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Tuesday, 29 September 2015

Is Reductive Stress a common feature of Atypical Autism?







Lay summary:


·        Oxidative injury can be caused by both oxidative stress and the opposite, reductive stress. 

·        Both extremes of redox balance are known to cause cardiac injury

·        Both extremes of redox balance disrupt mitochondria

·        It appears that either extreme of redox balance may occur in autism.


Reductive stress is the opposite of oxidative stress and I am calling it “Atypical Autism” because all the research shows that the great majority of autism and indeed schizophrenia is associated with oxidative stress.


NAC and stereotypy/stimming

Most young children with classic autism exhibit stereotypy/stimming; this kind of obsessive, repetitive behavior can really get in the way of daily life.  You can use the principles of ABA to limit or redirect this behavior, but it turns out that there is a biological cause for it.

Taking NAC (N-acetylcysteine) increases the body’s production of GSH, its main antioxidant.  Once the intake in NAC is high enough to shift the balance between oxidants and antioxidants the stereotypy/stimming stops all by itself.  This does not mean that the child will still not enjoy repetition.

In some children it takes quite a lot of NAC before any effect is visible, one parent mentioned no effect until 1,800 mg a day.  In other people, the effect starts with the first 600mg and just keeps growing before plateauing around 3,000 mg a day.

This variation makes sense; it all depends just how out of balance the oxidants/antioxidants were at the outset.

If you have access to lab testing you would look at the ratio between GSH and GSSG. This would give you a good indication of your Redox balance.


NAC and Nrf-2 Activators making things worse

In a small number of cases NAC and Sulforaphane/broccoli (a Nrf-2 activator) actually makes things worse.  This does not mean more stereotypy/stimming; I think it quite likely that in those people, stereotypy/stimming are not a feature of their "autism",

Worsening autism can be an increase in anxiety.

Anxiety is often a feature of Asperger’s.

Anxiety is not an issue at all in many cases of classic autism.

NAC is itself an anti-oxidant as well as increasing GSH.  

Sulforaphane/broccoli activates Nrf-2 which in turn affects the genes that control the antioxidant response.  If this make things worse, it seems likely that there was no oxidative stress; either redox was in balance or they are already at the other extreme, reductive stress.


Some Science

The summary below is from the following paper




“Whenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption.

This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells.

Therefore, ROS formation is a physiological response to stress.

The term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal. Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA. Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism.”


But reductive stress also leads to ROS formation


Reductive Stress and Oxidants

Reductive stress can be just as bad as oxidative stress and, very surprisingly, can have exactly the same negative effect on mitochondria (see below)




Abstract

To investigate the effects of the predominant nonprotein thiol, glutathione (GSH), on redox homeostasis, we employed complementary pharmacological and genetic strategies to determine the consequences of both loss- and gain-of-function GSH content in vitro. We monitored the redox events in the cytosol and mitochondria using reduction-oxidation sensitive green fluorescent protein (roGFP) probes and the level of reduced/oxidized thioredoxins (Trxs). Either H2O2 or the Trx reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), in embryonic rat heart (H9c2) cells, evoked 8 or 50 mV more oxidizing glutathione redox potential, Ehc (GSSG/2GSH), respectively. In contrast, N-acetyl-l-cysteine (NAC) treatment in H9c2 cells, or overexpression of either the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) or GCL modifier subunit (GCLM) in human embryonic kidney 293 T (HEK293T) cells, led to 3- to 4-fold increase of GSH and caused 7 or 12 mV more reducing Ehc, respectively. This condition paradoxically increased the level of mitochondrial oxidation, as demonstrated by redox shifts in mitochondrial roGFP and Trx2. Lastly, either NAC treatment (EC50 4 mM) or either GCLC or GCLM overexpression exhibited increased cytotoxicity and the susceptibility to the more reducing milieu was achieved at decreased levels of ROS. Taken together, our findings reveal a novel mechanism by which GSH-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.—Zhang, H., Limphong, P., Pieper, J., Liu, Q., Rodesch, C. K., Christians, E., Benjamin, I. J. Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.


Reductive Stress in Disease





Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production.

However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADP/NADPH and GSH/GSSG. Here we have further explored, using isolated intact and permeabilized cardiac mitochondria and purified NADP-dependent enzymes, how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems.

We show that one of the latter components, thioredoxin reductase 2, is converted into a potent NADPH oxidase during reductive stress, due to limited availability of its natural electron acceptor, oxidized thioredoxin. This finding may explain in part how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury.



Reductive stress: A new concept in Alzheimer’s disease



Reactive oxygen species play a physiological role in cell signaling and also a pathological role in diseases, when antioxidant defenses are overwhelmed causing oxidative stress. However, in this review we will focus on reductive stress that may be defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. This may occur in hypoxia and also in several diseases in which a small but persistent generation of oxidants results in a hormetic overexpression of antioxidant enzymes that leads to a reduction in cell compartments. This is the case of Alzheimer’s disease. Individuals at high risk of Alzheimer’s (because they carry the ApoE4 allele) suffer reductive stress long before the onset of the disease and even before the occurrence of mild cognitive impairment. Reductive stress can also be found in animal models of Alzheimer’s disease (APP/PS1 transgenic mice), when their redox state is determined at a young age, i.e. before the onset of the disease. Later in their lives they develop oxidative stress. The importance of understanding the occurrence of reductive stress before any signs or symptoms of Alzheimer’s has theoretical and also practical importance as it may be a very early marker of the disease.








 Oxidative Shielding

I was surprised that one of the very few papers to mention Reductive Stress is by Robert Naviaux, a well-known autism researcher.  He is the one behind Antipurinergic Therapy and Suramin as a therapy.  I just promoted him to my Dean’s List.




Abstract
In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed “oxidative shielding” response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health

In his paper Naviaux is quite right, it is much better to treat the cause of the oxidative/reductive stress; right now I do not know how to do this.



Oxidants as a therapy?

Most people with autism should avoid oxidants.

They should avoid paracetamol/ acetaminophen/Tylenol, because it depletes the body’s main antioxidant, GSH.  This is the mechanism behind why, at very high doses, it can kill you.  If they put NAC inside Tylenol, people could not use it to kill themselves.

One surprising oxidant that some people use to “treat” autism is MMS a, toxic solution of 28% sodium chlorite.  Is this the reason why there is such a cult therapy for drinking “bleach” to “cure” autism?

The only reason I mention this is that one reader whose child responded negatively to NAC and Sulforaphane had responded very positively to three doses of MMS some years ago.

For people with autism, and apparent reductive stress, I certainly do not suggest drinking bleach, but a few days of paracetamol / acetaminophen, as if you had the flu, might tell you a lot.

For most people with autism, Ibuprofen is a much better choice of painkiller;  it does not deplete GSH.









20 comments:

  1. Thank you so much for this post. I spent the day trying to read the scientific literature on reductive stress and Nrf2 stress response pathway, but as an Arts grad I found it really tough going.

    So what are the practical steps you should take to dampen Nrf2 activity and reductive stress? Is it just to be cautious in your use of anti oxidants and occasionally use an oxidant like paracetamol? And definitely avoid supplements known to activate Nrf2. I had always dismissed MMS as nonsense (anything with the word miracle in its name concerns me) but this new information about reductive stress and oxidants is really interesting.
    Nina

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    1. Nina, before getting too far into the science of treating reductive stress, I think it is well worthwhile seeing if giving paracetamol for a few days has any positive effect.

      If it did help, it might be the best solution. The other things would be inhibitors of glutathione synthesis, like buthionine sulfoximine.

      The problem of prolonged use, or overdose, of paracetamol is that if GSH is reduced too far, there can be liver and kidney damage. In someone with far too much GSH being produced, they are by definition, within reasonable limits, protected against such harmful effects.

      Most of medicine is trying to find ways to activate Nrf2, for example by reducing something called Keap 1. In reductive stress you would want to do the opposite.

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  2. Hi Peter -- you mention stimming -- how do you view stimming vs. chorea (from GAS mistakenly attacking basal ganglia) which are purposeless and intermittent --(like in Sydenhams Chorea)? Will chorea be responsive to oxidative stress helper agents like NAC? Ibuprofen and Tylenol are both mentioned to help stem inflammation in different ways I think?

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    1. Good questions. Tics, OCD and stereotypy all get mixed up together, but the causes can be entirely different. Since most people have only one child affected they are not aware of the difference.

      Much is known. For example Trichotillomania, which is compulsive hair pulling, is often caused by oxidative stress and responds to NAC.

      Some things defined as OCD are stereotypy (and respond to NAC) and others are really tics and more like Sydenhams Chorea (should not respond to NAC). Some problematic behavior like breath holding is probably stereotypy, it is easy to find out.

      The subject of GAS (group A streptococcus) and rheumatic fever is interesting and clearly underlies many types of chorea/tics. There will soon be a post on GAS and autism.

      Some types of tic, like foot flapping, can be caused by completely different things like low ferritin levels.

      So to answer your question I do not think NAC will help chorea, if it really is chorea.

      Ibuprofen and Tylenol are different. Ibuprofen has the anti-inflammatory properties and is also a PPAR gamma agonist. In some people with autism, Ibuprofen is effective all, or part of the time. In my son it helps some of the time and I found I could substitute another/safer PPAR gamma agonist and get the same effect. I use tangeretin/Sytrinol. This has nothing to do with tics/chorea/OCD, it relates to microglial activation.

      In all the people with oxidative stress Tylenol should be avoided, since it will make this imbalance worse.

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    2. Is the person experiencing chorea unaware or barely aware of their actions?Maybe unable to control them? I think this may be the dividing line.I go back to my own experiences with head banging and blackouts that led to wandering,that were due to undiagnosed seizures.

      You talk about classic autism and regressive autism of a metabolic/mitochondrial nature,but there is yet another type of autism that you do not talk about.There is autism that is purely,or mostly autoimmune.Autism cased by an autoimmune encephalopathy,usually seen in children born to mothers who have systemic autoimmune disease,like lupus,MS,or type 1 diabetes.In such families there is always a history of autoimmune disease.There has only recently started to be significant research into this subtype of autism.

      Chorea can sometimes be due to cerebral vasculitis,that is part of an autoimmune encephalopathy.

      Delete
  3. Peter,

    Have you investigated the use of CBD rich Hemp Oil as a therapy for epilepsy and now Autism? CBD rich Hemp Oil has received a lot of attention in the US press lately, mostly due to the case of Charlotte Figi, a little girl who was having 300 grand mal seizures a week that was reduced to 2-3 times a month with Hemp Oil.

    http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/

    The Hemp oils now being manufactured are rich in CBD and contain very little amounts of THC. So they are not psychoactive at all. CBD claims to have the following mechanism of action:

    The utility of CWHO (this is the brand of hemp oil) may be mediated in part by the
    endocannabinoid system (ECS), a set of cellular receptors and
    modulatory lipids present throughout the body. There is evidence
    linking the ECS to pain, memory, appetite, energy balance and
    metabolism, stress response (exploration, social behavior, and
    anxiety), immune function, female reproduction, autonomic
    nervous system function, thermoregulation, and sleep [1].
    CBD is a major cannabinoid that appears to have a wide range
    of potentially therapeutic effects [2]. CBD acts as an indirect
    antagonist of CB1 and CB2 receptors and is an inverse agonist of
    CB2 [3’4]. It also acts upon other receptors [5], including 5-HT1A
    receptors [6], which mediate antidepressant, anxiolytic, and
    neuroprotective effects, and opioid receptors, which mediate
    pain (analgesic) effects [7]. CBD may reduce symptoms of
    schizophrenia via stabilization of NMDA receptor brain circuits,
    which interact with GABA and Norepinephrine actions [8’9]. In a
    small double-blind study, CBD was shown to be associated with
    changes in regional brain blood flow and reduction in social
    anxiety [10].blood flow and reduction in social anxiety [12].

    I was curious to get your take on this thinking that you probably have already investigated this. However, I was surprised to see very little mention of this potential therapy in your blog. Check it out. I will be ordering some very soon and trialing it.

    https://cwbotanicals.com/
    https://www.theroc.us/research


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    1. JB, there is a drug based on CBD called Epidiolex in stage 3 trials for certain types of Epilepsy, including Dravet Syndrome. So that means there should soon be some solid reliable information on its effect

      http://www.gwpharm.com/Epidiolex.aspx

      It has been known for 40 years that CBD can improve some epilepsy.

      We saw in an earlier post that LSD many years ago was also shown to have some benefit in some people with autism. Nobody talks about this.

      I think CBD does look interesting, particularly if you have seizures. But you want CBD without any of the other ingredients of cannabis.

      Long term use of cannabis results in marked negative psychological effects.

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  4. When you say CBD without any of the other ingredients of Cannabis, are you referring to THC, or that and other substances? If THC is the main concern, there are companies now effectively breeding out the THC and enhancing the CBD levels. Check out https://cwbotanicals.com/. Their manufacturing standards are very impressive.

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    1. There are numerous substances within cannabis and some may be good and others bad. I am no expert. The product you refer to is quite expensive. Let us know if it is effective.

      Delete
    2. Hi JB,

      We tried the high CBD oil for my daughter from December '13 to May '14. It did not reduce the frequency of seizures, but we thought it might be preventing the progression from a simple seizure to a secondary tonic clonic. But the data after a few months of use showed that it was not quite so. Moreover, we were already using progesterone at that time, and had made the decision to start on verapamil, followed by bumetanide etc. so we stopped using it. CBD suppresses the activity of some of the p450 enzymes which are responsible for metabolizing most medicines, and also in the synthesis of most hormones. This is one of many things about cannabis that is not well studied and very little is known, and If your child is on other meds please monitor carefully while using cbd.

      'Charlotte's Web' as originally used by Charlotte Figi was a cannabis strain, not hemp. Cannabis is highly regulated, and it is very difficult to ship across states in the US. Hemp is not regulated as a restricted substance or medicine and can be grown and distributed easily. Even though cbd can be extracted from hemp, it is a very different substance, there are so many other compounds including kaempferol that are present in cannabis. What Charlotte Figi had would be quite different from the current 'charlotte's web'.

      RG

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  5. Hi Roger, Yes, he is often unaware of the chorea or is intermittent. The one clue is always milkmaid grip or hands moving like piano playing fingers when there is a flare. Sydenham's chorea is a type of autoimmune condition with encephaltis involved, and just as you noted -- docs are starting to wonder if it is broader and cerebral vasculitis is the better diagnosis and treatment. Who do you follow in this area and what are the treatments that you are effective? Is oxidative stress involved in this too? Is the mitochondrial involved? All in the last few days! Thanks very helpful!

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  6. Acetylcysteine is used mainly as a mucolytic, protects against acetaminophen overdose-induced hepatotoxicity by maintaining or restoring hepatic concentrations of glutathione.

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  7. Hi peter, Nandini responded very well to NAC. The therapist who comes to our home is very impressed. She feels Nandini is much more "happy" and willing to comply after taking NAC. Nandini also wants to talk a lot with NAC in her system. It's like she is suddenly aware of people around her and tries to communicate (rather loudly).But I don't see much improvements in OCD. Right now I give 500mg of NAC in the morning and 500mg in the afternoon. I'm thinking about increasing the dosage...and I have one more question for you..Can someone with mitochondria based autism still have high cholesterol levels?

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    1. NAC has a short half life, so it will work better when given more frequently, for example every 4 hours. There is also sustained release NAC. I think you can have high cholesterol and mitochondrial dysfunctions.

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  8. Peter--My son is a classic American-style "borderline case." He is undiagnosed and high functioning. No speech delays. No apparent cognitive deficits. No stereotypies (other than thumb sucking at night, which may or may not be one).

    His main deficits are emotional regulation (aggression) and some mild social difficulties.

    Would you think that NAC would be beneficial for this presentation of symptoms? Furthermore, would you go so far as to say that NAC is *contraindicated* for people without obvious stereotypies?

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    Replies
    1. Andrew, just buy some and try it. It is widely used even in very young children for other conditions.

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  9. Hi Peter,
    I tried NAC for a month for my son and the result was pretty disastrous: more aggressive behaviour and obsessive talk. I have to say that B12, DMG, TMG, they all made things worse in the past, so perhaps my son has reductive stress rather than oxidative? So if I try paracetamol and it works, does that mean he can keep on taking it indefinetely? I am confused, because he was prescribed the NAC to help detox from pesticides that came up on his hair test...
    Thanks, Giovanna

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    Replies
    1. Giovanna, I am not sure hair tests have any scientific validity. Long term use of paracetamol would be unwise. Just see if it makes him better for a day or two. If it does nothing, then perhaps his redox status is just right. Then you need do no more about it.

      Delete
    2. Thanks for your reply, Peter. I did hair test because I cannot do blood tests myself and the GP wouldn't think there is a good reason to do it anyway. The lab who tested his hair is called Bionetics, it's in England and they seemed genuine. A lot of people think that homeopathy has no scientific validity and I used to agree until I tried it, so there you go...But apart from that, my son is in a much better mood with paracetamol, second day today: 250mg in the morning and 250mg after lunch. So where do I go from here? I know he can't take paracetamol all the time. I also know his liver is overloaded and cannot detox by itself: his urine Ph is way too alkaline. Bioray has a range of kids products designed to detox gently and support the GI system, like Cytoflora, but the ones specific for the liver make my son more irritable again, he seems to be very sensitive to even one drop a day of the LiverLife. I don't thing my son has "classic" autism; he was diagnosed autistic based on his speech delay and occasional aggressive behaviour, but there were no other autistic symptoms, but the pediatric docs couldn't elaborate on the dx at all and there is no follow up. I am really grateful for the bloggers like you who put their knowledge out there, it really helps. Giovanna

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    3. Stop the paracetamol, wait a few days and then repeat with ibuprofen. Ibuprofen does not affect GSH. If his behaviour also improves with ibuprofen, then reductive stress is not the issue. If he responds well to paracetamol but not ibuprofen, that is relevant.

      One explanation would be reductive stress, which does exist. Some people’s heart disease is known to be connected to reductive stress.

      https://www.sciencedaily.com/releases/2013/10/131011135038.htm

      First you would need to be sure that you have reductive stress. You could measure GSH and GCCG, but that would need your doctor.

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