In my last post I pointed the finger at Nitric Oxide as being the main culprit for the dreadful, disabling and torturous symptoms experienced during ''protracted withdrawal'' . On further reading I realize I was unfair to pin all the blame on the one molecule..., NO is what I guess should be called an ACCOMPLICE....It it one of the gang of molecules trying to destroy our brains (and succeeding) but it is not NO alone that causes the damage...
For the massive amounts of severe damage to take place NO must be combined with superoxide to form peroxynitrite and it is the peroxynitrite, a free radical, that reeks havoc in the brain, causing damage, demyelination, axonal death and the loss of BBB integrity.
Glutamate and Perxoynitrite
For many years, across all psych drug message boards and support groups Glutamate has been a source of much interest and speculation, some have found taking micro doses of lamictal which can calm the neuronal messaging of Glutamate in the brain, has been helpful...others speak of this issue being an up-regulation of Glutamate receptors after coming off the drugs, and time needed for this imbalance to be corrected...but again, could we be missing a vital piece of information??
Dr GS Scott on his paper, Glutimate - stimulated peroxinitrite production in a brain derived endothelial cell line is dependant on N-Methyl D - aspartate (NMDA) receptors - speaks about the toxic properties of Glutamate in the brain, he gives the example that, ''in the animal model of MS it is demonstrated that pharmacological inhibition of specific glutamate receptors suppresses neurological symptoms and prevents BBB breakdown'' (1)
But it is not Glutamate itself that is doing the damage, oh no, its ''ONOO'' he states in his paper that ''Glutamate triggers the production of Nitric Oxide and Superoxide, which can lead to the formation of peroxynitrite (ONOO) , we propose that Glutamate contributes to BBB breakdown via the actions of ONOO.'' (1)
There are hundreds of studies also confirming the fact that excess levels of Glutamate cause the cycle of ONOO and cause mass cell damage in the brain...the question remains, what on earth can we do about it??
What Can We Do?
Ahhh, the question that always haunts me, so what can I do to help myself, how can I heal, what steps can I take that are not going to give me a massive set back??
As far as I can see right now there are a few things that need to be addressed
1) dont do anything to make it worse...by not doing anything to make it worse, I think that would include tapering any drugs, introducing new drugs to the bloodstream, taking any suppliments that will increase L-Arginine and keeping away from Oxiditive stress as much as possible.
2) address the BBB destruction - this remains a very difficult conundrum, supplements could help heal the brain and improve health but as our BBB are not working most supplements, substances
and medications prove to at best cause a setback and at worse possibly add to the damage.
Also, once again we are caught in a cycle, ONOO causes damage to the BBB, but our BBB breakdown makes it hard to address the ONOO cycle...I guess its down to taking any ''treatment'' very slowly and monitoring oneself for any worsening as I try to heal myself.
3) address the ONOO cycle -
By addressing the ONOO cycle, there are 3 prongs of attack
1) Limit or inhibit uptake of Nitric Oxide
2) Limit or inhibit Superoxides
3) Address the high levels of damaging Peroxynitrite in the brain.
Logic would tell me that addressing the Peroxinitrite itself should be the first line of defense, as its presence is what is causing the damage, NO, and superoxide can be damaging, but put together they form a monolithic monster of epic proportions, this beast has to be taken down first right?
So how do we do that? There is no simple answer but there are ideas...
URIC ACID
Uric Acid is a scavenger of Peroxynitrate, there are studies into the second phase now that show it can be helpful with both parkinsons and MS, Uric acid can be increased using the supplement INOSINE. http://en.wikipedia.org/wiki/Inosine
DC Hooper et al published a study called Uric Acid, a natural scavenger or peroxynitrite, in experimental allergic encephalomyelitis and multiple sclorosis...
In this study he experiments with increasing Uric Acid to mice who have been given poisons and developing the chronic form of EAE with remissions and exacerbation, he found that ''Uric Acid administration was found to have strong therapeutic effects in a dose dependent fashion'' he further points out this could be because mice, unlike humans have a rapid clearance of uric acid.so humans could require a much lower dose.
He also draws attention to the fact that ''A possible association between MS, the disease on which EAE is modeled and uric acid is supported by the finding that patients with MS have significantly lower levels of serum Uric Acid than Controls.'' (2)
There are also severeal studies that show a correlation between parkinsons symptoms and low levels of Uric Acid, and state that treatment with UA (Inosine) holds much promise for the treatment of Parkinsons (3, 4, 5)
However, if Uric Acid is too high in the body there are risks, the formation of Uric Acid Kidney stones, which although can be passed without medical treatment are still painful, and also an increased risk of Gout, neither of those sound very appealing, but at this point I would glady trade my symptoms for kidney stones and gout, and Im hopeful that if treatment was successful in scavenging the peroxinitrite, that other interventions could be put in place to control the production of future peroxynitite...for example
LIMIT THE NITRIC ACID PRODUCTION
This is the next port of call, studoes into the brains of patients with MS, Parkinsons, demntia and alzeimers all present with higher than normal levels of Nitric Oxide..so what can I put in place to lower these levels?
1) avoiding L-arginine and L-arginine rich foods.
2) avoiding exercise that causes the heart rate to go up - this causes the production of NO.
3) avoid vitamin D, especially D3 (6)
4) AVOID VITAMIN E (7)
5) Avoid foods high in histamine (8) It seems that we have another cycle here, histamine causes an increase in NO, and NO causes an increase in mast call activation (see previous blog post for more on this)
6) Have iron/Folic acid levels checked, Iron can bind to NO and that renders the Iron inactive - it seems ferritin is the best choice of supplement in this case, but again so much caution has to be used in supplementing when suffering with withdrawal syndrome.
''it is likely that adequate ferritin levels act to reduce some of the negative effects of excess NO through its antioxidant function. NO in turn, helps to protect against the release of oxidative free iron from iron-containing compounds (Puntarulo 97, Juckett 96)'' (8)
7) L-LYSINE - l-lysine is an inhibitor of L-arginine uptake, therefore it stands to reason that supplementing with Lysine could quell the overproduction of NO by making less available Arginine ...in one study on rats, L-arginine was tested to see if this theory would work, the conclusion was as follows...
''l-lysine, an inhibitor of cellular l-arginine uptake, reduces NO production and exerts beneficial haemodynamic effects in endotoxaemic rats. l-lysine also reduces hyperlactataemia and tends to blunt the development of organ injury in these animals. Contrastingly, l-lysine has no effects in the absence of endotoxin and thus appears to act as a selective modulator of iNOS activity.'' (9)
another study, conducted on NO levels in pigs lungs concluded with this statement
''We found that increasing the vascular Larginine concentration increased NO production in both groups, furthermore, these experiments provided evidence for the forst time that inhibiting L-arginine uptake using L-lysine decreased NO in the pig Lung'' (10)
Now, you may be thinking, but this is in the BRAIN not the body, well perhaps this is where our weakened and leaky BBB is to our advantage. :)
8) Acetyl-L-carnitine - I am very leery of this particular substance as it crosses the BBB, although as everything in our bodies crosses the BBB due to its degrading im trying to keep an open mind, I will readdress this supplement once I have done more research on it.
ok, last but certainly not least, would be to control or inhibit the production of Superoxide...this is once again, tricky business, but it can be done...
1) The way to keep superoxide lower and counter its deleterious effects is with a substance called superoxide dismutase...or SOD.
In a study called Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophilia model of parkinsons disease - tests were carried out to see if SOD would have an impact on the disease..the finding were as follows
''We show that dopaminergic neurons are specifically sensitive to hyperoxia induced oxidative stress and that mutant forms of alpha-synuclein show an enhanced toxicity under these conditions suggesting synergic interactions. In addition, the co-expression of Cu/Zn superoxid dismutase protects against the dopaminergic neuronal loss induced by mutant alpha-synuclein overexpression thus identifying oxidative stress as an important causative factor in the pathology of autosomal-dominant Parkinsonism.'' (11)
another Parkinsons study indicates that SOD decreases over time/duration of the disease
''A negative correlation between SOD activity and duration of the disease was observed, while there was no relationship between L-Dopa treatment and SOD activity'' (12)
But supplementing with SOD is not easy, the SOD protein is easily deactivated by the harsh acids and enzymes contained in the digestive tract...hoever scientists discovered that coupling the SOD molecule with a protective protein derived from wheat or other plants, it could be delivered intact
to the intestines and absorbed into the bloodstream.
In which case the only way enhance SOD in the body would not be through food groups where the molecule is quickly destroyed and rendered useless but through the supplement SOD/gliadin.
So that concludes my thinking for today, that by conbining the use of Inosine, SOD/gliadin and L- lysine, the dangers of peroxynitrite could be ameliorated, its not certain, far from it, but its the best Ive got.....for now......
(5) search for nitric oxide, great reading http://www.tcolincampbell.org/courses-resources/article/parkinsons-disease-functional-therapeutics-in-neurodegenerative-disease/category/neurology-1/?tx_ttnews%5BbackPid%5D=76&cHash=1baa9c9f447b427bf03891ce2536df16
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