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Friday, 9 June 2017

Garlic in Autism – Miscreant Microglia?  ACE inhibition? or even Nitric Oxide?



Many people avoid garlic because it gives you bad breath, but if you eat enough of it, it can be a potent drug.



There is a substantial amount of research about garlic and general health - it is consistently positive. However, there is an odd resistance to tell people about it.  A good example is this quote from the website of the UK’s National Health Service.

“Studies using high concentrations of garlic extracts have been associated with improved blood circulation, healthier cholesterol levels and lower blood pressure, all of which reduce the risk of cardiovascular disease. However, current evidence does not support the use of garlic supplements to improve health.”

Which sounds like “garlic is really good for you, but don’t eat it”.
Garlic has numerous different modes of action that have a potential health benefit, the best known relate to your heart and circulation, but there are others. 

Garlic and Neurological Conditions with Activated Microglia

There is recent research showing positive effects on the activated microglia.  Activated microglia, the brain’s immune cells, is a feature of autism and other diseases, like Alzheimer’s.

Some people try and treat activated microglia in autism using therapies like:-

·        Minocycline

·        Ibudilast

Some researchers use garlic to try to minimize the damage caused by activated microglia.

They tend to use capsules that contain aged garlic.  It is important not to cook it and there is a difference between fresh garlic, aged garlic and steamed garlic. 



Table 1. Principal Organosulfur Compounds in Commercial Garlic Preparations
Product
Principal Organosulfur Compounds
Delivers allicin-derived compounds?
Fresh garlic cloves
Cysteine sulfoxides (Alliin)
γ-glutamylcysteines
Yes, when chopped, crushed, or chewed raw.
Minimal, when garlic cloves are cooked before crushing or chopping.
Powdered garlic (tablets)
Cysteine sulfoxides (Alliin)
γ-glutamylcysteines
Varies greatly among commercial products.
Enteric-coated tablets that pass the USP allicin release test are likely to provide the most.
Steam distilled garlic oil (capsules)
Diallyl disulfide
Diallyl trisulfide
Allyl methyl trisulfide
Yes
Garlic oil macerate (capsules)
Vinyldithiins
Ajoene
Diallyl trisulfide
Yes
Aged garlic extract™
(tablets or capsules)
S-Allylcysteine
S-Allylmercaptocysteine
S-1-Propenylcysteine
Minimal

  


  


Now, a new study finds that one of these compounds, called FruArg, may protect the brain from age-related disease like dementia and Alzheimer’s.

As a carbohydrate derivative of garlic, there’s a relatively high concentration of FruArg in aged garlic extract (AGE), the authors wrote — AGE is typically sold as supplements. Looking at isolated FruArg’s impact on brain cells, researchers from the University of Missouri found it could protect brain cells from an overexcited immune response caused by environmental factors like pollution and smoking, as well as normal aging, brain injuries, and drinking lots of alcohol.
“Microglia are immune cells in the brain and spinal cord that are the first and main line of defense in the central nervous system,” said lead author Zezong Gu, an associate professor of pathology and anatomical sciences at the university’s School of Medicine. “Unlike other mature brain cells that seldom regenerate themselves, microglial cells respond to inflammation and environmental stresses by multiplying. By massing themselves and migrating toward an injury site, they are able to respond to inflammation and protect other brain cells from destruction.”
But microglia also tread a line between benefiting the body and harming it, protecting only to an extent. A byproduct of their function is nitric oxide, a free radical. And when a lot of microglia are produced, so are nitric oxide molecules, which can lead to oxidative stress and inflammation within the brain and nervous system. As we’ve all heard before, however, antioxidants fight oxidative stress, and in this case, that antioxidant compound is FruArg. 

For their study, Gu and his colleagues applied stress to a cell model of microglial cells and then added FruArg to them once nitric oxide concentrations rose. They found the microglial cells “adapted to the stress by reducing the amount of nitric oxide they produced.” What’s more, FruArg also promoted the production of antioxidants, which then went on to protect and heal other brain cells. “This helps us understand how garlic benefits the brain by making it more resilient to the stress and inflammation associated with neurological diseases and aging,” Gu said. 

Full study:- 


Collectively, these results suggest that AGE and FruArg attenuate neuroinflammatory responses and promote resilience in LPS-activated BV-2 cells by suppressing NO production and by regulating expression of multiple protein targets associated with oxidative stress. 



Effects of aged garlic (AGE) extract and FruArg on gene expression and signaling pathways in lipopolysaccharide-activated microglial cells 

These effects could be modulated by treatment with both AGE and FruArg. These findings suggests that AGE and FruArg are capable of alleviating oxidative stress and neuroinflammatory responses stimulated by LPS in BV-2 cells.

  

Abstract

: The anti-neuroinflammatory capacities of raw and steamed garlic extracts as well as five organosulfur compounds (OSCs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglia. According to those results, steaming pretreatment blocked the formation of alliinase-catalyzed OSCs such as allicin and diallyl trisulfide (DATS) in crushed garlic. Raw garlic, but not steamed garlic, dose-dependently attenuated the production of LPS-induced nitric oxide (NO), interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). DATS and diallyl disulfide at 200 and 400 μM, respectively, displayed significant anti-neuroinflammatory activity. Meanwhile, even at 1 mM, diallyl sulfide, S-allyl cysteine and alliin did not display such activity. Inhibition of nuclear factor-κB activation was the mechanism underlying this protective effect of raw garlic and DATS. Analysis results indicated that the anti-neuroinflammatory capacity of raw garlic is due to the alliin-derived OSCs. Importantly, DATS is a highly promising therapeutic candidate for treating inflammation-related neurodegenerative diseases.

As expected, raw garlic extract inhibited NO, proinflammatory cytokine, and chemokine production by through suppression of NF-κB activation in LPS-activated BV2 microglia; it also had a potent anti-neuroinflammatory capacity. Additionally, steaming pretreatment abolished both the anti-neuroinflammatory capacity and alliin-derived OSCs formation of garlic simultaneously. In sum, this study demonstrates that alliinase catalysis and chemical transformation are essential for the formation of active OSCs, which are responsible for the anti-neuroinflammatory capacity of garlic. Based on above, it is suggested that consumers to crush or cut raw garlic before cooking in order to obtain more health benefits of garlic. As one of the most potent anti-neuroinflammatory components of garlic, DATS is highly promising for use as a dietary agent to prevent inflammation-related neurodegenerative disease. 



Garlic as an ACE inhibitor 

We saw in a recent post how too much angiotensin II is likely a problem in schizophrenia and some autism.  The biomarker of those affected would be high levels of IL-17a. 



There are numerous references in the literature to garlic being an ACE inhibitor, which will reduce the level of angiotensin II and hence IL-17 and IL-17a. 


Although garlic extract administration had no significant effect on serum glucose, it significantly strongly decreased the serum ACE activity. ACE activity was higher in diabetic than nondiabetic rats, but in diabetic animals treated with garlic extract, the elevation of ACE activity did not occur. These results suggest that garlic extract might have value as ACE inhibitor to prevent some vascular complications of diabetes mellitus.


So perhaps some people with autism, who respond to garlic are actually not feeling the microglia effect, but actually the angiotensin II reducing effect. 


Activation of calcium-dependent nitric oxide synthase and the subsequent production of nitric oxide is probably the most novel mechanism yet claimed by which garlic can exert its therapeutic properties.
   

Conclusion  

Garlic has numerous health benefits and different types of processing lead to very different chemical compositions.  So it does depend how you take your garlic.

Does any type of garlic provide a benefit in any type of autism? 
For one reader fresh garlic is effective in treating autism, whereas aged garlic is not; this is not what she expected. This would of course suggest something about its mode of action. 
Perhaps some people are actually benefiting from a reduction in angiotensin II.  Or maybe it is production of nitric oxide?
There are actually other natural ACE inhibitors that you might be using by accident.
People trying to make tasty drinkable sulforaphane, using the Australian mixture of broccoli and pomegranate powders, are actually also making an ACE inhibitor.  

The results suggest that the PJ extract could prevent the development of high blood pressure induced by Ang II in diabetic rats probably by combating the oxidative stress induced by diabetes and Ang II and by inhibiting ACE activity.




All we can say is some people with autism respond to specific types of garlic, but nobody can be sure what the mode of action is; there are several possible credible explanations.  





12 comments:

  1. I suppose you could mix fresh garlic in pasta sauce. My son loves tomato based pasta sauce, but I am not so sure my wife would be up for our kids having dragon breath 24/7. How much garlic do you think one would need for this intervention?

    I also came across an interesting paper I read on Tourette Syndrome:

    http://www.cell.com/neuron/fulltext/S0896-6273(15)01127-7

    and one thing I did not know of before was that GABA antagonism in the nucleus accumbens will lead to a big increase in extracellular dopamine. In this particular paper they had found that vocal tics orginated from disinhibition of the nucleus accumbens leading to synchronization between the nucleus accumbens and the anterior cingulate cortex, part of which is responsible for initiating speech. They could reliably produce this pathological alpha brain rhythm by applying biciculine in a select part of the nucleus accumbens.

    This suggests, another avenue of reducing excess dopaminergic signaling is to simply improve GABA inhibition (obviously the most discussed topic on this blog). Fix GABA inhibition and you may help to normalize dopamine issues via preventing an excess amount of activity in the mesolimbic pathway. Of course many GABAergic drugs have many side effects and addiction issues, so brute force solutions are probably going to do more harm than good, but perhaps this is where much of the improvement with low-dose clonazepam occurs in that by improving GABA inhibition in the nucleus accumbens, you also reduce excessive dopamine signaling as well.

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    1. Tyler, it would be good to get feedback from people who have experience of using garlic. There are many.

      The question is what part of the garlic might give a potential health benefit. If it is allicin it will be hard to avoid the smell, because it makes more than just your breath smell.

      There are odorless garlic supplements.

      As soon as you crush or cut a clove of garlic, the cell walls are split so that an enzyme called alliinase is released, which converts alliin into allicin. Allicin gives garlic its smell.

      Aged garlic has little allicin, so should smell much less.

      I think some people cut a clove of garlic into thin slices and hide it in food. If it is not cooked you should need very little. You could add it to the pasta sauce just before serving.

      I would see if it does any good and then worry about the smell.

      Aged garlic works via a different mechanism and so you might try that as well.

      Delete
  2. Hi Peter, Tyler, and community,

    I've actually been using kyolic aged garlic as part of my treatment protocol for a while, and my daughter has been steadily improving, but I use so many things I can't say if this has any impact. I will say that we think we've seen some improvement lately after adding L-Aspartic Acid thanks to your recommendation Tyler (always appreciate your input!).

    I have to be honest, I didn't realize aged garlic lacks Allicin, so I too will think about how to get that into my daughter's diet (she's very picky, as many of our kids are, about their food)

    What I can suggest is a recipe for those in the community who want to try fresh garlic but don't know how to add it into their kids diet.

    A while back, my mom made an amazing appetizer / side dish (it can also be a dip or sauce) that we loved, and I looked online and the following is the closest recipe I could find:

    https://www.thespruce.com/yogurt-garlic-sauce-recipe-2355489

    When my wife and I tried to make it, we kept adding fresh minced garlic as it never felt garlicky enough - then we realized why - it takes a while for the garlic flavor and intensity to permeate the dish. After a few hours, we realized we had put in waaaaay too much garlic. The benefit of this experience is that you can load this up with fresh garlic, and if you give it fast enough, your child will get tons of garlic before the flavor permeates the dish. Don't let it sit as the longer it sits, the much more garlicky it becomes and the kids may not like it as much. It's actually quite refreshing, especially if you serve it cool, and include little bits of cucumber and dill.

    Hey, it's delicious so mom and dad may like it too ;-)

    AJ

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  3. Was going through search results on stuff relating to autism and the medial prefrontal cortex and happened to stumble across this gem:

    Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism

    https://www.readbyqxmd.com/read/27638451/agmatine-rescues-autistic-behaviors-in-the-valproic-acid-induced-animal-model-of-autism

    This paper was released this year and since I use small amounts of agmatine today (larger amounts seemed to increase cognition considerably but seemed to have tolerance and withdrawal issues that affected behavior) I found this paper pretty amazing.

    The reason I thought agmatine would be a good idea was its effects on the endogenous opioid system which much research suggests is dysregulated in autism. In this paper, they postulate it is the NMDA antagonism that seems to provide the most benefit.

    I would be interested if other people would trial this (agmatine sulfate which is a popular supplement for its vasodilating effects and which you can get at bulksupplements.com) to see if they have had same or similar results as I have had. Like I said before, when I used it in sufficient amounts I got very lucid and acute cognitive gains, but this didn't seem to last more than a few days then I had really bad irritability. Of course, the behavior issues could always of been something else since controlling for variables is really hard to do (sleep, etc.), especially when you are already employing various interventions.

    In light of this paper, I will probably try and increase the dose and see what happens since my son does not have to attend school for a few more months (summer break here in the USA).

    ReplyDelete
  4. Hi Tyler,

    Count me in for the trial!

    I'm ordering it today, will keep everyone posted. A boost in cognition would be a game changer for us, so fingers crossed

    AJ

    ReplyDelete
  5. Hi, Dear Community

    I had a severe allergic reaction to bumetanide, thus i can't take it anymore. Are there any alternatives? Would taking Torsemide be equally efficient?

    I'm helpless.:( What should i do?

    Clara

    ReplyDelete
    Replies
    1. Clara, you might already have read Agnieszkas comment that bumetadine in some brands contains yellow colourant (which can be really bad for some people). Maybe worth to check up what your bumetanide form contains?
      /Ling

      Delete
    2. Clara, if you have an allergy to sulfonamide drugs, the loop diuretic normally used in the US is Etacrynic acid. It blocks NKCC2, if it also blocks NKCC1 and does not block KCC2 and crosses the blood brain barrier it should do the same job as bumetanide. If you are allergic to bumetanide rather than the coloring, you may also be allergic to Torsemide. You would also be allergic to many other drugs that contain sulphur/sulfa.

      There is no proven direct alternative to bumetanide, so you will have investigate.

      Delete
  6. I don't like the flavor of fresh garlic so can i eat honeyed garlic instead? I think that it's more nutritional than just eating garlic.

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    Replies
    1. It all depends what chemicals you want from the garlic. If you want Allicin it will taste/smell of garlic, unless it has some special coating.

      Delete
  7. I use garlic extensively. For myself, I crush garlic and swallow it from the spoon with water like you would a handful of pills. (eat something before you do this and after to avoid getting a feverish sick come over you...if you even eat half a piece of toast or anything you will be fine.) Start small. It is powerful. For my 2 sons with autism they of course are not going to swallow raw garlic. So the next best thing is loads of crushed garlic simmered for 2 minutes in butter and we put it on our popcorn and they all eat it. You can strain the garlic out and the butter will be super garlicky and use it on your popcorn to get kids used to it. When we started this we had cut out all treats so this became a treat to my kids. WE also use lots of crushed garlic in pizza sauces, on pizza, pretty much in everything my boys eat. Of course crushed raw garlic is the most powerful (in 3 days taking a crushed spoonful swallowed with water, it will kill any infection I have), but crushed garlic briefly cooked is still powerful and can become a delicious taste for children. We find garlic to be our most powerful tool, and next would be cucumbers, celery etc. for their powerful effects on neuro inflammation. Don't let perfection stop you...progress, not perfection. Start with crushing garlic and taking one tiny piece and swallowing it, or if you cant handle that, cook it in butter and it become the yummiest thing in the world, as do onions cooked in butter. Onions and garlic are very powerful food medicine for kids with autism. ANd all of us.

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    1. Megan, What benefits do you see in your boys specifically? Do you get short term effect, long term effect, etc. Thanks, Maria

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