Suramin: A Stress Perspective of this Very Old Drug and Autism

This is a study to get REALLY excited about.  Not only the potential (with funding) for drug possibilities, but its potential for uncovering the underlying mechanism for autism.

Let’s talk about that.  The drug, Suramin, is over 100 years old and was used for African Sleeping Sickness. Sleeping Sickness is a parasitic infection from the Tetse fly that attacks the blood and neurological systems resulting in death.  It’s unclear exactly what Suramin does, but it is suggested in humans to reverse the messaging of what the researcher’s theoretically call the “Cell Danger Response“. The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm.

Bradley J. Fikes of the San Diego Tribune has written several excellent articles on the subject and the researcher. Dr. Robert Naviaux, professor of genetics in the departments of medicine, pediatrics and pathology of the University of California San Diego.

Fikes interviewing Dr. Naviaux:

Question: What is the purpose of the study?

ANSWER: The first thing you need to know about our paper is that it is not about suramin. Our research is aimed at finding a unifying cause for autism and an explanation for why it, and nearly 20 other chronic diseases, have been increasing over the past 30 years.

Suramin partly works through the Purigenic system. Purigenic signalling is a very primitive and ancient pathway within our stress defense system.  One mechanism of action of Suramin, like other anti-parasitics, could be that it is an antioxidant. Antioxidants have the potential to kill parasites such as these.  Surmanin has a very powerful antioxidant action when used for other conditions like arthritis (study). And this could be the same mechanism we see in autism.

This is additional evidence for the Stress Perspective of Autism which I have written about, as a person with autism, going on 10 years.

The Purigenic signalling is the very cellular-most level signalling of a response to stress.  There are of course many others ways in which we see this type of stress leading to autism. Including the amygdala, HPA axis, BDNF, oxytocin, mTor, Glutamate signalling and any number of susceptible genes to stress signalling. But this is evidence to the very core of what is going on, quite definitive if it holds true.

Fikes again interviewing Naviaux:

QUESTION: How is purinergic signaling connected to the CDR?

ANSWER: In a second discovery from the lab, we found that extracellular nucleotide signaling called “purinergic signaling” maintains the CDR. This led us to the possibility of a unified approach to the treatment of autism.

Antipurinergic drugs can treat the abnormal metabolic syndrome that causes autism by sending a cellular “all’s clear” or safety signal like the one that is announced when a fire is extinguished, telling you it is safe to return to school.

Suramin is just the oldest antipurinergic drug available, and the only one that inhibits the particular purinergic receptors that cause autism. Many more antipurinergic drugs are in development. Suramin is just the first of a whole new class of medicines, like the first statin for high cholesterol or the first beta blocker for high blood pressure.

QUESTION: How does suramin work?

ANSWER: Pharmacologically, suramin has several actions. One of its best-studied actions is as an inhibitor of purinergic signaling. Inside the cell, nucleotides like ATP and UTP are energy carriers and important molecules in normal metabolism. Stressed cells release ATP and other molecules made by mitochondria into the extracellular space through channels in the cell membrane.

Extracellular ATP (eATP) is an ancient danger signal. It is called a “damage associated molecular pattern” or DAMP. When too much eATP is released, it binds to purinergic receptors and activates the CDR.

Suramin inhibits the binding of eATP and eADP to these receptors and sends the cellular equivalent of the “all’s clear” or safety signal. In this capacity, suramin and other antipurinergic drugs are a kind of molecular armistice therapy, signaling the cellular war is over, the danger has passed and cells can return to “peacetime” jobs like normal neurodevelopment, growth, and healing

We could certainly see this as further evidence that at the heart of autism is a stress adaptation. This is a major potential discovery.  Autism as a function of oxidative stress. While I may rail against reductionism and linear thinking, these types of singular points of evidence do exist, as is demonstrated by this study.  As a matter of fact many studies and researchers are converging on this conclusion (of autism as oxidative stress). However, the assumption is to see autism when a stress creates damage to a cell or a system. In this particular study it is suggesting that stress and this cellular system is turned on and turning it off could solve some problems, which is true.  However, some may mistakenly assume that this means something is broken in autism and we can simply fix it.

While we can reduce something down to the smallest variable and potentially see the cause (or at least the causal mechanism at the smallest level). I had always suspected it would exist, and this purigenic signalling, mitochondrial function and “Cell Danger Response” may be it.  It is very exciting. However, what I continue to warn against in reductionism is that when we have points of facts, we tend to only see the facts in an on or off fashion. Instead of the larger picture of what those facts need to be plugged into. In this case the larger picture is the story of Autism.

Because stress isn’t a single point. Stress is about the communication between us and the environment. Getting our facts straight and making adjustments accordingly.  Stress is about motivation, processing information and making good decisions.  It is clear that if a cell is constantly in “danger mode” it can do little else. This is problematic and can lead to many (let’s say here co-morbid) conditions and features of the negative symptoms and diseases of immune, inflammation and digestion we find in the autism spectrum and beyond.

This is the difficulty thinking in linear terms to the exclusion of the nonlinear world we live in. Many will jump to the conclusion that if autism is stress (damage) then we need to stop the stress (via get rid of toxins or potentially via antipurigenic drugs) and we can solve autism (which is not the conclusion of this research). Unfortunately that logic is from the old paradigm and stress is much more complicated. By the time stress has adapted a system, you can’t simply turn off the stress to fix it. Stopping the reactions of stress, such as the “danger signal” can be of immense benefit and we see that from the study. What we also learn is that turning this off ALONG with other therapeutic interventions will likely find the most benefit. As we can imagine. A strong antioxidant on an individual that has amplified stress processing could be immensely helpful. And we see additional evidence of this in studies of antioxidants targeting other signalling stress hubs such as Curcumin, Phenols, Acetylcysteine, Resveratrol and Sulforaphrane, which are showing some success in treating aspects of autism.

But several questions remain about side effects (such as skin rash) and completeness of these interventions, such as… is the danger signal on for a reason? has the danger signal irrevocably adapted the system to be balanced in its own way? just how many steps, new adaptations and rebalances will have to happen to get them onto a better this presumably better track of stress balances? I would guess this will take a very concerted, systematic, step-by-step and individualized care. Interventions that take stress mechanisms, such as complex feedback systems, oxidative and antioxidant strategies, social enrichment, occupational therapies, etc. into consideration. (Read the reaction of subjects from the parents perspective from the Tribune)

So while the linear cause of autism is being shown to be stress, the nonlinear cause, the cause within the cause, is the system itself. We now have a general culprit and the unifying core mechanism, but we still have to transfer that information to a systems model, and in a systems model, the system is always its own cause.  Stress is just the instigator, the ether that the actions exist in.  Stress has to act on some thing in order to create that thing, that thing being autism. So some form of autism HAS to exist in order for stress to create an autism we see as a disorder… that form is likely the “Peripheral Minds” (See more on this theoretical model).

Theory of Peripheral Minds

The medical interpretation of autism is often one of weakness.  That “well they had an underlying mitochondrial disease”…. however this doesn’t explain the entirety of the spectrum. Nor does it explain the traits and features that are positive. What does, is stress as a framework or model for understanding the complex dynamic of amplified traits from this constant or intermittent “danger signal” being activated.

So if we hypothesize that the core of autism is the BAP, or Peripheral Minds (in short form “creative minds”), that are unique (from the average 40% of population), then we could theorize that those minds are more particularly sensitive and vulnerable to stress.  Autism could be seen as a stress-adaptation because of a combination of stress impacts and decreased resilience.  The core of autism is the unique thinking type because this creates the unique responses to stress.

If we know that stress is the cause and different people handle stress differently.  We could look towards “Peripheral Minds” via evidence to be found in Behavioral Genetics,  Personality Research and Stress Resilience.

In furthering our discussion of how our current medical model medicalizes autism as a vulnerability or weakness. As a result of a flaw in the system creating a disease. Hence the many articles touting this as a “cure” for autism (India Today, MMN, Seeker). Which is unequivocally incorrect. Autism isn’t a disease, nor does it fit in that model. On the other side, Autistic advocates will claim that autism is “just different’. But looking at it from a Peripheral Minds Stress Perspective, these minds are the starting points of this difference, which then become amplified minds under stress.  But it’s not because they are weak or damaged, but merely because their phenotype personality handles stress differently. “Autism Traits” which depending on the stress, how long and how you adapted can become “Autistic Dysfunction”. (We can see an example of this sensitivity susceptibility in the “Orchid Child” Hypothesis)

And that is where we can include the larger context, or in this case,  the “Theory of Peripheral Minds” as the unifying theory.  Along with what Dr. Naviaux proposes which is his “Theory of the Cell Danger Response” as the unifying cause of autism. While I like it and of course it is an essential component and truly remarkable accomplishment, it’s still not enough to be fully unifying. Maybe on the micro-level but not on the macro-level or “big picture” level. The big picture requires a paradigm shift of science.  The “Cell Danger Response” is one of the best starting points and likely the smoking gun of scientific discoveries into the causal pathways of autism.  It’s a huge accomplishment from this decade of dedication from this team in San Diego.

Again, from Bradley Fikes San Diego Tribune:

QUESTION. What exactly is the cell danger response (CDR)?

ANSWER: The CDR is a natural and universal cellular response to any injury or stress. Its purpose is to help protect the cell and to jump-start the healing process. But sometimes the CDR gets stuck. This prevents completion of the natural healing cycle and can permanently alter the way the cell responds to the world. When this happens, cells behave as if they are still injured or in imminent danger, even though the original cause of the injury or threat has passed.

On a molecular level, the defended set points for cellular homeostasis are altered. This creates a pathological metabolic memory— an abnormal cellular response — that leads to chronic disease.

And from AutismSpeaks:

Normally, healthy cells stop releasing these danger signals when an infection or other stress resolves. According to Dr. Naviaux’s “cell danger response” theory, autism can result when a stress during early brain development triggers a chronic danger response. The stress that starts this chain of events can come from an environmental influence, a genetic problem or a combination of both, he proposes. The result is chronic brain inflammation and frayed connections between brain cells.  “When the brain cells stop talking, so do children,” he says.

Temporary Fix and Small Piece of a Larger Puzzle

Reprogramming a stress amplified individual (system) isn’t going to be as easy as flipping a switch, especially that late in the game. Which is great that there was already discussion in Naviaux’s interview that what might be best is using drugs like these as a combination therapy with other stress-reprogramming and learning therapies. Ease the brain? Its time to learn. I like it. It’s a lot of what building stress resiliency is all about. Learning how the brain responds to stress, the needs it has, the resources and uniqueness it needs for accommodations and disability advocacy.

Conclusion from Fike’s interview:

Additionally, Naviaux said, “that during the time the children were on suramin, benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, applied behavioral analysis and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.”

Naviaux and colleagues do not believe CDR is the cause of ASD, but rather a fundamental driver that combines with other factors, such as genetics or environmental toxins. And suramin, at this stage, is not the ultimate answer.

 

 

References (in progress):

Autism symptoms of five boys improve in early trial of century-old drug by Bradley Fikes. San Diego Tribune May 26 ,2017 LINK

Dr. Naviaux’s Lab

https://healthsciences.ucsd.edu/som/medicine/divisions/med-genetics/research/Pages/Naviaux-Lab.aspx

Oxidative stress in autism. Abha Chauhan, Ved Chauhan LINK

Stress During Pregnancy leads to Autism LINK

How do Genes Sway the Sensitivity of Resilience of a Child PsychologyToday LINK

Al-Askar M, Bhat RS, Selim M, Al-Ayadhi L, El-Ansary A. Postnatal treatment using curcumin supplements to amend the damage in VPA-induced rodent models of autism. BMC Complementary and Alternative Medicine. 2017;17:259. doi:10.1186/s12906-017-1763-7. LINK

Neuropsychopharmacotherapeutic efficacy of curcumin in experimental paradigm of autism spectrum disorders. LINK

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. LINK ScienceDirect

Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders.
Calabrese V, et al. .J Neurosci Res. 2016 Dec;94(12):1488-1498. doi: 10.1002/jnr.23893. Epub 2016 Sep 19. LINK

The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders LINK

Linking Mitochondria to Synapses: New Insights for Stress-Related Neuropsychiatric Disorders LINK
Taylor JL, Corbett BA. A Review of Rhythm and Responsiveness of Cortisol in Individuals with Autism Spectrum Disorders. Psychoneuroendocrinology. 2014;49:207-228. doi:10.1016/j.psyneuen.2014.07.015. LINK

Autism Speaks-funded Study Links Neuroligin Gene Mutations to Oxidative Stress LINK

Raising an Orchid Child in a Dandelion World.  Kristy Ramirez
posted on May 30, 2017. On Parent.Co. LINK

 

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