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A New Potential Cause for Alzheimer’s: Arginine Deprivation
Tom(ek)
Posted: Wednesday, April 15, 2015 4:41 AM
Joined: 12/21/2011
Posts: 62


The group did find CD11c microglia and arginase, an enzyme that breaks down arginine, are highly expressed in regions of the brain involved in memory, in the same regions where neurons had died.

Blocking arginase using the small drug difluoromethylornithine (DFMO) before the start of symptoms in the mice, the scientists saw fewer CD11c microglia and plaques develop in their brains. These mice performed better on memory tests.

“All of this suggests to us that if you can block this local process of amino acid deprivation, then you can protect -- the mouse, at least -- from Alzheimer’s disease,” Kan said.

DFMO is being investigated in human clinical trials to treat some types of cancer, but it hasn’t been tested as a potential therapy for Alzheimer’s. In the new study, Colton’s group administered it before the onset of symptoms; now they are investigating whether DFMO can treat features of Alzheimer’s after they appear.

https://today.duke.edu/2015/04/arginine



Lane Simonian
Posted: Wednesday, April 15, 2015 10:28 AM
Joined: 12/12/2011
Posts: 4835


This is the likely explanation (paraphrased from a special issue of Biofactors: Free Radicals in Biology and Medicine, p. 113):

Arginine depletion is caused by arginase and nitric oxide synthase activity (which occurs for example during inflammation). In situations of arginase depletion, there is an increased production of superoxides and peroxynitrites. Increased production of peroxynitrites from all three isoforms of nitric oxide synthase [constitutive, neuronal, and inducible] have been demonstrated in situtations of arginine depletion. In this situation, the electrons produced by nitric oxide synthases are transferred to oxygen to form superoxide anions. The remaining arginine produces nitric oxide which combines with superoxide anions to produce peroxynitrite which leads to cell death in inflammatory conditions such as asthma.


The oxidation of BH4 by peroxynitrites worsens this situation (my addition).

Serenoa
Posted: Friday, April 17, 2015 4:28 AM
Joined: 4/24/2012
Posts: 484


Thanks for the post Tom(ek). I'm seeing all kinds of connections here. This is significant. I also agree with what Lane posted. I need to spend more time on this. Here is one connection I found so far.

Diabetes-induced Coronary Vascular Dysfunction Involves Increased Arginase Activity

"Increases in arginase activity have been reported in a variety of disease conditions characterized by vascular dysfunction. Arginase competes with NO synthase for their common substrate arginine, suggesting a cause and effect relationship. We tested this concept by experiments with streptozotocin diabetic rats and high glucose (HG)-treated bovine coronary endothelial cells (BCECs). Our studies showed that diabetes-induced impairment of vasorelaxation to acetylcholine was correlated with increases in reactive oxygen species and arginase activity and arginase I expression in aorta and liver."

This may be one reason Arginase activity is increased in microglia in the first place.

Lane Simonian
Posted: Friday, April 17, 2015 9:55 AM
Joined: 12/12/2011
Posts: 4835


I think this is part of it, Serenoa, as high levels of glucose increase oxidative stress and high levels of oxidative stress increase arginase activity.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268202/

My research friend Carlos Oliveira pointed out on Alzheimer's Reading Room that increasing arginase activity may be a double-edged sword. It may increase the beneficial form of nitric oxide but under conditions of oxidative stress arginine may also increase inducible nitric oxide which combines with superoxide anions to form peroxynitrites. The following article discusses all the ways arginine may either benefit or harm people with Alzheimer's disease. I am just going to post the header for the primarily negative section.

L-Arg, as a Precursor of NO, Affects AD via Influencing Oxidative Stress


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600464/

And one last clue, one of the presenilin gene mutations involves the substitution of leucine with arginine. Leucine keeps g protein-coupled receptors in a deactivated state and arginine activate g protein-coupled receptors and the overactivation of g protein-coupled receptors is one of the steps to oxidative stress in Alzheimer's disease.

So arginase activity may be one more result of oxidative stress. However, decreasing arginase activity may not help; it might actually make things worse.



Lane Simonian
Posted: Friday, April 17, 2015 9:58 AM
Joined: 12/12/2011
Posts: 4835


I cannot edit on these boards any more, but an important correction: decreasing arginase activity may be a double-edged sword.
Lane Simonian
Posted: Friday, April 17, 2015 11:36 PM
Joined: 12/12/2011
Posts: 4835


A few general thoughts about all the "breakthrough" studies over the last few months (Biogen, ultrasounds, arginine, etc.).

It is not a breakthrough until it works in human beings.

Don't compare drug results against placebo results. What matters is if there is a significant reversal in cognitive decline over a period of years.

What may be neuroprotective before Alzheimer's disease may be neurodestructive after one has the disease.

Don't be thrown off by what is high (amyloid plaques) or low (arginine) "biomarkers". Most of these are simply consequences of the disease and decreasing them or increasing them may make little difference or actually make things worse.

Understand what causes the disease. Then you know how to reduce the risk of getting Alzheimer's disease and how to partially reverse the disease.

Please, please let there be a story in the next few months that offers real promise.

Serenoa
Posted: Saturday, April 18, 2015 6:21 AM
Joined: 4/24/2012
Posts: 484


I am not looking for a "breakthrough" cure for the type of Alzheimer's that is affecting most people. I realized a while back that drugs cannot cure chronic degenerative diseases like Alzheimer's. The "breakthrough" that excites me (as you mentioned Lane) is one that points to a primary cause for the disease that can be corrected or changed. I think this study is an important clue.

So, why did the researchers find increases in Arginase activity? And, why are they associating that with immune system (microglia) suppression? Put in another way, what is the body (of a rat in this case) trying to do by increasing Arginase and depleting Arginine? The homeostasis (balance) of Arginine in the body is off. Why? What effect is that having? Is it good or bad in relation to the disease. The researchers say inhibiting Arginase restored Arginine homeostasis (thus supplying NOS with ability to produce NO and I guess activating immune response) and the disease was reversed.

So what is the take-away, the most important piece of evidence from this study? Maybe we should now be asking how is Arginine homeostasis relevant to Alzheimer's? What throws it off balance? How does it affect the immune system of humans?


Lane Simonian
Posted: Saturday, April 18, 2015 10:14 AM
Joined: 12/12/2011
Posts: 4835


Fantastic questions, Serenoa. Without being so focused, these were some of the questions that I began to ask when I read the story. Here are some potential answers.

NO produced by endothelial NOS is needed for normal vascular function. During diabetes, aging and hypertension, elevated levels of arginase can compete with NOS for available l-arginine, reducing NO and increasing superoxide (O2.−) production via NOS uncoupling. Elevated O2.− combines with NO to form peroxynitrite (ONOO-), further reducing NO. Oxidative species increase arginase activity, but the mechanism(s) involved are not known. Our study determined the mechanism involved in peroxynitrite and hydrogen peroxide-induced enhancement in endothelial arginase activity.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268202/

Peroxynitrites and hydrogen peroxide likely increase arginase activity via an hydroxyl radical (peroxynitrites and hydrogen peroxide are the key oxidants in Alzheimer's disease).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585818/

Now if arginase were the only source of superoxide anions in Alzheimer's disease and arginine were the only source of inducible nitric oxide in Alzheimer's disease, either one would help treat the disease. But unfortunately neither is the case.

Here is a link to a helpful chart (the text beneath the chart is useful, too) followed by an important research finding.

http://www.nature.com/nri/journal/v5/n8/fig_tab/nri1668_F1.html

These results reveal that arginase acts as a central regulator of trophic factor-deprived motor neuron survival by suppressing nitric oxide production and the consequent peroxynitrite toxicity.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570095/

So increased arginase activity may be the body's attempt to reduce peroxynitrite levels just as amyloid plaques are the body's attempt to reduce hydrogen peroxide levels. Unfortunately, both attempts fail, as there are other sources of superoxide anions in Alzheimer's disease and while amyloid plaques lower levels of hydrogen peroxide they have no effect on peroxynitrite production.

Here may be the key to it all (although this study involves motor neurons but it also applies to other neurons):

When incubated with nor-NG-hydroxy-nor-l-arginine (NOHA), the normally resistant trophic factor-deprived motor neurons showed a drop in survival rates, whereas trophic factor-treated neurons did not. NOHA-induced motor neuron death was inhibited by blocking nitric oxide synthesis and the scavenging of superoxide and peroxynitrite, suggesting that peroxynitrite mediates NOHA toxicity.

Lane Simonian
Posted: Saturday, April 18, 2015 10:41 AM
Joined: 12/12/2011
Posts: 4835


I left out a discussion of arginase, microglia, and peroxynitrites in Alzheimer's disease. Arginase may increase microglia activation early in Alzheimer's disease partially via peroxynitrites (microglia further increase the production of peroxynitrites), but as the disease progresses peroxynitrites kill microglia. Thus there is inflammation early in Alzheimer's disease that declines as the disease progresses.


Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology

Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the [amyloid] deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation...However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood.


J Neurochem. 1999 May;72(5):1948-58.
Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia.

Peroxynitrite inhibited the activity of isolated KGDHC [alpha-ketoglutarate dehydrogenase], nitrated tyrosine residues of all three KGDHC subunits, and reduced immunoreactivity to antibodies against two KGDHC components. Thus, our data suggest that inhibition of the mitochondrial respiratory chain diminishes aerobic energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vulnerable to NO. and peroxynitrite that result from microglial activation. Thus, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.




Lane Simonian
Posted: Saturday, April 18, 2015 1:08 PM
Joined: 12/12/2011
Posts: 4835


I wrote these comments on another website, but they are more succinct and clearer that what I wrote above:

Arginine depletion often occurs in cases of inflammation which is an early problem in Alzheimer's disease. Arginine depletion increases the production of superoxide anions without sufficiently reducing levels of inducible nitric oxide. Superoxide anions combine with inducible nitric oxide to form peroxynitrites--which is likely the primary cause of Alzheimer's disease.

The best way to go after Alzheimer's disease is to limit the production of peroxynitrites, scavenge them, and reverse part of the damage they do to the brain. Some of the most effective peroxynitrite scavengers such as syringic acid and ferulic acid in panax ginseng and eugenol in rosemary essential oil via aromatherapy have already done this.

http://www.ncbi.nlm.nih.gov/pm...

http://onlinelibrary.wiley.com...



It took a few days, but now to complete the circle. Peroxynitrites and hydrogen peroxide which are the principal oxidants in Alzheimer's disease increase arginase activity. Argninase increases superoxide anion production and arginine increases inducible nitric oxide production (superoxide anions combine with inducible nitric oxide to produce peroxynitrites). If arginase were the only source of superoxide anions and arginine were the only source of inducible nitric oxide they would both protect the brain against Alzheimer's disease, but since they are not neither helps in the treatment of the disease. Indeed inhibiting arginase activity (unless you use peroxynitrite and hydrogen peroxide scavengers) will likely make the disease worse as inducible nitric oxide is the rate limiting compound in the formation of peroxynitrites. Researchers keep going after enzymes (arginases, acetylcholinesterases, BACE1, gamma secretases, etc.) and byproducts of Alzheimer's disease (amyloid oligomers, amyloid plaques, and neurofibrillary tangles) whereas they need to go after the oxidants that cause all of these things. If they did, effective treatments for Alzheimer's disease would be available in years rather than decades.


To be more accurate, if arginase were the only source of superoxide anions then inhibiting arginase would help protect against and treat Alzheimer's disease. If arginine were the only source of inducible nitric oxide then lowering arginine levels would help protect against and treat Alzheimer's disease. But since they are not the only sources, it does no good to inhibit either arginase or lower arginine levels. Again, Alzheimer's disease is caused by oxidants. It is the oxidants that cause the overactivation of enzymes and the accumulation of amyloid and tau. Treat the initial cause rather than the subsequent consequences and you have a very good chance of effectively treating if not curing Alzheimer's disease.


Serenoa
Posted: Saturday, April 18, 2015 7:18 PM
Joined: 4/24/2012
Posts: 484


Thank you Lane. I have looked at several of your links to the research. I would like to put it in my own very simplistic terms. This helps me to grasp these complex mechanisms and theories.

The original article states that arginase activity is increased leaving an arginine deficiency which reduces the amount of nitric oxide produced by NOS. And so they say arginase is the problem and we simply have to inhibit this enzyme to fix the problem of not enough nitric oxide for healthy cell functioning. But, according to my analysis of your info Lane, and my own thoughts, here is the real story:

A neuron is sick and struggling to survive due to oxidative damage from whatever cause.
Sick cells generally commit suicide (apoptosis) when they can no longer function.
Sometimes they commit suicide using the nitric oxide made in the cell by NOS.
In a last ditch effort to save itself, the cell decreases nitric oxide production by increasing arginase activity which uses up arginine which is a substrate for the production of nitric oxide.
Therefor, increased arginase activity is NOT the problem, it is a SYMPTOM.

So why did arginase inhibition work in mice? Maybe because the Alzheimer's in mice is caused by genetics and there is no oxidative damage taking place. Therefor, the reduction in nitric oxide (caused by increased arginase activity) had no purpose in cell survival and only served to inactivate the cell (microglia in this case) which prevented it from removing plaques and tangles and regeneratiing neurons. Without the oxidative molecules around there was no repercussions from increasing nitric oxide production in the cell.


Lane Simonian
Posted: Saturday, April 18, 2015 8:56 PM
Joined: 12/12/2011
Posts: 4835


All I can say is brilliant. I have not been able to put this together in the same way. Something about mice models of Alzheimer's disease has been bothering me for a long time. I know it is not the same as Alzheimer's disease as in human beings but how is it different. And this may very well be it, the level of oxidative and nitrostative stress in mice engineered to have Alzheimer's disease is much less than in human beings--it is all genetics and nothing else. So all the things arginine does that are positive in the absence or near absence of oxidative stress (such as increased nitric oxide levels) become negative in the presence of oxidative and nitrostative stress. Either what is working in mice with memory loss has an opposite effect in human beings with memory loss or it is not strong enough to reverse memory loss in human beings.
Lane Simonian
Posted: Saturday, April 18, 2015 9:48 PM
Joined: 12/12/2011
Posts: 4835


I think you just hit the nail on the head, Serenoa.

As shown in Table 1, the evidence for increased free radical-mediated damage in cerebral cortex and hippocampus (HP) of the most widely used transgenic model of AD, the Tg2576 mouse, is variable, and suggests that local factors such as inbred substrains or diet may be as important as transgene expression in producing oxidative damage in these mice. Studies of oxidative damage in other transgenic mouse models are fewer but appear to show more consistently increased free radical damage to cerebral cortex, especially APP-PS1 models.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2459222/

The level of oxidative stress (and presumably the level of cognitive decline) may be less in mice with Alzheimer's-like disease than in human beings and therefore the "disease" is easier to reverse in mice than in human beings.

Serenoa
Posted: Sunday, April 19, 2015 6:33 AM
Joined: 4/24/2012
Posts: 484


That is high praise coming from you Lane. Thanks.

I think we can put the causes of chronic degenerative diseases into two general categories: PREVENTABLE and NOT PREVENTABLE. Preventable being cased by things you can change like avoiding toxins in the environment, lifestyle, diet. Not preventable being genetic or physical injury, infection, etc. The practical point is that one must be addressed with medical intervention, i.e. drugs, surgery, etc., the other cannot successfully be treated through drugs or other medical interventions. Of course there is overlap, but let's keep it simple for this thought experiment.

Genetic cause --> one faulty pathway --> damage --> disease. In this case medical intervention fixes faulty pathway and makes the faulty gene irrelevant. Cell functions normally again.

Environmental cause --> many faulty pathways --> damage --> disease. In this case medical intervention fixes one faulty pathway but does not make the environmental cause irrelevant. This cause affects many pathways to cause damage and the cell still cannot function normally.

So fixing one or two faulty pathways in Alz mice successfully compensates for the genetic defect(s). Fixing these pathways in a chronic degenerative type of Alz in humans does not compensate (or only partially compensates) for the environmental cause which is doing damage on many levels. Just thinking out loud. Does this ring true to you Lane?


Serenoa
Posted: Sunday, April 19, 2015 7:53 AM
Joined: 4/24/2012
Posts: 484


I should add that the terms "chronic" and "degenerative" should probably only apply to diseases caused by environmental factors like toxic exposure, poor nutrition, constant stress, etc.

Lane Simonian
Posted: Sunday, April 19, 2015 10:13 AM
Joined: 12/12/2011
Posts: 4835


Praise well-deserved.

There are several ways to look at genetic versus diet/environmental/lifestyle causes of Alzheimer's disease. Both can sometimes have more than one pathway that they impact (but rarely more than two). For presenilin 1 gene mutations, the substitution out of leucine can stop the inactivation of g protein-coupled and inactivate the neuroprotective phosphatidylinositol 3-kinase/Akt pathway. Glucose can increase myo-inositol levels and increase the expression of platelet derived growth factor receptors (a receptor tyrosine kinase receptor). All of these are keys as there are four principal pathways/compounds involved in Alzheimer's disease: high levels of myo-inositol, overactivation of receptor tyrosine kinase, overactivation of g protein-coupled receptors, and inhibition of the phosphatidylinositl 3-kinase/Akt pathway.

The problem with genetic mutations especially those that cause a loss of function is how do you work around the gene--in some cases certain medicines or therapies may work and other cases not. Whereas with stress, diet, environmental exposures, and lifestyle choices you can reduce the risk of Alzheimer's disease by removing what is triggering the oxidative stress (which is easier said than done in many cases), as you note, Serenoa.

I have wondered if certain diets increase the risk for Alzheimer's disease (high sugar, high fructose, high carbohydrate, high salt) and other diets lessen the risk for Alzheimer's disease (Mediterranean diet or a diet from India or the high use of spices, fruits, and vegetables in general) does a person with a gene for early onset Alzheimer's disease get the disease even earlier or somewhat later in life depending on their diet? The gene is creating the oxidative stress that will eventually cause Alzheimer's disease, but if you minimize other stressors that should delay the onset of the disease.

For the mice bred to have Alzheimer's disease through gene manipulation, their diet seemed to affect their levels of oxidative stress. Presumably mice with less oxidative stress would be easier to "cure" than mice with more oxidative stress. And if that memory loss is caused primarily by one oxidant (hydrogen peroxide) and not as much by a combination of oxidants (hydrogen peroxide and peroxynitrites) it would be even easier, in part because the neuroprotective phosphatidylinositol 3-kinase/AKT pathway would not be so inhibited by nitration and things that stimulated this pathway (arginine, ultrasounds, etc.) might still work.

http://www.ncbi.nlm.nih.gov/pubmed/9826526

http://www.ncbi.nlm.nih.gov/pubmed/16410804

http://www.ncbi.nlm.nih.gov/pubmed/11689461

Lane Simonian
Posted: Sunday, April 19, 2015 10:57 AM
Joined: 12/12/2011
Posts: 4835


I am looking for more clues of how transgenic mice with an Alzheimer's-like disease differs from actual Alzheimer's disease. Here is a small clue:

Since the administration of 3NTyr10-Aβ into the brain of young APP/PS1-mice triggers deposition of Aβ, NOS2 inhibition may alter the progression of Alzheimer’s disease and thus represents a potentially new therapeutic approach.

3NTyr (3-nitrotyrosine); NOS2--Inducible nitric oxide; Amyloid Precursor Protein mutation, Presenilin1 gene mutation

So in the case of young transgenic mice, you actually had to put nitrotyrosine (nitrotryosine is often one of the footprints for peroxynitrites) into the brains of the mice to have the "desired" effect.

Old transgenic mice would be a much more accurate model for Alzheimer's disease, because then you would get the full-extent or close to the full extent of the oxidative damage that occurs in Alzheimer's disease (in addition to amyloid and tau tangles).


Total and mitochondrial peroxynitrite levels were significantly higher in aged compared with young mice (I parsed the young mice part together).

Lane Simonian
Posted: Sunday, April 19, 2015 6:20 PM
Joined: 12/12/2011
Posts: 4835


Better yet:

However, transgenic mice do not develop extensive neuronal loss, like human AD patients. This can be ascribed to the amount of time needed: in human AD progresses over decades while transgenic mice are kept only for 2 years. Another problem may be related to background strains: (i) the most used mice strain is C57BL/6 which may be more resistant to excitotoxicity, (ii) the heterogeneity of humans is more complex compared with inbred mouse strains, (iii) fundamental differences between mice and humans exist ().

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685797/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC20575/

Excitotoxicity is one of the main sources of peroxynitrite formation as Alzheimer's disease progresses.

However, transgenic mice do not develop extensive neuronal loss, like human AD patients.

Activation of PHOX alone causes no death, but when combined with expressed iNOS results in extensive neuronal death via peroxynitrite production.

http://www.ncbi.nlm.nih.gov/pubmed/17956292

Mice with an Alzheimer's-like disease have lower levels of peroxynitrites and less peroxynitrite-mediated damage than people with Alzheimer's disease. Thus, many things that work in mice don't work in human beings.





Serenoa
Posted: Tuesday, April 21, 2015 5:24 AM
Joined: 4/24/2012
Posts: 484


Yes, I agree. It is interesting how they sometimes introduce an alteration to cause the disease in mice then provide an intervention that counteracts the alteration they have induced.

I was looking for clues to GM-CSF's interaction with arginase and found this perplexing article.

Induction of Intracellular Arginase Activity Does not Diminish the Capacity of Macrophages to Produce Nitric Oxide in vitro

"Arginase activity appears to be inhibited during high-output NO synthesis. Taken together, our results show that NO production by Mφ is not compromised by conditions that increase intracellular arginase activity."


Lane Simonian
Posted: Tuesday, April 21, 2015 6:55 PM
Joined: 12/12/2011
Posts: 4835


Perplexing is a good word for this study. Here is another one.

Abstract

Nitric oxide (NO) synthesis was measured in the liver, lung, spleen and kidney of lipopolysaccharide-treated male rats using the nitric oxide spin trap, iron (II)-diethyldithiocarbamate (FeDETC2). Nitric oxide formation in vivo was determined by the increase in intensity of the characteristic triplet hyperfine EPR spectrum of [NO-FeDETC2]. Intravenous bovine liver arginase, at a dose which completely depleted circulating arginine, significantly reduced the formation of nitric oxide in these tissues. The general decrease in NO levels was confirmed by the decrease in plasma nitrite levels. These results directly demonstrate that NO formation in endotoxic shock depends on extracellular arginine; depletion of plasma arginine may be a useful therapeutic strategy.

So even when you deplete arginine altogether nitric oxide is still produced. Nitrites and nitrates in food produce nitric oxide and this may account for their potential link to Alzheimer's disease.

Moreover, macrophages produce peroxynitrites and when peroxynitrites are scavenged they produce nitrites some of which may be converted to nitric oxide. So it is possible to have nitric oxide production without arginine.


Serenoa
Posted: Thursday, April 23, 2015 5:17 AM
Joined: 4/24/2012
Posts: 484


This has been a great thread. Complex things have become clearer to me. I am more convinced that oxidative damage is the cause. Balance in molecular systems is everything. And, mice only tell us part of the story. Thanks Lane.

Jimmyvihufuva
Posted: Monday, May 18, 2015 4:40 AM
Joined: 5/18/2015
Posts: 2


very interesting indeed. Is this an actual clinical trial currently?
Fascinating to read about how complex our nervous system is.
Thanks for sharing.


HowDoYouDeal
Posted: Wednesday, January 15, 2020 10:52 PM
Joined: 2/17/2019
Posts: 347


Didn't the three wise men bring Gold Frankincense and Myrr? Are there any instances where Frankincense is consumed, not just inhaled?