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

Oxidative Stress in Diabetes Mellitus and the Role Of

Vitamins with Antioxidant Actions

“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)

Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity

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, E_hc (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 E_hc, 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

Reductive Stress Increases Reactive Oxygen Species Production in Cardiac Mitochondria: A Key Role of Thioredoxin Reductase

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.

Oxidative Shielding or Oxidative Stress?

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.