for spinal injuries. Inhibitors of ATP binding to the purinic receptor P2X7, block inflammation and provide dramatic improvement in the return of function in animal models of spinal injuries. Most of the common inhibitors of P2X7 signaling must be injected directly into the traumatized tissue to block inflammation, because they can’t cross the blood-brain barrier. An exception is Brilliant Blue G.
Brilliant Blue G Blocks Trauma Inflammation
Brilliant Blue G, a.k.a. Coomasie Brilliant Blue,
should be very well known to molecular biologists, because it is the com
monly used stain for proteins separated on SDS-PAGE gels. I used that dye literally thousands of times to stain gels and I even tried it to stain the extracellular matrix surround cartilage-secreting cells, chondrocytes, grown in culture. I have included one of those pictures just for old times sake.BBG can be injected IV i
nto mice and the result is amazing. Not only do the mice become blue, but they recover much better from experimental spinal trauma. BBG in the blue mice blocks inflammation due to the surge in tissue ATP and the mice heal their trauma and regain function.It would be amazing if BBG worked on people with spinal injuries. I expect the rapid development of a suitable drug to help spine and head trauma patients.
Can Manipulation of Hibernation Cure Chronic Diseases?
A big question
is whether or not similar drugs might be used to block inflammation that supports cancer and other forms of chronic illness. Alternatively, in some instances the problem is that bacteria are suppressing local inflammation and inducing tissue hibernation to produce chronic illness. Under these circumstances, the induction of local inflammation or elimination of hibernation may make the bacteria vulnerable to attack.references:
Borlongan CV, Hayashi T, Oeltgen PR, Su TP, Wang Y. Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol. 2009 Jun 17;7:31.
W. Penga, M. L. Cotrinaa, X Hana, H Yua, L. Bekara, L. Bluma, T. Takanoa, G.-F. Tiana, S. A. Goldman and M. Nedergaard. 2009. Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. PNAS 106:12489
9 comments:
DR. Ayers
You have the most provocative topics... So, blue brains aren't that bad? B Ames made some similar (unpublished) observations for mitochondria, one of my readers informed me.
I prefer to neuroprotect and preserve my organs by obtaining delta opioids (enkephalins) via intensive interval training and mimic hibernation via ketosis (intermittent fasting or low LOW carb Paleo eating).
Don't know if it is being done at this time to harvest organs for transplant (eg, like Apple's founder Steve Jobs' new liver); a protocol with DADLE increased multiorgan tissue viability from 14hrs to 46 hrs.
Bears are very COOL. As are ALL your insights and critical observations!!
Superfit produce more enkephalins with intense interval training 20 or + min.
Organ preservation with DADLE
-G
BTW...gluten/gliadin and casein have opioid-binding properties (that is why they are SO addictive and naloxone works during wheat/casein withdrawal & in autism). Do you think gluten/casein may interfere with organ preservation and viability? Opioids, like Enkephalins, participate in growth regulation some research suggest. Opioid growth factor (OGF) can control tumor growth in vitro and in mice.
Dr. B G,
By 'blue brains", I mean injecting BBG and letting it cross the blood brain barrier and bind/stain nervous tissue to block inflammation (or Alzheimer's plaque formation, etc.).
Enkephalins may facilitate hibernation of tissue infected with cryptic bacteria and enhance chronic infections. Intense exercise also results in a plume of inflammatory cytokines consistent with release of hibernation and exposure of cryptic bacteria to the immune system. Interesting possibilities, no?
Inflammation-based cancer should be exposed by opioids, as you point out.
The gluten/gliadin and casein observations are tantalizing. Do you have guesses as to why (evolutionary advantage) gliadin was originally present in grains? Is tissue transglutaminase an attempt to detoxify gliadins? Or is tTG the target of gliadin assault?
I think that gut flora might be very important for all types of transplants. It is certainly critical for digestive tract transplants. That suggests that gliadin may be important. Anti-tTG and gliadin might be very interesting during transplants. It would be interesting if simultaneous bone marrow transplants facilitate primary transplants by ameliorating autoimmunity.
Dr. Ayers!
Fascinating all the connections with cryptic bacteria! (I was kidding about blue organs... it was Sunday...restraining myself *ha*). HERE
is Dr. Ames and his group's findings: methylene blue may slow PD or AD.
I totally agree gut flora is T-H-E foundation of optimal health and longevity. Bile acids and enzymes from the gallbladder and pancreas are essential. Most who have calcified their thyroids, pituitary, pineals, adrenals, coronary arteries (95% of all diabetics and MetSyn), ovaries (PCOS), livers (NASH), also undoubtedly have calcified and unfunctional gallbladders. (My dad's a surgeon... guess what paid for college? CHOLEYS)
Supplementation of digestive enzymes I found is a must in 50% of chronic conditions that I see, otherwise digestion/conjugation of proteins, plant material, fat-soluble vitamins and fatty acids occurs suboptimally (accompanied by gas and bloating... and STAGNATION of blood vitamin D concentraions despite mega 20,000 IU doses... seriously). I haven't verified but gut flora must work synergistically with our enzymes and bile acids... right? I discovered that Vitamin A cannot be absorbed without the aid of some gut flora to conjugate first (and without vitamin A, thyroid hormones T2 T3 T4 cannot be activated).
I've read a lot on your blog regarding plant host defenses. I suspect that gliadin/gluten is another factor in plant defenses.
This article appears to suggest that.
The effect of grain albumins, globulins and gliadins on larval development and longevity and fecundity of some stored product pests. Entomologia Experimentalis et Applicata 1985.
Dual transplants are being done... kidney tx + injected bone marrow
http://www.reuters.com/article/healthNews/idUSN2364870520080124
But... if caught early enough... why not low carb high fat Paleo + high dose vitamin ADEK2 and EPA DHA ALA + taurine?
Perhaps human evolution attempts to escape consequences of massive overdoses of grains/gluten. Like tTG?
Hemochromatosis may be one example -- grain-eating iron-deficient women may have been de-selected (eg, died from pregnancy or birth complications, anemia, etc) during evolutionary pressures?
Thank you,
G
Med Hypotheses. 2008;70(3):691-2.
Hemochromatosis: a Neolithic adaptation to cereal grain diets.
Naugler C.
Department of Laboratory Medicine, Dalhousie University, 5788 University Avenue, Halifax, Nova Scotia, Canada B3H 2Y9. nauglerc@dal.ca
The Neolithic period in Europe marked the transition from a hunter-gatherer diet rich in red meat to an iron-reduced cereal grain diet. This dietary shift likely resulted in an increased incidence of iron deficiency anemia, especially in women of reproductive age. I propose that hereditary hemochromatosis and in particular the common HFE C282Y mutation may represent an adaptation to decreased dietary iron in cereal grain-based Neolithic diets. Both homozygous and heterozygous carriers of the HFE C282Y mutation have increased iron stores and therefore possessed an adaptive advantage under Neolithic conditions. An allele age estimate places the origin of the HFE C282Y mutation in the early Neolithic period in Northern Europe and is thus consistent with this hypothesis. The lower incidence of this mutation in other agrarian regions (the Mediterranean and Near East) may be due to higher dietary intakes of the iron uptake cofactor vitamin C in those regions. The HFE C282Y mutation likely only became MALADAPTIVE in the past several centuries as dietary sources of iron and vitamin C improved in Northern Europe.
PMID: 17689879
Dr. B G,
If you like to put big pieces into the puzzle, you should read/scan this article on stomach acid production: PMID: 15823700
It is from Medical Hypothesis and very provocatively lays out the necessary reactions for acid hydrolysis in the stomach. It makes a good case for the role of iron and seems to me to suggest that a lot of redox reactions take place in the stomach that are overlooked. That may explain why plants mixed in the diet may be helpful in protecting omega-3s.
It seems that diet and supplements to craft our gut flora may provide some simple fixes that now require elaborate medical interventions.
Thanks for your comments.
Kyle,
In reference to your comment:
"Hi Dr. Ayers,
I was unable to find another way to contact you. I have an eicosanoid related question for you and couldn't find another forum (ie email) to reach you at.
I recently finished “Enter the Zone” and was discussing with a number of Crossfitters…What are your thoughts on Sears’ advice to avoid eggs and red meat due to the arachidonic acid (“AA”)? Given that he believes AA forms the basis for the production of bad eicosanoids, he strongly advises against consuming these foods.
Paleo-promoters, however, seem to aggressively promote eggs and red meat as true paleo and health foods. How do you reconcile this? Does it have to do w/ grass-fed vs grain-fed, traditional vs. pastured?
Thanks for the clarity!
- Kyle"
I agree with Sears in general. I think that the ratio of omega-6 to omega-3 is the primary factor, but the quantity of omega-6, ARA, is also important. That means that above some level of ARA consumption, it is difficult to compensate by omega-3 supplementation. This probably means that the optimal 6/3 ratio lowers as the total amount of omega-6 increases.
Hundreds of studies on the effectiveness of omega-3/anti-inflammatory treatments of dozens of diseases have been systematically corrupted by using a population with elevated consumption of omega-6 vegetable oils.
So the bottom line on eggs and red meat comes down to how much omega-6 is in the eggs and meat, how much is in the rest of the diet and how much omega-3 is present. It probably also matters on the mix in each meal and what the contribution is from lipid storage. It is obviously hard to do controlled experiments. It is much easier to eliminate obvious sources of omega-6 oils, e.g. vegetable oils, enhance the omega-3s by eating grass-fed meat/eggs and enjoying your exercise.
If you had an indicator of inflammation, such as a tendon that tended to pain. You could adjust your omega-3 intake to eliminate the inflammation/pain. It would report your status. Virtually any sign of wear and tear, is actually mismanaged inflammation and shouldn't be ignored at any age. Bodies don't wear out, they flame out.
Thanks for the comments.
Dr. B G,
I forgot to get back to you about blue brains, a la methylene blue (MB). It is interesting that MB is also used as a dye for DNA. MB also has essentially the same structure as toluidine blue (TB). TB binds to heparan sulfate HS). That means to me that it is likely that MB binds to HS or since all of these interactions are based on hydrophobic faces, MB may bind to one of the HS binding sites.
I think that it is likely that MB has its effects on Alzheimer's via the amyloid interaction with heparan sulfate during plaque formation. Or it may interfere with the binding of the HS-amyloid complex to the cell surface that is involved in toxicity.
Thanks for stimulating the blue brain thoughts.
HOW exactly does BBG cross the blood brain barrier? I'm giving a seminar on medicinal chemistry design of barrier crossing drugs, and am fascinated with BBG; however, I cannot find a single piece of literature that details HOW it crosses the barrier! HELP!
Does BBG cross because it is lipophilic? I doubt this due to it's large molecular weight and ionic character. Can you clear this up?
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