Sulforaphane’s positive effects on brain health and autism | Jed Fahey
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Parents and care providers of children and adults with autism often report that fever temporarily ameliorates the altered behavioral patterns of their charges. Emerging scientific data corroborates these reports, suggesting that triggering the body's fever response might offer promise as a therapeutic strategy for people with autism. Sulforaphane, an isothiocyanate compound derived from broccoli sprouts, has been shown to trigger the fever response, upregulating heat shock proteins and other related mechanisms. In this clip, Dr. Jed Fahey describes the beneficial effects of sulforaphane in modulating the symptoms of autism and other brain disorders.
Rhonda: So we're talking about aging and also brain inflammation and, I mean, obviously, there's been some interesting studies on sulforaphane in the brain.
Jed: Yeah. So this is an area where we're actually spending a lot of our time now, is partnering on clinical trials that are looking at just that. So it turns out that the neurologists and those who have been studying the brain and diseases of the brain for a long time in, I guess, the fairly recent past have determined that inflammation is a huge component of a number of those conditions. Schizophrenia, autism, Alzheimer's are among them. And so we can we can speculate as to how that inflammation has an effect. As far as I'm aware, you don't see increases in brain volume. It's not that kind of inflammation, but markers of inflammation clearly are up in people with these conditions and can be reversed in some cases with anti-inflammatory drugs.
And so people have come to us recently with the question, "Okay, we know sulforaphane reduces inflammation. You know, can it possibly help with autism, Alzheimer's and schizophrenia?" The three that we're actually looking at. I should back up, though, and say that sulforaphane, and isothiocyanates like it, have many effects. They do affect many pathways. We talked about Nrf2. I may have made it seem like that was the best thing since sliced bread, and the only thing. It's not the only thing. We also mentioned antibiosis, selective antibiosis against Helicobacter. What we haven't talked about yet is the fact that sulforaphane actually inhibits the NF-kappaB pathway, which is one of the main inflammatory pathways in the body. And there's even some, as it's called, crosstalk between the Nrf2 pathway and the NF-kappaB pathway, so the inflammatory and cytoprotective pathway.
Sulforaphane also, sorry, up-regulates the so-called heat shock response. And I'll try to tie these together in a second. But there are a number of other pathways in which it's active, the mTOR pathway is another. So with all of these biochemical pathways that sulforaphane targets, many of them seemed to come together in a few of the neurodegenerative or neurodevelopmental diseases. And so autism was really the first one that I guess I can say was put in our lab or came to our attention.
So Dr. Andy Zimmerman, a colleague at...who was at the time at Harvard Medical School and the Mass General Hospital came to Paul Talalay back, I don't know exactly when, 2008 or 2009 or 2010 or somewhere in that range. And Andy Zimmerman had shown previously, this was published in 2007, that the so-called fever response of children with autism was real. He sort of codified it and got it in print. Apparently, psychiatrists and caregivers had been commenting anecdotally for a long time that some of their charges, their kids or the people they're giving care to who had autism, when they got a fever, they got better. Their symptoms reversed or relapsed. So autism is characterized by a number of things including repetitive motions, not making eye contact, social and behavioral impairment, if you will.
And so a lot of these characteristics got a lot better when kids had fevers. And so back to Dr. Zimmerman, he knew that we and others had shown that sulforaphane was effective in up-regulating the heat shock response. And so his question to Paul was, "Hey, why don't we see if sulforaphane also helps autism because in half of the kids, when they get a fever, the symptoms go away or they don't go away, but they rela-,..."
Rhonda: Improve.
Jed: "They improve and that's likely related to this heat shock response. Wouldn't it be interesting if sulforaphane has an effect?" As all of us got thinking about it, there were clearly a number of other mechanisms by which sulforaphane could be acting including reduction of inflammation and enhancement of the antioxidant enzymes. You know, more effective clearance of oxidative, reactive oxygen and reactive nitrogen species.
Rhonda: Right. I never thought about heat shock protein playing a role in autism. That's very interesting. I mean, neurodegenerative diseases for sure, but I didn't... And so that's an interesting connection he was making that I wouldn't have made, but I can see how he is making it. It's very interesting.
Jed: Yes. So the paper is 2007, Curran, C-U-R-R-A-N, is the first author. We'll get you a copy. So yeah, it's a fascinating potential connection. And so that was sort of...that was what got the collaboration started. So we supplied broccoli sprout extract, and they, up in Boston, looked at, I guess it was about 44 subjects, all men, all young men, boys, men. As you probably know, autism is about four to one, male to female in terms of its incidence in this country, anyway. And less than or more than 1 in 100 kids now are born with autism. So it's a huge problem. I don't need to go into detail about why it's such a big problem, but, because you're an expert on autism among other things.
Rhonda: Not really.
Jed: But, well, you've studied it. So at any rate, we did this trial. It was published in 2014. We, for various reasons, biomarkers of inflammation of the Nrf2 pathway and heat shock response were not evaluated in blood from those subjects. But what we showed was a rather dramatic reduction in many of the symptoms of autism in about half of the subjects compared to placebos. Those who were given placebo instead of broccoli sprout extract in which there was no detectable change.
Rhonda: I think it was, like, a 37% improvement in, if I remember correctly from your paper. Yeah, it was very, very robust from a small amount.
Jed: It was dramatic. Right, the n was small, the number of subjects was small, but it was a dramatic improvement. I am so sad that we never got the biomarker data from those subjects, although theoretically, it's still available. As a result of that trial, a lot of people got interested in the possibilities. And so Dr. Zimmerman and his team, including the Cullman Chemoprotection Center here, have a follow-up grant from the Department of Defense to study a younger cohort, male and female, boys and girls, about 50 subjects. But a similar trial design and it is going to be...it is biomarker-rich. So we've already done a pilot study with 10 subjects in which we evaluated... We refined our ability to collect samples and to process the biomarker samples. We're collecting blood from all of them. And this is a trial design where, half of them, half of the subjects are getting, actually, Avmacol, one of the supplements, the dietary supplements, the one with glucoraphanin and myrosinase, half of them are getting that, half of them are getting a placebo for, I think, it's 15 weeks, for about the same amount of time as we gave subjects in the previous trial.
Biomarker-rich, then there's a washout period, and then everybody goes on the sulforaphane product, the Avmacol, for another 15 weeks. Dr. Hua Liu and I...she's doing most of the biomarker work here at Hopkins. She and I were just up in Worcester, Massachusetts. The team is now at UMass Medical Center in Worcester, Massachusetts. They've processed about a third of the subjects. So we're about a third of the way through completing the trial. And we're very excited, obviously, about what we may find and about getting to the task of processing these biomarkers.
Rhonda: Very exciting. And what was the dose difference from the first trial? The first trial, the dose of...
Jed: Well, it's a little complicated, but if you bear with me, the first trial delivered sulforaphane-rich broccoli sprout extract.
Rhonda: Okay.
Jed: Okay. Remember that's 70% bioavailable, okay. This trial's delivering glucoraphanin plus myrosinase. It's calibrated to deliver about the same amount as the previous trial. So between 100 and 150 micromoles per subject per day.
Rhonda: Is there a reason why you're not doing a dose response or trying higher doses, as well, to see if there's a more robust effect?
Jed: The next trial will do that.
Rhonda: Okay, so that's in the pipeline?
Jed: Well, it's in this pipeline.
Rhonda: Okay.
Jed: Yeah. So, I mean, look, after a trial like this, especially one where we were not able to publish biomarker results, there are many people saying, "Wow, that's really interesting, but it's got to be repeated." So we and others are trying to repeat it just essentially as closely as possible to the way it was designed. You know, it does make sense and it's unfortunate. If these trials weren't so damned expensive, I mean, we could try all...
Rhonda: It's expensive and long to do.
Jed: We could try all conditions.
Rhonda: I know, I imagine. It's very, very exciting.
Jed: It's exciting, but it's very expensive, its labor-intensive, and it also...you know, you've got the hopes, and fears, and desires, and tears of a lot of people involved. Jed: It's exciting, but it's very expensive, its labor-intensive, and it also...you know, you've got the hopes, and fears, and desires, and tears of a lot of people involved. These are conditions that hurt to see people going through. And so to do a whole bunch of trials with a whole bunch of conditions might also make the people who are suffering from these conditions really think that this is...that we already have the answer. This is why I'm so afraid of some of the cancer prevention trials that are being done. You know, people get on their high horse and they don't know what they're talking about.
You know, again, one of the most frequently heard things, for me, is, "Oh, scientists at Johns Hopkins say this cures cancer." I mean, I've heard that said about so many things, not just, certainly not just our work. It ain't true. We would love for it to be true, but same thing with autism, I guess if it were cheap and easy to do and nobody cared about the subjects involved, there'd be a lot of trials, a lot of them would be lousy trials, and a lot of people would have their hopes raised only to maybe 10 or 15 years down the road find out that, yeah, those trials weren't really done that well. So all of the oversight, all of the self-criticism and the peer criticism is probably worth it because I think it does serve a purpose. Anyway, back to the story, so, enough philosophizing. So we have this follow-up trial underway. Interestingly, there are four other, additional autism trials using all using Avmacol, and this is if it doesn't work, I'm to blame because I identified it as something that looked like it was the best of what was out there, and I got the company to agree...
Rhonda: I mean, this is something that's available for people right now.
Jed: It's available, and we know that it produces sulforaphane and we know that it's a decent product and it has been through all sorts of quality assurance. But so when people who came to us and said, "We'd like to do an autism trial. We'd like to model it after Andy's original trial, essentially, try to replicate the findings. We want more of that sulforaphane that you produced for it." And my answer has had to be, "I don't have any more. And I'll show you, as my witness, I'll show you our freezer and show you that we don't have any more in our clinical freezer. So we just can't produce any more." And so we had to suggest that people switch to something commercial.
So four other studies, one of them has finished its patient accruals at UCSF, and we're in the process now of evaluating biomarkers, and they're using metabolomics to evaluate biomarkers. They're looking at small molecules produced by the various metabolic pathways that are either induced or up-regulated or not and hope to be able to make some correlations with symptom reduction and biochemistry. There is a trial just starting at the University of North Carolina, there's a trial at Rutgers. I'm not sure how far along they are, pretty far along, I think. And all three of those trials are about the same order of magnitude as our original trial, 20 to 50 patients or subjects.
The other trial is in China and there are, I'm going to get this wrong, there are either 120 or 180 subjects. And that's just starting to study drug or supplement is they're...and this is at a school for autistic kids in Changsha, China. And you can read the descriptions of most of these trials, I think all of them, on clinicaltrials.gov, which is the government's database for clinical trials. So, again, all these studies are looking at biomarkers of inflammation, as you say, IL-6 is one of the key markers that people are looking at, COX-2, TNF-alpha. The supposition is that those markers are going to go down. The supposition is that markers of Nrf2 activation are going to go up, and heat shock protein markers are going to go up. We'll see.
Rhonda: Well, I mean, it's been shown in people that don't have autism that are given sulforaphane at least, I guess, it may depend on the dose, but it has been shown. The heat shock protein, that really caught my attention. I came across it when I was reading about sulforaphane and how it can be neuroprotective for Alzheimer's disease, Parkinson's, and even Huntington's. These are all diseases of protein aggregation of which heat shock proteins play a major role in repairing and preventing, both. They do both. So I was very surprised. I guess not that, it wasn't that shocking once I found out that sulforaphane activates, because it is a stress response pathway, heat shock proteins do respond to stress like heat stress. So I guess I wasn't that shocked, but I was a little surprised at first to see that it plays a role. And possibly, that's how it's helping prevent and protect against some of these neurodegenerative diseases.
Jed: Very possible, yeah, yeah.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
An antagonistic association between two organisms (especially microorganisms), in which one is adversely affected.
A molecule that inhibits oxidative damage to DNA, proteins, and lipids in cells. Oxidative damage plays a role in the aging process, cancer, and neurodegeneration. Many vitamins and plant-based compounds are antioxidants.
A developmental disorder characterized by impaired social interaction, behavioral problems, and poor communication. Autism typically manifests in early childhood and is slightly more common among boys than girls. In clinical trials, sulforaphane, a compound derived from broccoli and broccoli sprouts, reduces the characteristic behaviors associated with autism.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
A glucosinolate (see definition) found in certain cruciferous vegetables, including broccoli, Brussels sprouts, and mustard. Glucoraphanin is hydrolyzed by the enzyme myrosinase to produce sulforaphane, an isothiocyanate compound that has many beneficial health effects in humans.
A family of proteins produced by cells in response to exposure to stressful conditions. Heat shock proteins are expressed in response to heat as well as exposure to cold and UV light, and during wound healing and tissue remodeling. Many heat shock proteins function as chaperones by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by cell stress. A 30-minute 73ºC sauna session in healthy young adults has been shown to cause a robust and sustained increase in the production of heat shock proteins for up to 48 hours afterward.[1]
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.
Byproduct of a reaction between two compounds (glucosinolates and myrosinase) that are found in cruciferous vegetables. Isothiocyanates inhibit phase I biotransformation enzymes, a class of enzymes that transform procarcinogens into their active carcinogenic state. Isothiocyanates activate phase II detoxification enzymes, a class of enzymes that play a protective role against DNA damage caused by reactive oxygen species and carcinogens. Examples of phase II enzymes include UDP-glucuronosyltransferases, sulfotransferases, N-acetyltransferases, glutathione S-transferases, and methyltransferases.
A class of proteins present in many edible plants, such as grains or legumes. Lectins are carbohydrate-binding molecules. They have been referred to as antinutrients for their ability to impair absorption of some nutrients. Many lectins possess hemagglutinin properties, which means they can bind to blood cells and cause them to aggregate. Cooking typically denatures lectins in foods.
An enzyme that participates in genetic pathways that sense amino acid concentrations and regulate cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. It plays key roles in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are the subject of many studies), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
A family of enzymes whose sole known substrates are glucosinolates. Myrosinase is located in specialized cells within the leaves, stems, and flowers of cruciferous plants. When the plant is damaged by insects or eaten by humans, the myrosinase is released and subsequently hydrolyzes nearby glucosinolate compounds to form isothiocyanates (see definition), which demonstrate many beneficial health effects in humans. Microbes in the human gut also produce myrosinase and can convert non-hydrolyzed glucosinolates to isothiocyanates.
A broad range of disorders caused by the progressive death of neurons in the central and peripheral nervous systems. Common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington’s disease, and multiple sclerosis. Although treatments are available for some neurodegenerative diseases, there are currently no cures.
A rapid-acting transcription factor that responds to harmful cellular stimuli, such as reactive oxygen species, IL-1B, bacterial endotoxin (lipopolysaccharide or "LPS"), ionizing radiation, and oxidized LDL. Incorrect regulation of NF-kB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. Several viruses, including the AIDS virus HIV, have binding sites for NF-kB. In the case of HIV, the presence of NF-kB is believed to be involved in switching the virus from a latent to an active state.
A protein typically present in the cytoplasm of mammalian cells. Nrf2 can relocate to the nucleus where it regulates the expression of hundreds of antioxidant and stress response proteins that protect against oxidative damage triggered by injury and inflammation. One of the most well-known naturally-occurring inducers of Nrf2 is sulforaphane, a compound derived from cruciferous vegetables such as broccoli.
Highly reactive molecules that have the ability to oxidize other molecules and cause them to lose electrons. Common oxidants are oxygen, hydrogen peroxide, and superoxide anion.
Overtime proteins unintentionally accumulate damage from reactive oxygen and nitrogen species. These compromised proteins aggregate together and can promote aging as well as progressive diseases such as Alzheimer's and Parkinson's disease.
Nitrogen-containing chemically-reactive molecules generated by the immune system. RNS are produced in animals when nitric oxide reacts with superoxide to form peroxynitrite. They can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
A related byproduct, reactive oxygen species, is generated by oxidative phosphorylation and immune activation. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from RNS (nitrosative stress) and ROS (oxidative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
A mental disorder characterized by abnormal social behavior and failure to understand what is real. Common symptoms include false beliefs, unclear or confused thinking, hearing voices that others do not, reduced social engagement and emotional expression, and a lack of motivation. People with schizophrenia often have additional mental health problems such as anxiety disorders, major depressive illness, or substance use disorders.
An isothiocyanate compound derived from cruciferous vegetables such as broccoli, cauliflower, and mustard. Sulforaphane is produced when the plant is damaged when attacked by insects or eaten by humans. It activates cytoprotective mechanisms within cells in a hormetic-type response. Sulforaphane has demonstrated beneficial effects against several chronic health conditions, including autism, cancer, cardiovascular disease, diabetes, and others.
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Sulforaphane News
- Sulforaphane extends lifespan and healthspan in worms via insulin and insulin-like growth factor-1 signaling.
- Paul Saladino, MD explains how we may have overstated the health benefits of plants and especially sulforaphane
- NRF2 much of a good thing (December 2017)
- A pilot trial finds sulforaphane treatment increased glutathione levels in the blood & hippocampus region of the brain in healthy people.
- A new study found sulforaphane (found in broccoli sprouts) improved behavior & social responsiveness in children with autism.
