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PPAR, tyrosine nitration and Alzheimer's disease
Lane Simonian
Posted: Sunday, August 14, 2016 6:29 PM
Joined: 12/12/2011
Posts: 4863


This further helps to explain why peroxisome proliferator activated receptor--PPAR)--agonists such as various non-steroidal anti-inflammatory drugs and GM-CSF (granulocyte macrophage-colony stimulating factor) are not more effective in the treatment of Alzheimer's disease.


Nitration of tyrosine residues in proteins has been observed in many inflammatory tissues of arthritis, ulcerative colitis, septic shock and ischemia-reperfusion injury [and I will add Alzheimer's disease]...
 
Together, these results indicate that nitration of PPARgamma during inflammation may be involved in a reduction in the control of inflammatory responses and also in the development of resistance to PPARgamma ligand-based therapies against inflammation.

http://www.ncbi.nlm.nih.gov/pubmed/12163159

PPAR is a particularly important receptor because it helps activate the neuroprotective phosphatidylinositol 3-kinase.


Interestingly, gemfibrozil induced the activation of PI3K in microglia and this is the first demonstration of activation of PI3K by any PPAR agonist in any cell type.

Activation of p85-associated PI3K (p110) by gemfibrozil and abrogation of the gemfibrozil-mediated inhibitory effect on LPSinduced expression of proinflammatory molecules in microglia by wortmannin suggests that gemfibrozil possibly exerts its antiinflammatory effect through the activation of p85-associated PI3K. 

 

http://www.jimmunol.org/content/179/6/4142.full.pdf

 

The key to using PPAR agonists for Alzheimer's disease is to first de-nitrate the receptor.  This can be done with a number of compounds such as eugenol in various essential oils via aromatherapy; terpenes such as eugenol, cannabidiol, and low levels of THC in CBD oil (using the essential oil of marijuana), and ferulic acid, syringic acid, vanillic acid, p-coumaric acid, and maltol in panax ginseng. 



Lane Simonian
Posted: Thursday, August 18, 2016 3:57 PM
Joined: 12/12/2011
Posts: 4863


The general aspects of this study are likely more important than the particulars:


Rutin concentration dependently protected ONOO(-) [peroxynitrite] induced SERCA1 activity...Upon treatment with ONOO(-), this flavonoid also prevented SERCA1 from thiol group oxidation and significantly reduced tyrosine nitration and protein carbonyl formation.


Much of the damage done to the brain in Alzheimer's disease is the result of either cysteine (which contains a thiol group) oxidation and tyrosine nitration.  Rutin would decrease the tyrosine nitration of PPAR and allow GM-CSF to better activate PPAR and from there the neuroprotective phosphatidylinositol-3 kinase/Akt pathway.  It took me four years, but I finally understand why the combination of rutin and GM-CSF helped your mother, Serenoa.



Lane Simonian
Posted: Friday, August 19, 2016 9:17 AM
Joined: 12/12/2011
Posts: 4863


Some more progress:

Cannabidiol reduces ABeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement.

 

Neuroprotective Effects of Cannabidiol Involve Inhibition of Glutamine Synthetase Nitration in Diabetic Retina

Cannabinoids, Ketogenic Diets, Holy Basil, And The Ppar Connection

A large number of terpenes and flavonoids are present in cannabis [16]. Many of the same terpenes and flavonoids present in cannabis are abundant throughout the natural world. There is a large number of terpenes and flavonoids that are PPAR agonists [14]. 

Eugenol [in some cannabis strains and various essential oils] is a PPAR gamma agonist

In Vitro Activity of the Essential Oil of Cinnamomum zeylanicum and Eugenol in Peroxynitrite-Induced Oxidative Processes

The essential oil and eugenol showed very powerful activities, decreasing 3-nitrotyrosine formation 

It is just a matter of time before the best combination of these compounds is found for the treatment of Alzheimer's disease.





Serenoa
Posted: Friday, August 19, 2016 6:35 PM
Joined: 4/24/2012
Posts: 484


Funny that you remembered the Rutin. Even I had forgotten about that. I recall that she continued the Rutin long after the first Leukine treatments but it had no effect by itself. And now I am just remembering that she did not use Rutin the second time she tried Leukine treatment a few years later (at least that is what I recall without looking at my notes). Very interesting. Combinations of treatments addressing more than one aspect or pathologic factor of the disease may be the solution.
Lane Simonian
Posted: Friday, August 19, 2016 10:46 PM
Joined: 12/12/2011
Posts: 4863


I was trying to remember the antioxidant that your mother took, but could not.  Then I was looking for something else and rutin come up.  So it was more luck than good memory on my part.

I do think that combination treatments may be the answer.  Even when two compounds share similar modes of action, they still might add to each other rather than duplicate themselves.