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Showing posts with label Cinnamon. Show all posts
Showing posts with label Cinnamon. Show all posts

Wednesday 1 November 2017

OAT3 inhibitors for Bumetanide - Probenecid, but also Aspirin, Chlorogenic acid (Coffee), Epicatechin (Cocoa, Cinnamon) and more.


Today’s post is about OAT3, highlighted by the green lines.
The interventions reduce renal excretion and raise plasma
concentration rather than directly improving transport across the BBB

Today’s post is a collaboration. Our reader Ling pointed out research trying to boost the bioavailability of bumetanide using something clever called an OAT3 inhibitor.  This would reduce the rate at which the body excretes bumetanide and thus potentially improve its therapeutic effect.
Petra, our reader from Greece, pointed out that in her son Bumetanide seemed to work better when taken with Greek coffee and that that Greek Grandpas like to take their diuretics with a steaming Greek coffee.
Most people, me included, automatically think caffeine when someone mentions coffee.
So I assumed that caffeine might be an OAT3 inhibitor and I did make some experiments on that basis. There is no research data to support caffeine as an OAT3 inhibitor.
Recently I was again looking for other potential Bumetanide boosters.  The obvious one is called Probenecid.  Probenecid is used to treat gout because it lowers uric acid.
Aspirin has some odd effects; low dose aspirin will raise uric acid, but high dose aspirin will lower it. Aspirin is an OAT3 inhibitor.
OATs are a very niche subject, to add to the confusion sometimes you are better looking for SLC22A8, the gene that encodes the transporter. 
There was an earlier post on this subject, which showed that many NSAIDs inhibit OAT3, including Knut’s favourite Ponstan. They are not so well suited to continued use.

At the end of my little investigation I figured it out; there are many OAT3 inhibitors available, including some in your kitchen.  


Key points on OAT3 (Organic Anion Transporter 3)
If you want to increase the peak concentration and indeed the half-life of a drug that is excreted from the body by OAT3 (organic anion transporter 3), an OAT inhibitor is what you need.
The drug Probenecid is by far the best known OAT3 inhibitor and it is very potent. It has long been to boost the performance of penicillin type antibiotics to treat tough bacterial infections.
Probenecid, if available, may very well be the ideal bumetanide booster.
For adults a simple option is Greek/Turkish coffee. I see little downside as long as you can handle the caffeine. The Greeks live a long time and drink plenty of coffee.
For those who do not like caffeine you can go to active components within the coffee, which seem to be the chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid). They are sold as a weight loss supplement, the long established version is the French-made Svetol, but there are now others. They still contain 2- 3% caffeine.
Epicatechin, found in cinnamon, dark chocolate and high flavanol cocoa is another OAT3 inhibitor. Cocoavia, made by Mars, is used by some readers of this blog. Cocoa flavanols do clever things with nitric oxide (NO) and have been shown to improve mild cognitive impairment (MCI) and heart health by improving blood vessel elasticity.
Catechins are flavanols belonging to a family of closely related compounds, such as epicatechin, epigallocatechin, epicatechin gallate (EGC), and epigallocatechin gallate (EGCG). They are all slightly different. Catechin itself is not an OAT3 inhibitor; EGCG may or may not be.
Low dose aspirin is likely the cheapest OAT3 inhibitor. It also increases peripheral circulation, which could benefit some. Low dose aspirin has the downside of a small bleeding risk, mainly in old people, and there is a risk of Reye’s syndrome if given during/after a viral infection.
I think for adults a Greek coffee may be the best. For people who have a profound benefit from Bumetanide, I think they should look into Probenecid.
Personally I think Svetol is worth a try.
Coffee that has been extensively processed (just as we saw with cocoa) may not have the same chlorogenic acid content as the more gritty coffee used in the Balkans. Coffee consumption is actually associated with many neurological benefits, reducing the incidence of Parkinson’s and Alzheimer’s; the common mistake in research is the assumption that the effect must be from caffeine.











  
The health effects of decaffeinated Coffee
My eureka moment in this post was reading about gout and coffee and then decaffeinated coffee. 




So then it was a question of finding what in coffee could be the OAT3 inhibitor. At which point I found a very insightful paper that tells you everything, once you realise that:

Coffee = chlorogenic acids  = 1,3- and 1,5-dicaffeoylquinic acid


Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions

3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids

Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus  pmol mg 10  , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.










Lay off the Lycopene?
Lycopene does the opposite of what we want. Too much lycopene may lower the effectiveness of a drug that is excreted via OAT3. 

2.29. Lycopene

Lycopene is a carotenoid pigment found in tomato [94]. Lycopene from dietary sources has been shown to reduce the risk of some chronic diseases including cancer and cardiovascular disorders [95]. The administration of lycopene significantly normalized the kidney function and antioxidant status of CSP-treated animals. Furthermore, lycopene also increased the expression of the organic anion and cation transporters (OAT and OCT, resp.) including OAT1, OAT3, OCT1, and OCT2 in the renal tissues [9698]. In addition, lycopene also decreased the renal efflux transporters (multidrug resistance-associated protein [MRP]-2 and MRP4) levels and induced Nrf2 activation, which activated the antioxidant defense system [99]. Furthermore, lycopene protected against CSP-induced renal injury by modulating proapoptotic Bax and antiapoptotic Bcl-2 expressions and enhancing heat shock protein (HSP) expression [97].

https://www.hindawi.com/journals/omcl/2016/4320374/                                                                                                                  

Aspirin
I actually started out this post by looking at what dose of aspirin might be effective in inhibiting OAT3.  We do know that Aspirin is indeed an OAT3 inhibitor.  


I did find the answer, but along the way you do end up having to look at uric acid. 
Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1 Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1. 
Uricosuric drugs increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. 
In general, uricosuric drugs act on as urate transporter 1 (URAT1). URAT1 is the central mediator in the transport of uric acid from the kidney into the blood.  By their mechanism of action, some uricosurics (such as  probenecid) increase the blood plasma concentration of certain other drugs and their metabolic products  – this is their effect on OAT3.
Probenecid is a medication that increases uric acid excretion in the urine.
Atorvastatin is a so-called secondary uricosuric. High dose aspirin should also be called a secondary uricosuric.
Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics and low dose aspirin. 
Low dose aspirin inhibits OAT1 and OAT3 which reduces urate secretion, but high dose aspirin inhibits URAT1 and reduces urate re absorption. This is sometimes known as the biphasic effect.
So low dose aspirin will increase plasma uric acid, but high dose aspirin has the same effect as Probenecid, it lowers plasma uric acid levels.
So Aspirin and Probenecid both affect URAT1 and OAT3. 






At what dose is Aspirin an OAT3 inhibitor?
If we just want aspirin to inhibit OAT3 and not inhibit URAT1, what dose is effective? Fortunately this has been answered in the research. The typical low dose of aspirin (75mg) used preventatively in older people is OAT3 inhibiting, it raises plasma uric acid.  





Salicylate

Salicylic acid and its derivatives are the most prescribed analgesic, antipyretic, and anti-inflammatory agents. Salicylates have a “paradoxical effect” on the handling of uric acid by the kidney. The action of salicylates on uric acid excretion depends on the dose of salicylates. At doses of less than 2.5 g/day, salicylates cause the retention of uric acid by blocking the tubular secretion of uric acid, while at dose of higher than 3 g/day, they cause increased urinary excretion of uric acid [70]. Mini-dose aspirin, even at a dosage of 75 mg/day, caused a decrease in uric acid excretion and raised serum uric acid level [71]. It has been suggested that the “paradoxical effect” of salicylate can be explained by two modes of salicylate interaction with URAT1: (1) acting as an exchange substrate to facilitate uric acid reabsorption, and (2) acting as an inhibitor for uric acid reabsorption [72]. Low dose of salicylate interact with OAT1/OAT3, the uric acid secreters [73].

Low dose aspirin leads to decreased renal excretion of uric acid and raised serum uric acid levels, which can cause a gout attack in those predisposed to this condition.
High doses of aspirin lower serum uric acid concentration.

Reye’s Syndrome
In children aspirin is very rarely used because of the risk of Reye’s syndrome. Reye’s syndrome causes severe liver and brain damage. It is a type of severe mitochondrial failure that can occur after a viral infection like flu or chickenpox, but it almost only occurs when aspirin has been prescribed. Nobody knows for sure the exact mechanism of the disease.
So do not give aspirin to children with a viral infection.  We already know to avoid paracetamol/acetaminophen (Tylenol in the US) in babies/children and people with autism. Paracetamol/acetaminophen depletes the body’s key antioxidant GSH. 
If someone overdoses on Paracetamol/acetaminophen you give them a high dose of NAC to prevent death. 


Conclusion
Given how long it takes to develop new drugs, I think that improving the pharmokinetics of bumetanide is a pretty obvious thing to do. 
Diamox is an OAT3 inhibitor and our reader Agnieszka found it beneficial only when administered along with Bumetanide.
Strong coffee is an OAT3 inhibitor and this was found to enhance bumetanide by Petra’s son with Asperger’s.
Cinnamon which contains epicatechin, another OAT3 inhibitor, did seem to be helpful in Monty who also takes bumetanide.
I suspect Diamox may be the most potent OAT3 inhibitor of those three
The interesting OAT3 inhibitors seem to be:-

·        Probenecid

·        Low dose aspirin

·        Epicatechin (cocoa, cinnamon ..)

·        Chlorogenic acids (coffee and decaffeinated green coffee extracts) 

Cinnamon, high flavanol cocoa and indeed coffee (minus the caffeine) have numerous health benefits.
Note that Catechin has no effect on OAT3. EGCG was not tested but in other studies has been shown it does affect.



The logical next step would be to improve bumetanide transport across the blood brain barrier.










Wednesday 4 October 2017

Sodium Benzoate and GABRA5 - Raising Cognitive Function in Autism


I am still looking for additional cognitive enhancing autism therapies. It seems the best way to find them may actually be to reread my own blog.
A long time ago I suggested that Cinnamon could well be therapeutic in autism, most likely (but not entirely) due to the sodium benzoate (NaB) it produces in your body.


Sodium benzoate (NaB) is both a drug used to reduce ammonia in your blood and a common food additive that acts as a preservative.
NaB has many biological effects.  One effect relates to a protein called DJ-1, which is produced by a Parkinson’s gene (PARK7). I had noticed that when the body tries to turn on its anti-oxidant genes after the switch Nrf2 is activated, the process cannot proceed without enough DJ-1.  This is why Peter Barnes, from my Dean’s list, suggested that patients with COPD might benefit from more DJ-1.  COPD is a kind of severe asthma which occurs with severe oxidative stress, the oxidative stress stops the standard asthma drugs from working, which is why so many people die from COPD. Oxidative stress is a key feature of most autism.
To make more DJ-1 you can use sodium benzoate (NaB) which is produced gradually in the body if you eat cinnamon. So in theory cinnamon is like sustained release NaB, it is also extremely cheap.
Independently of all this NaB has been trialled in schizophrenia and a further larger trial is in progress.  Autism is not schizophrenia, but the hundreds of genes miss-expressed in autism do overlap with the hundreds of genes miss-expressed in schizophrenia, so I call schizophrenia autism’s big brother. 

GABAA α5 subunit
The scientist readers of this blog may recall that there are two sub-units of the GABAA receptor that I am seeking to modify, to improve cognition.  One is the α3 subunit and the other is the α5 subunit. Low dose clonazepam works for α3.
The α5 subunit is the target of a new drug to improve cognition in people with Down Syndrome (DS).
Very recent research links the same sub-unit to autism, so it is not just me looking at this.

Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior                                                                                                              

As is often the case, it looks like some people might need to “turn up the volume” from α5GABAA receptors and others might need to turn it down.
I had yet to find a practical way to affect α5GABAA. Now I have realized that I have already stumbled upon such a way to do it.
Pahan, a researcher in Chicago, has shown that he can improve cognition in mice using cinnamon. He noted that in poor learners GABRA5 was elevated, but that after one month of cinnamon GABRA5 was normalized. 

Cognitive loss in autism, schizophrenia and Down Syndrome
Most people might associate MR/ID with autism and indeed Down Syndrome; you likely do not really consider people with schizophrenia to have MR/ID. In reality, cognitive loss is a common feature/problem in schizophrenia and indeed bipolar, just not enough to be called MR/ID.
Those researching schizophrenia seem to focus on NMDA receptors, whereas my blog only goes into the great depths of science when it comes to GABAA . To the schizophrenia researchers NaB is interesting because it is a d-amino acid oxidase inhibitor, which means that it will enhance NMDA function.  So if you are one of those people with too little NDMA activity (NMDAR hypofunction) then sodium benzoate should make you feel better.
The schizophrenia researchers think NaB is helpful because of its effect on NMDA, for me it is GABRA5 that is of great interest. The same should be true for parents of kids with Down Syndrome (DS). We have seen that bumetanide should, and indeed does, help DS.  It looks to me that NaB/Cinnamon should further help them and no need to wait for Roche to commercialize their GABRA5 drug. 

NaB and Cinnamon
I am yet to determine how much NaB is produced by say 3g of cinnamon.
The clinical trials of NaB use 1g per day in adults. People using cinnamon, like Dr Pahan, for cognition or just lowing blood pressure and blood sugar use around 3g.
It is quite difficult to give a teaspoonful of cinnamon to a child, whereas NaB dissolves in water and does not taste so bad. 

NaB and Cinnamon Trials
I did trial cinnamon by putting it in in large gelatin capsules and at the time I did think it had an effect, but I doubt I got close to Dr Pahan’s dosage.
A prudent dose of NaB would seem to be 6mg/Kg twice a day. This is similar to what is now being trialed in schizophrenia.
A small number of people do not tolerate NaB and logically also cinnamon.  They are DAAO inhibitors, just like Risperidone. People who are histamine intolerant need to avoid DAAO inhibitors. If you have allergies it does not mean you are histamine intolerant.
I did try NaB on myself and I did not notice any effect.


Conclusion
I had already obtained some NaB to follow up on my earlier trial of cinnamon.  Having read about the effect of NaB on GABRA5 expression, I am even more curious to see if it helps.
Any positive effect might be due to DJ-1 boosting the effect of Nrf-2, it might be boosting NMDA or it might be reducing GABRA5 expression. In some people all three would be useful.


Press release:- 


Pahan a researcher at Rush University and the Jesse Brown VA Medical Center in Chicago, has found that cinnamon turns poor learners into good ones—among mice, that is. He hopes the same will hold true for people.

His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.

"The increase in learning in poor-learning mice after cinnamon treatment was significant," says Pahan. "For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds."

Pahan's research shows that the effect appears to be due mainly to sodium benzoate—a chemical produced as cinnamon is broken down in the body.

In their study, Pahan's group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. 


In analyzing baseline disparities between the good and poor learners, Pahan's team found differences in two brain proteins. The gap was all but erased when cinnamon was given. 


"Little is known about the changes that occur in the brains of poor learners," says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment." 


The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the cells—namely in the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells

As for himself, Pahan isn't waiting for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon powder mixed with honey as a supplement every night.  
Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide. 


The paper itself:- 


This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity. 

We have seen that cinnamon and NaB modify T cells and protect mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Cinnamon and NaB also upregulate neuroprotective molecules (Parkin and DJ-1) and protect dopaminergic neurons in MPTP mouse model of Parkinson’s disease.  Recently, we have seen that cinnamon and NaB attenuate the activation of p21ras, reduce the formation of reactive oxygen species and protect memory and learning in 5XFAD model of AD. Here we delineate that NaB is also capable of improving plasticity in cultured hippocampal neurons. Our conclusion is based on the following: First, NaB upregulated the expression of a number of plasticity-associated molecules (NR2A, GluR1, Arc, and PSD95) in hippocampal neurons. Second, Gabra5 is known to support long-term depression. It is interesting to see that NaB did not stimulate the expression of Gabra5 in hippocampal neurons. Third, NaB increased the number, size and maturation of dendritic spines in cultured hippocampal neurons, suggesting a beneficial role of NaB in regulating the synaptic efficacy of neurons. Fourth, we observed that NaB did not alter the calcium dependent excitability of hippocampal neurons, but rather stimulated inbound calcium currents in these neurons through ionotropic glutamate receptor. Together, these results clearly demonstrate that NaB is capable of increasing neuronal plasticity.

These results suggest that NaB and cinnamon should not cause health problems and that these compounds may have prospects in boosting plasticity in poor learners and in dementia patients. In summary, we have demonstrated that cinnamon metabolite NaB upregulates plasticity-associated molecules and calcium influx in cultured hippocampal neurons via activation of CREB. While spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones, oral administration of cinnamon and NaB increased memory consolidation-induced activation of CREB and expression of plasticity-related molecules in vivo in the hippocampus of poor learning mice and improved their memory and learning almost to the level that observed in untreated good learning ones. These results highlight a novel plasticity-boosting property of cinnamon and its metabolite NaB and suggest that this widely-used spice and/or NaB may be explored for stimulating synaptic plasticity and performance in poor learners.


The schizophrenia trials:-







Plenty of people with schizophrenia now self-treat with NaB; just look on google.

P.S.
There is now is a small trial in autism:-

A Pilot Trial of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added on Augmentative and Alternative Communication Intervention for Non-Communicative Children with Autism Spectrum Disorders

https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile


Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.


Thursday 27 August 2015

Cinnamon (Cinnamaldehyde), Mast Cells (Allergy) & Autism










A reader of the previous post on cinnamon left a helpful comment highlighting research that suggests yet another reason why Cinnamon might be an effective treatment for some types of autism.






Abstract
BACKGROUND:
Mast cells (MC) are main effector cells of allergic and other inflammatory reactions; however, only a few anti-MC agents are available for therapy. It has been reported that cinnamon extract (CE) attenuates allergic symptoms by affecting immune cells; however, its influence on MC was not studied so far. Here, we analyzed the effects of CE on human and rodent MC in vitro and in vivo.
METHODS:
Expression of MC-specific proteases was examined in vivo in duodenum of mice following oral administration of CE. Release of mediators and phosphorylation of signaling molecules were analyzed in vitro in human MC isolated from intestinal tissue (hiMC) or RBL-2H3 cells challenged with CE prior to stimulation by FcεRI cross-linking.
RESULTS:
Following oral treatment with CE, expression of the mast cell proteases MCP6 and MC-CPA was significantly decreased in mice. In hiMC, CE also caused a reduced expression of tryptase. Moreover, in hiMC stimulated by IgE cross-linking, the release of β-hexosaminidase was reduced to about 20% by CE. The de novo synthesis of cysteinyl leukotrienes, TNFα, CXCL8, CCL2, CCL3, and CCL4, was almost completely inhibited by CE. The attenuation of mast cell mediators by CE seems to be related to particular signaling pathways, because we found that activation of the MAP kinases ERK, JNK, and p38 as well as of Akt was strongly reduced by CE.
CONCLUSION:
CE decreases expression of mast cell-specific mediators in vitro and in vivo and thus is a new plant-originated candidate for anti-allergic therapy


In a later study by the same authors they identify Cinnamaldehyde as the main mediator of cinnamon extract in mast cell inhibition.



A chemistry note:

Cinnamon contains three major compounds (cinnamaldehyde, cinnamyl acetate and cinnamyl alcohol), which are converted into cinnamic acid by oxidation and hydrolysis, respectively. In the liver, this cinnamic acid is β-oxidized to benzoate that exists as sodium salt (sodium benzoate; NaB) or benzoyl-CoA.

As is often the case with natural substances with medicinal properties, it is unclear which constituent provides the benefit, or whether there is a synergistic benefit between them.

As I suggested in an earlier post, even though Sodium benzoate (NaB) has been shown to be the reason for some of cinnamon’s benefits and is widely available, I propose to use cinnamon itself.

The mast cell benefits of cinnamon come from cinnamaldehyde and may not be produced by the metabolite NaB.
  



Purpose

In terms of their involvement in allergic and inflammatory conditions, mast cells (MC) can be promising targets for medical agents in therapy. Because of their good compliance and effectiveness, phytochemicals are of great interest as new therapeutic tools in form of nutraceuticals. We found recently that cinnamon extract (CE) inhibits mast cell activation. Here, we analysed the effects of a major compound of CE, cinnamaldehyde (CA), on mast cell activation. 

Conclusions

CA decreases release and expression of pro-inflammatory mast cell mediators. This inhibitory action is similar to the effects observed for CE indicating CA as the main active compound in CE leading to its anti-allergic properties.



Conclusion

Today’s post gives a particular reason for people with autism, allergies and mast cell issues to trial cinnamon.

The only thing to be careful of is histamine intolerance.  This does affect several readers of this blog.

The main cause of histamine intolerance is an impaired histamine degradation caused by genetic or acquired impairment of the enzymatic function of DAO or HNMT.

One reader pointed out that the cheap 23andme genetic test includes the genes for histamine intolerance (this service is no longer available in all countries).

The sodium benzoate (NaB) produced by cinnamon is a DAO inhibitor and so will further impair histamine degradation in people with genetic impairment.  

In most people, even if they have allergies, a teaspoon of cinnamon will not affect their ability to degrade histamine.











Friday 7 August 2015

Has anyone tried Cinnamon (or Sodium Benzoate) for Autism?




I have written several posts about Cinnamon and its metabolite Sodium Benzoate. I know that some readers are now using it for its cholesterol lowering and insulin sensitivity improving properties that were shown in the clinical trials I highlighted.













But has anyone tried it for autism?


The first time I wrote about it I did acquire a big bag of the correct variety (Cinnamomum verum or Ceylon Cinnamon) and also a bag of the very high flavanol (epicatechin) cocoa.  My cinnamon trial was limited to seeing what it looked/tasted like when added to the Polypill concoction Monty, aged 12 with ASD, drinks at breakfast.  It was rather like adding a teaspoonful of fine sand, so not much “testing” took place.

Now that Monty has shown an ability, and even enjoyment, for pill swallowing, things are much simpler.  The cinnamon can be put inside gelatin capsules; it’s a little messy, but no great trouble.

Having recently been researching about the gene enhancers and silencers, which are controlled by the 95% of your DNA that rarely gets studied (the exome is the part everyone studies and some people test for abnormalities), it did occur to me that I already have two safe substances, that I have both researched and acquired, which have a gene expression enhancing effect.


Cinnamon “Experiment”

Even though summer is the wrong time to test anything in Monty, aged 12 with ASD, since his pollen allergy triggers a regression, I decided to make a trial.  I have 1 kg of this special cinnamon, and so it’s not like I need to ration it.

I gave about 2.5ml of cinnamon split into three daily doses using some gelatin capsules that used to be full of another supplement (choline).


Results so far:-

Complete absence of summertime bad behaviors, which are already 90% subdued by Verapamil, but do sometimes present themselves.

Interesting behavioral developments:- 


·        Like many people with autism, Monty likes order.  So turn off lights, shut doors, wash dirty hands etc.  The latest surprise was that when I took something from the rear of my car and he shut the tail gate (boot). Given the size of my car, for someone of his small stature, this is quite an achievement, since he really has to stretch on his toes.  This is the first time he has ever done this and now he does it every time.

·        Monty can brush his teeth and get dressed, but his clothes are sitting there on his bed.  The other day when told to go upstairs and brush his teeth, he returned fully clothed, having chosen/found his clothes all by himself.

·        On awakening, sometimes Monty might say “can I have a glass of water”, to which he might be told go downstairs and get water, and usually someone would go down with him.  Recently I find him in the early morning sitting at the kitchen table playing on his iPad with the glass of water he served himself with.

·        Piano playing also seems to be going very well, indeed on Wednesday after his piano lesson the teacher started telling me that she has taught 73 children with autism and never has she had someone start at his beginning level and progress so far.  This is clearly not down to cinnamon (it was greatly helped by bumetanide, atorvastatin and NAC), but why is she telling me this now, after over three years of lessons?

·        Speech for people with Classic autism, even when it develops, is always a little odd, reading a book out loud or singing does not mean you can speak.  It is as if the mother tongue is a foreign language and needs to be translated in your head. So for me it would be like speaking German.  It is my fourth language, I know lots of words, but I cannot think in German.

Many people with autism like to know their schedule. Today Monty was going to go swimming, amongst other things, but a change of plan meant we had gone to eat.  So I said to Monty “I am too full to go swimming, we will go later”.

A few minutes later as I stopped the car, Monty says “swimming when Dad feels better”.

There is nothing super clever in that statement, but it is not the sort of unprompted comment I usually get to hear for son number two.


These are all little steps and may be coincidental, but normally with Monty things go backwards in summer.  Even effective interventions appear to lose their effectiveness. 

I still keep an open mind on cinnamon, but I did just order a big bag of empty gelatin capsules.


Anybody else tried Cinnamon?

It would be useful to know from people who found that Bumetanide or Sulforaphane were effective for autism, whether cinnamon also has a positive effect.

There are several reasons why it may help:-

·        Change in NMDA signaling, affecting the excitatory/inhibitory balance
·        Affects gene expression related to oxidative stress (why cinnamon helps reduce cholesterol and improve insulin sensitivity)
·        Increases BDNF, Brain-derived neurotrophic factor  (aka “brain fertilizer”)
·        NaB (sodium benzoate) reduces Microglial and Astroglial Inflammatory Responses
·        NaB exerts its anti-inflammatory effect through the inhibition of NF-κB
·        NaB suppresses the activation of p21ras in microglia
·        NaB can also regulate many immune signaling pathways responsible for inflammation, glial cell activation, switching of T-helper cells, modulation of regulatory T cells

NF-κB is the master regulator of inflammation in the same way that Nrf 2 is for oxidative stress.

Incorrect regulation of NF-κB has been linked to cancer, inflammatory, and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory


In autism it seems that we want to activate Nrf2 but to inhibit NF-κB.  Safely inhibiting NF-κB is the Holy Grail for many diseases.


We covered RAS in earlier posts.  The RAS protein is abnormally active in cancer.

So called RASopathies are developmental syndromes caused by mutations in genes that alter the Ras subfamily.  RASopathies are often associated with autistic symptoms and/or intellectual disability/mental retardation.

Common inhibitors of RAS are statins and Farnesyltransferase inhibitors.  Most Farnesyltransferase inhibitors are expensive cancer research drugs, but one is gingerol.

Since statins do very clearly improve the autism of Monty, aged 12 with ASD, I did try adding gingerol as my “Statin plus” therapy.  At the dose I used there was no noticeable effect.

However, I now learn that “NaB suppressed the activation of p21ras in microglia”.  P21, RAS, and p21ras are different names for the same protein.  So it would seem that NaB is therefore a RAS inhibitor and perhaps a more potent one than gingerol.
   
Too much BDNF, just like too much lawn fertilizer, may not be a good thing.

BDNF is low in schizophrenia, but is thought to be elevated in “most” autism.
   



 Abstract
Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology of several neurodegenerative disorders. This study explores the anti-inflammatory property of cinnamon metabolite sodium benzoate (NaB) in microglia and astrocytes. NaB, but not sodium formate, was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF-α and IL-1β) and surface markers (CD11b, CD11c, and CD68) in mouse microglia. Similarly, NaB also inhibited fibrillar amyloid β (Aβ)-, prion peptide-, double-stranded RNA (polyinosinic-polycytidylic acid)-, HIV-1 Tat-, 1-methyl-4-phenylpyridinium+-, IL-1β-, and IL-12 p402-induced microglial expression of iNOS. In addition to microglia, NaB also suppressed the expression of iNOS in mouse peritoneal macrophages and primary human astrocytes. Inhibition of NF-κB activation by NaB suggests that NaB exerts its anti-inflammatory effect through the inhibition of NF-κB. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on iNOS expression, and NF-κB activation by hydroxymethylglutaryl-CoA, mevalonate, and farnesyl pyrophosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the anti-inflammatory effect of NaB. Furthermore, we demonstrate that an inhibitor of p21ras farnesyl protein transferase suppressed the expression of iNOS, that activation of p21ras alone was sufficient to induce the expression of iNOS, and that NaB suppressed the activation of p21ras in microglia. These results highlight a novel anti-inflammatory role of NaB via modulation of the mevalonate pathway and p21ras.

  



ABSTRACT Experimental allergic encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), the most common human demyelinating disease of the central nervous system. Sodium benzoate (NaB), a metabolite of cinnamon and a FDA-approved drug against urea cycle disorders in children, is a widely used food additive, which is long known for its microbicidal effect. However, recent studies reveal that apart from its microbicidal effects, NaB can also regulate many immune signaling pathways responsible for inflammation, glial cell activation, switching of T-helper cells, modulation of regulatory T cells, cell-to-cell contact, and migration. As a result, NaB alters the neuroimmunology of EAE and ameliorates the disease process of EAE. In this review, we have made an honest attempt to analyze these newly-discovered immunomodulatory activities of NaB and associated mechanisms that may help in considering this drug for various inflammatory human disorders including MS as primary or adjunct therapy.



Conclusion

Rather to my surprise, Cinnamon does seem to have a noticeable cognitive effect in the type of autism I am interested in.  It appears, rather like the statin, to promote improved adaptive behavior by reducing inhibition and increasing spontaneous thought and actual decision making.

Of all the many possible modes of action, I am thinking that inhibition of NF-κB and/ or RAS inhibition are most likely since the effect is very similar to that produced by the statin.

I will certainly continue with cinnamon and when my size 000 gelatin capsules arrive, I will look at different doses.  Currently the dose is about 2.5 ml split three times a day, using size 00 gelatin capsules.