Intranasal Insulin for Some Autism vs IGF-1 and NNZ-2566

 

Very often the simplest solutions are the best and very often, when fault finding a problem, people overlook the obvious.  

I seem to be forever having to mend things and I find this all the time.

Back in 2013, when I knew much less about autism, I wrote about the experimental use of insulin like growth factor 1 (IGF-1) in autism.  

It’s a Small World – IGF-1 and NNZ-2566 in Autism

It turned out that in autism the many different growth factors can be disturbed (too much, or too little) and this variation does indeed define some specific types of autism.  For example in Rett Syndrome there are very low levels of Nerve Growth Factor (NGF); low levels of NGF in some older people is the cause of their dementia.  In more common types of autism NGF is actually elevated.

IGF-1 is very well studied.

 

IGF-1 is a primary mediator of the effects of growth hormone (GH). 

Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver,kidney, nerves, skin, hematopoietic cell, and lungs. This would explain why adults abusing GH may end up needing hip and knee replacements.

Before getting into the science, IGF-1 has long been available as a drug to treat children with growth delays.  In the US this drug is being used on children with a type of autism called Phelan-McDermid Syndrome.

Now, regular readers will recall from my last post on intranasal insulin that it was in this very syndrome that there was a successful intranasal insulin.

So most likely without delving into the science at all it looks like IGF-1 and intranasal insulin are both options to treat the same dysfunction.

Using IGF-1

Clinical Trial in 22q13 Deletion Syndrome (Phelan-McDermid Syndrome)

Using Intranasal Insulin

Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.

NNZ-2566

This is an Australian drug that is a modified version of IGF-1 (a so called analog).  They modified it so that it can be taken orally rather than by injection.  The developer has a very thorough presentation showing why they think it should be effective in autism.  

  

NNZ-2566 - Rationale for use in Autistic Spectrum Disorders

The Science

The first thing to note is that insulin and IGF-1 act as messengers.  Disruption in growth factor signaling can have serious consequences.

Insulin and IGF-1 both activate the same insulin receptor (IR).

Most people think that insulin is a just a hormone produced in their pancreas that regulates the amount of glucose (sugar) in their blood.  It does of course do that, but it actually does much more.

  

Insulin receptors are expressed all over the body including the brain.

Here is a relatively simple presentation explaining the role of insulin signaling in the brain:-

The role of insulin receptor signaling in the brain

Now for the diehard scientists among you that have been reading about all those signaling pathways that lie behind autism, cancer and many other hard to treat conditions, look at the graphic below.

We know the importance of RAS.  Impaired RAS signaling underlies the RASopathies, one feature of which is cognitive loss (MR/ID), another is autism.

We also know the importance of Akt (PKB/protein kinase B) in some types of autism.  PTEN appears again.

So irrespective of an undoubtedly important effect on glucose and insulin resistance, we should expect activation of insulin receptors in the brain, in some types of autism, to have a further positive effect.

It would seem to be a potential therapy for RASopathies.

As is often the case, there are extreme dysfunctions of RAS and I suggest there are more mild dysfunctions.

I suggest that some people with autism and some cognitive dysfunction have a partial RASopathy.

Since autism contains both extremes of many dysfunctions, there will undoubtedly be types of autism that respond negatively, or not at all, to activation of insulin receptors in the brain.

Practicalities

Nobody likes injections and that is necessary to give IGF-1.

NNZ-2566 is an experimental autism drug and on past performance that means it will take decades to reach the market, if ever.

That leaves insulin which was sitting all along in your local pharmacy.

Intranasal insulin was once investigated for use in diabetics, but it did not work.  It is not absorbed into the blood stream.

This is of course the huge advantage for people with autism, since we only want to activate the insulin receptors in the brain.  If you are not diabetic why would you want to have any effects in the rest of the body?

Indeed there are known major side effects of injecting IGF-1 or GH (growth hormone) into adults.  All kinds of things start growing and this can lead to terrible results.

The fact that all the studies show that intranasal insulin does not enter the blood stream and so lower blood glucose levels, makes it a much better drug for autism than IGF-1 or indeed NNZ-2566.

Insulin

There are various types of insulin and the main difference is that some are modified to be longer acting.

The basic insulin is soluble or clear insulin, and nowadays is synthetic rather than derived from pigs.  Examples include Humulin Regular/R/S by Lilly.

The standard concentration is 100 IU/ml.

The trials in Alzheimer’s and other conditions varied in dosage but generally used about 20 to 40 IU per day.

This is not a trivial dose.  If injected, rather than inhaled, that dose would have a significant effect on lowering blood sugar and would be dangerous.

My antihistamine nasal spray gives a metered dose of 0.14 ml.

So without any dilution, if filled with off the shelf insulin it would dispense 14 IU per spray.

So no special high tech drugs, dilutants/diluents or dispensers appear to be necessary. Some trials do use fancy inhalers, like the one in the video at the end of this post.

To be prudent it might be wise to dilute the insulin so as to gradually increase the dose.  Maybe in some people the nasal membrane is more permeable than in others.  Some of the trials did this, but most did not.

A fridge is required, because insulin needs to be kept chilled.

I do wonder why nobody seems to be researching this in autism.  Silly point, as one insulin researcher commented on the earlier post; there is no big money to be made, hence no interest.

Insulin & Alzheimer’s

The reasons that intranasal insulin improves Alzheimer’s, and likely will Down Syndrome, may differ to those help in (some) autism.

Beta amyloid is key to Alzheimer’s (and early onset Alzheimer’s in Down Syndrome) but is not a known issue in autism.  Central insulin resistance is an issue in Alzheimer’s and might well be in autism.  

Perhaps people with mitochondrial dysfunction (an energy conversion dysfunction) might particularly benefit from increased glucose uptake in the brain.  It appears that mitochondrial dysfunction plays a role in insulin resistance. 

Role of Mitochondrial Dysfunction in Insulin Resistance

The activation of the RAS pathway might be highly beneficial to some people with autism.  

Here is a good film, which refers to the studies from previous posts and shows the effect on one man with Alzheimer's. 

Insulin and Alzheimer's (approx. 22 min.)

 You also see their fancy inhaler device.

Has anyone tried Cinnamon (or Sodium Benzoate) for Autism?

I have written several posts about Cinnamon and its metabolite Sodium Benzoate. I know that some readers are now using it for its cholesterol lowering and insulin sensitivity improving properties that were shown in the clinical trials I highlighted.

Cinnamon and DJ-1 as a general Anti-Oxidant and perhaps Much More

Is DJ-1 expression negatively associated with severity of Autism? If so, Sodium Benzoate (Cinnamon) may well be beneficial

Sodium benzoate (Cinnamon) trialed for Schizophrenia (Adult-onset Autism)

NMDAR hypo-function causing E/I imbalance in Autism and Schizophrenia – Baclofen, Sodium benzoate and Cinnamon (again)

But has anyone tried it for autism?

The first time I wrote about it I did acquire a big bag of the correct variety (Cinnamomum verum or Ceylon Cinnamon) and also a bag of the very high flavanol (epicatechin) cocoa.  My cinnamon trial was limited to seeing what it looked/tasted like when added to the Polypill concoction Monty, aged 12 with ASD, drinks at breakfast.  It was rather like adding a teaspoonful of fine sand, so not much “testing” took place.

Now that Monty has shown an ability, and even enjoyment, for pill swallowing, things are much simpler.  The cinnamon can be put inside gelatin capsules; it’s a little messy, but no great trouble.

Having recently been researching about the gene enhancers and silencers, which are controlled by the 95% of your DNA that rarely gets studied (the exome is the part everyone studies and some people test for abnormalities), it did occur to me that I already have two safe substances, that I have both researched and acquired, which have a gene expression enhancing effect.

Cinnamon “Experiment”

Even though summer is the wrong time to test anything in Monty, aged 12 with ASD, since his pollen allergy triggers a regression, I decided to make a trial.  I have 1 kg of this special cinnamon, and so it’s not like I need to ration it.

I gave about 2.5ml of cinnamon split into three daily doses using some gelatin capsules that used to be full of another supplement (choline).

Results so far:-

Complete absence of summertime bad behaviors, which are already 90% subdued by Verapamil, but do sometimes present themselves.

Interesting behavioral developments:- 

·        Like many people with autism, Monty likes order.  So turn off lights, shut doors, wash dirty hands etc.  The latest surprise was that when I took something from the rear of my car and he shut the tail gate (boot). Given the size of my car, for someone of his small stature, this is quite an achievement, since he really has to stretch on his toes.  This is the first time he has ever done this and now he does it every time.

·        Monty can brush his teeth and get dressed, but his clothes are sitting there on his bed.  The other day when told to go upstairs and brush his teeth, he returned fully clothed, having chosen/found his clothes all by himself.

·        On awakening, sometimes Monty might say “can I have a glass of water”, to which he might be told go downstairs and get water, and usually someone would go down with him.  Recently I find him in the early morning sitting at the kitchen table playing on his iPad with the glass of water he served himself with.

·        Piano playing also seems to be going very well, indeed on Wednesday after his piano lesson the teacher started telling me that she has taught 73 children with autism and never has she had someone start at his beginning level and progress so far.  This is clearly not down to cinnamon (it was greatly helped by bumetanide, atorvastatin and NAC), but why is she telling me this now, after over three years of lessons?

·        Speech for people with Classic autism, even when it develops, is always a little odd, reading a book out loud or singing does not mean you can speak.  It is as if the mother tongue is a foreign language and needs to be translated in your head. So for me it would be like speaking German.  It is my fourth language, I know lots of words, but I cannot think in German.

Many people with autism like to know their schedule. Today Monty was going to go swimming, amongst other things, but a change of plan meant we had gone to eat.  So I said to Monty “I am too full to go swimming, we will go later”.

A few minutes later as I stopped the car, Monty says “swimming when Dad feels better”.

There is nothing super clever in that statement, but it is not the sort of unprompted comment I usually get to hear for son number two.

These are all little steps and may be coincidental, but normally with Monty things go backwards in summer.  Even effective interventions appear to lose their effectiveness. 

I still keep an open mind on cinnamon, but I did just order a big bag of empty gelatin capsules.

Anybody else tried Cinnamon?

It would be useful to know from people who found that Bumetanide or Sulforaphane were effective for autism, whether cinnamon also has a positive effect.

There are several reasons why it may help:-

·        Change in NMDA signaling, affecting the excitatory/inhibitory balance

·        Affects gene expression related to oxidative stress (why cinnamon helps reduce cholesterol and improve insulin sensitivity)

·        Increases BDNF, Brain-derived neurotrophic factor  (aka “brain fertilizer”)

·        NaB (sodium benzoate) reduces Microglial and Astroglial Inflammatory Responses

·        NaB exerts its anti-inflammatory effect through the inhibition of NF-κB

·        NaB suppresses the activation of p21^ras in microglia

·        NaB can also regulate many immune signaling pathways responsible for inflammation, glial cell activation, switching of T-helper cells, modulation of regulatory T cells

NF-κB is the master regulator of inflammation in the same way that Nrf 2 is for oxidative stress.

Incorrect regulation of NF-κB has been linked to cancer, inflammatory, and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory

In autism it seems that we want to activate Nrf2 but to inhibit NF-κB.  Safely inhibiting NF-κB is the Holy Grail for many diseases.

We covered RAS in earlier posts.  The RAS protein is abnormally active in cancer.

So called RASopathies are developmental syndromes caused by mutations in genes that alter the Ras subfamily.  RASopathies are often associated with autistic symptoms and/or intellectual disability/mental retardation.

Common inhibitors of RAS are statins and Farnesyltransferase inhibitors.  Most Farnesyltransferase inhibitors are expensive cancer research drugs, but one is gingerol.

Since statins do very clearly improve the autism of Monty, aged 12 with ASD, I did try adding gingerol as my “Statin plus” therapy.  At the dose I used there was no noticeable effect.

However, I now learn that “NaB suppressed the activation of p21^ras in microglia”.  P21, RAS, and p21^ras are different names for the same protein.  So it would seem that NaB is therefore a RAS inhibitor and perhaps a more potent one than gingerol.

   

Too much BDNF, just like too much lawn fertilizer, may not be a good thing.

BDNF is low in schizophrenia, but is thought to be elevated in “most” autism.

   

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Reduces Microglial and Astroglial Inflammatory Responses

 Abstract

Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology of several neurodegenerative disorders. This study explores the anti-inflammatory property of cinnamon metabolite sodium benzoate (NaB) in microglia and astrocytes. NaB, but not sodium formate, was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF-α and IL-1β) and surface markers (CD11b, CD11c, and CD68) in mouse microglia. Similarly, NaB also inhibited fibrillar amyloid β (Aβ)-, prion peptide-, double-stranded RNA (polyinosinic-polycytidylic acid)-, HIV-1 Tat-, 1-methyl-4-phenylpyridinium⁺-, IL-1β-, and IL-12 p40₂-induced microglial expression of iNOS. In addition to microglia, NaB also suppressed the expression of iNOS in mouse peritoneal macrophages and primary human astrocytes. Inhibition of NF-κB activation by NaB suggests that NaB exerts its anti-inflammatory effect through the inhibition of NF-κB. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on iNOS expression, and NF-κB activation by hydroxymethylglutaryl-CoA, mevalonate, and farnesyl pyrophosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the anti-inflammatory effect of NaB. Furthermore, we demonstrate that an inhibitor of p21^ras farnesyl protein transferase suppressed the expression of iNOS, that activation of p21^ras alone was sufficient to induce the expression of iNOS, and that NaB suppressed the activation of p21^ras in microglia. These results highlight a novel anti-inflammatory role of NaB via modulation of the mevalonate pathway and p21^ras.

  

Immunomodulation of experimental allergic encephalomyelitis by cinnamon metabolite sodium benzoate.

ABSTRACT Experimental allergic encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), the most common human demyelinating disease of the central nervous system. Sodium benzoate (NaB), a metabolite of cinnamon and a FDA-approved drug against urea cycle disorders in children, is a widely used food additive, which is long known for its microbicidal effect. However, recent studies reveal that apart from its microbicidal effects, NaB can also regulate many immune signaling pathways responsible for inflammation, glial cell activation, switching of T-helper cells, modulation of regulatory T cells, cell-to-cell contact, and migration. As a result, NaB alters the neuroimmunology of EAE and ameliorates the disease process of EAE. In this review, we have made an honest attempt to analyze these newly-discovered immunomodulatory activities of NaB and associated mechanisms that may help in considering this drug for various inflammatory human disorders including MS as primary or adjunct therapy.

Conclusion

Rather to my surprise, Cinnamon does seem to have a noticeable cognitive effect in the type of autism I am interested in.  It appears, rather like the statin, to promote improved adaptive behavior by reducing inhibition and increasing spontaneous thought and actual decision making.

Of all the many possible modes of action, I am thinking that inhibition of NF-κB and/ or RAS inhibition are most likely since the effect is very similar to that produced by the statin.

I will certainly continue with cinnamon and when my size 000 gelatin capsules arrive, I will look at different doses.  Currently the dose is about 2.5 ml split three times a day, using size 00 gelatin capsules.

RAS signaling, Autism, Cancer and Gingerols

Sytrinol (Tangeretin), sacrificial Gummy Bear and Gingerol

Today’s post follows on from an earlier one that introduced the term RASopathy.  A RASopathy is a disease characterized by over-activation of the RAS protein.

RASopathies are of interest because if you have one, you are highly likely to also have autism.

RAS dysfunction is also present in many types of cancer and there are existing drugs to inhibit RAS signaling.  It has been claimed that:-

"If RAS proves to be a key player in autism …  it might suggest new treatments for autism, as many cancer drugs inhibit RAS signaling."

Regular readers of the Simons Foundation autism blog may have read the following:

RAS pathway, a potentially unifying theory of autism

  

Cancer pathway connects autism to set of rare disorders

If RAS proves to be a key player in autism, she says, it might suggest new treatments for autism, as many cancer drugs inhibit RAS signaling.

RAS-based interventions

My Polypill already has one RAS-based component, the statin.  This (the statin) is now being patented by the University of California.

Statins as Treatment for Cognitive Dysfunction Associated with RASopathies

Innovation

Professor Alcino Silva and colleagues at the UCLA department of Neurobiology have repurposed HMG-CoA reductase inhibitors (or statins) to reverse the cognitive dysfunction associated with RASopathies. By blocking HMG-CoA reductase, the drug prevents overactivation of the Ras protein, which leads to deficits in long term potentiation, a mechanism of learning and memory. Using in vivo models of NF1 and Noonan Syndrome, the researchers have shown that lovastatin is able to restore both LTP deficits and cognitive function to wild-type levels.

Applications

• Treatment of cognitive dysfunction associated with NF1

• Treatment of cognitive dysfunction associated with Noonan syndrome

• Treatment of other disorders driven by hyperactivation of the Ras-MAPK pathway

Advantages

• Statins would represent the first and only drug available to treat the cognitive defects observed in NF1, Noonan and other RASopathies
• Statins have already been approved by the FDA as a cholesterol-lowering drug, demonstrating an amenable safety profile in humans
• Effectiveness in restoring cognitive function has been demonstrated in vivo

  

The studies using Lovastatin were positive:-

Lovastatin as treatment for neurocognitive deficits in neurofibromatosistype 1: phase I study

Lovastatin regulates brain spontaneous low-frequency brain activity in neurofibromatosis type 1.

However in the following trial in the Netherlands, Simvastatin was shown not to be effective in NF-1.

Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

The UCLA team seem to think Lovastatin has potential, even though Simvastatin appears not to.

There is a comprehensive presentation from Silvalab at UCLA below,

Mechanisms and Adult Treatments for Neurodevelopmental Disorders

It seems that in Rett Syndrome (not a RASopathy) statins may also help.

Statins Suppress Rett Syndrome Symptoms in Mice

So choose your statin with care. 

We use Atorvastatin.  It works; but it has various possible modes of action, one of which is RAS.  Another is upregulating PTEN.

Upregulating PTEN is good, but if used to excess it may lead to reduced insulin sensitivity and type 2 diabetes.

However, anti-oxidants, sulfurophane and PPAR gamma agonists (Gingerols, tangeretin) all increase insulin sensitivity so this tiny risk can be mitigated.  Verapamil protects beta cells (that produce insulin) from damage.

Statin MAX

I was interested in further increasing the RAS inhibition to see if there would be further cognitive or other improvement.  This is not possible via increasing the dose of statin, but it is possible by using Farnesyltransferase inhibitors, these are mainly anti-cancer research compounds, but one is the flavonoid Gingerol.

Ginger is another of those substances that has been used for centuries in traditional medicine. Gingerols are found in uncooked ginger.

Gingerols in “Medicine”

Fortunately ginger has many claimed medical benefits, ranging from arthritis to cancer prevention and treatment.  As a result standardized concentrated versions are widely available.

When it comes to my experiments, one problem has been the taste of the substance and the loss in bioavailability by having to open up/crush the various substances.

Swallowing Pills

Swallowing pills is not an option for some people, but in some cases you lose the effect of a drug if you remove the outer coating.  This is true with the drugs that lower the acidity of your stomach (Proton Pump Inhibitors).  They are designed to dissolve in the acidity of your intestines and not before.

Sytrinol ,the tangeretin flavonoid that is an attractive PPAR gamma inhibitor, is packed in a thick capsule, because the research shows this increases its bioavailability.  So me squeezing it out on a piece of toast will dilute its potency.  

Having obtained my high gingerol content potion, the first thing I did was to open the capsule and taste it.  Not nice at all.

Monty, aged 11 with ASD, has an elder brother who makes an enormous fuss on the very rare occasion he has to swallow a tablet.

Having overcome the usual autism problems of visiting a dentist and a hairdresser, the time had come for Monty to learn how to swallow pills.

In the end it was a non-event.

Having agreed that a gummy bear would be the reward and with the usual glass of water sitting beside it, the lesson began.  I put a NAC pill on my tongue and he put a Tangeretin capsule on his.

Before I could even suggest he drank some water, he had swallow the Tangeretin and bitten the head off the gummy bear.

This was swiftly followed by the rather odd smelling gingerol capsule.

So, rather unexpectedly, I can proceed with my gingerol investigation.

Gingerol may or may not be effective in our type of autism, but the research is highly promising in several other areas, some comorbid^* with autism.

·        Asthma^*

·        Ulcerative Colitis^*

·        Arthritis ^*

·        Alzheimer’s Disease

·        Cancer^*

No data suggests people with ASD are prone to Alzheimer’s, although some Alzheimer’s drugs do help some people with ASD.  It may just be that people with ASD do not make it to their eighties. 

Safety

Ginger is very widely used and I do not see any safety issues, just taste issues.

Asthma

Active Components of Ginger Potentiate b-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Clinical Relevance

Natural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonist–induced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.

Ginger Compounds May Help Treat Asthma

Arthritis

Comparative Effects of Two Gingerol-Containing Zingiberofficinale Extracts on Experimental Rheumatoid Arthritis1

“In conclusion, these data document a very significant joint-protective effect of these ginger samples, and suggest that non-gingerol components are bioactive and can enhance the antiarthritic effects of the more widely studied gingerols.”

Arthritis. Some research shows that taking ginger can modestly reduce pain in some people with a form of arthritis called “osteoarthritis.” One study shows that taking a specific ginger extract (Zintona EC) 250 mg four times daily reduced arthritis pain in the knee after 3 months of treatment. Another study shows that using a different ginger extract (Eurovita Extract 77; EV ext-77), which combines a ginger with alpinia also reduces pain upon standing, pain after walking, and stiffness. Some research has compared ginger to medications such as ibuprofen. In one study, a specific ginger extract (Eurovita Extract 33; EV ext-33) did not work as well as taking ibuprofen 400 mg three times daily for reducing arthritis pain. But in another study, taking ginger extract 500 mg twice daily worked about as well as ibuprofen 400 mg three times daily for hip and knee pain related to arthritis. In another study, a specific ginger extract combined with glucosamine (Zinaxin glucosamine, EV ext-35) worked as well as the anti-inflamatory medication diclofenac slow release 100 mg daily plus glucosamine sulfate 1 gram daily. Research also suggests that massage therapy using an oil containing ginger and orange seems to reduce short-term stiffness and pain in people with knee pain.

Ulcerative Colitis

Pharmacological Activity of 6-Gingerolin Dextran Sulphate Sodium-induced Ulcerative Colitis in BALB/c Mice

Gingerols are phenolic compounds in ginger (Zingiber officinale), which have been reported to exhibit anti-inflammatory, antioxidant, and anticancer properties. The present study aimed at evaluating the possible pharmacologic activity of 6-gingerol in a mouse model of dextran sulphate sodium (DSS)-induced ulcerative colitis. Adult male mice were exposed to DSS in drinking water alone or co-treated with 6-gingerol orally at 50, 100, and 200 mg/kg for 7 days. Disease activity index, inflammatory mediators, oxidative stress indices, and histopathological examination of the colons were evaluated to monitor treatment-related effects of 6-gingerol in DSS-treated mice. Administration of 6-gingerol significantly reversed the DSS-mediated reduction in body weight, diarrhea, rectal bleeding, and colon shrinkage to near normal. Moreover, 6-gingerol significantly suppressed the circulating concentrations of interleukin-1β and tumor necrosis factor alpha and restored the colonic nitric oxide concentration and myeloperoxidase activity to normal in DSS-treated mice. 6-Gingerol efficiently prevented colonic oxidative damage by increasing the activities of antioxidant enzymes and glutathione content, decreasing the hydrogen peroxide and malondialdehyde levels, and ameliorated the colonic atrophy in DSS-treated mice. 6-Gingerol suppressed the induction of ulcerative colitis in mice via antioxidant and anti-inflammatory activities, and may thus represent a potential anticolitis drug candidate.

PPARγ

6-gingerol inhibits rosiglitazone-induced adipogenesis in 3T3-L1 adipocytes.

Abstract

We investigated the effects of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone) on the inhibition of rosiglitazone (RGZ)-induced adipogenesis in 3T3-L1 cells. The morphological changes were photographed based on staining lipid accumulation by Oil-Red O in RGZ (1 µmol/l)-treated 3T3-L1 cells without or with various concentrations of 6-gingerol on differentiation day 8. Quantitation of triglycerides content was performed in cells on day 8 after differentiation induction. Differentiated cells were lysed to detect mRNA and protein levels of adipocyte-specific transcription factors by real-time reverse transcription-polymerase chain reaction and Western blot analysis, respectively. 6-gingerol (50 µmol/l) effectively suppressed oil droplet accumulation and reduced the sizes of the droplets in RGZ-induced adipocyte differentiation in 3T3-L1 cells. The triglyceride accumulation induced by RGZ in differentiated 3T3-L1 cells was also reduced by 6-gingerol (50 µmol/l). Treatment of differentiated 3T3-L1 cells with 6-gingerol (50 µmol/l) antagonized RGZ-induced gene expression of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein α. Additionally, the increased levels of mRNA and protein in adipocyte-specific fatty acid binding protein 4 and fatty acid synthase induced by RGZ in 3T3-L1 cells were decreased upon treatment with 6-gingerol. Our data suggests that 6-gingerol may be beneficial in obesity, by reducing adipogenesis partly through the down-regulating PPARγ activity.

6-Shogaol and 6-gingerol, the pungent of ginger, inhibit TNF-alpha mediated down regulation of adiponectin expression via different mechanisms in 3T3-L1adipocytes

ABSTRACT In this study, we demonstrated that the two ginger-derived components have a potent and unique pharmacological function in 3T3-L1 adipocytes via different mechanisms. Both pretreatment of 6-shogaol (6S) and 6-gingerol (6G) significantly inhibited the tumor necrosis factor-alpha (TNF-alpha) mediated downregulation of the adiponectin expression in 3T3-L1 adipocytes. Our study demonstrate that (1) 6S functions as a PPARgamma agonist with its inhibitory mechanism due to the PPARgamma transactivation, and (2) 6G is not a PPARgamma agonist, but it is an effective inhibitor of TNF-alpha induced c-Jun-NH(2)-terminal kinase signaling activation and thus, its inhibitory mechanism is due to this inhibitory effect.

Microglial Activation

Inhibitors of Microglial Neurotoxicity: Focus on

Natural Products

Abstract: Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation.

Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed.

Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.

8. Gingerol from Zingiber officinale

Ginger, the rhizome of the plant Zingiber officinale, has a long history of medicinal use. In traditional oriental medicine, ginger has been used to treat a wide range of ailments including stomach aches, diarrhea, nausea, asthma, respiratory disorders, toothache, gingivitis, and arthritis [98-100]. Several studies have shown that ginger inhibits pro-inflammatory cytokines, including IL-1β, IL-2 , TNF-α, and interferon (IFN)-gamma [101]. Ginger also has been shown to decrease synthesis of pro-inflammatory prostaglandins and leukotrienes via inhibition of COX-2 and 5-lipoxygenase (5- LOX) enzymes, which are the targets for numerous anti-inflammatory pharmaceuticals.

Grzanna et al. tested the effects of a ginger extract on THP-1 monocytic cells to determine whether it can block the induction of pro-inflammatory cytokines in these cells stimulated with LPS. The results of this study suggest that the anti-inflammatory properties of the ginger extract may provide beneficial effects similar to those of currently used COX inhibitors [102].

Recently, Jung et al. reported that the hexane fraction of Zingiberis Rhizoma Crudus extract inhibits the production of nitric oxide and pro-inflammatory cytokines in LPS-stimulated BV-2 microglial cells via the NF-κB pathway [103]. The authors indicated that ginger hexane extract significantly inhibited the excessive production of NO, PGE2, TNF-α, and IL-1β in LPS-stimulated BV-2 cells. Ginger extract also attenuated the mRNA expressions and protein levels of iNOS, COX-2, and proinflammatory cytokines. The molecular mechanisms that underlie ginger hexane extract-mediated attenuation of neuroinflammation were related to the inhibition of the phosphorylation of three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK), and the activation of NF-κB [103].

6-Gingerol (Figure 2B), one of the active ingredients of ginger, has been reported to impart ginger with its anti-inflammatory properties. The 6-gingerol inhibited the production of pro-inflammatory cytokines from LPS-stimulated macrophages, and inhibited COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester-stimulated mouse skin [104-105]. Data indicate that several doses of 6-gingerol selectively inhibit production of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-12 by murine peritoneal macrophages in the presence of LPS stimulation.

The authors also revealed that 6-gingerol does not affect antigen presenting cell (APC) function or cell surface expression of MHC II and co-stimulatory molecules [105]. These remarkable beneficial properties of ginger and 6-gingerol and the lack of gastrointestinal and renal side effects distinguish it from other NSAIDS. Considering the broad spectrum of ginger’s anti-inflammatory actions and its safety record in clinical trials, it is likely to be a valuable dietary supplement in the treatment of neurodegenerative and neuroinflammatory diseases. However, the ability of gingerol to cross bloodbrain barrier has not yet been explicitly demonstrated and needs further investigation.

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Alzheimer’s Disease

At least in rats, we know that Gingerol does cross the blood brain barrier.

Protective effects of ginger root extract on Alzheimer disease-induced behavioral dysfunction in rats.

Abstract

The aim of this study was to assess the ability of a traditional Chinese medicinal ginger root extract (GRE) to prevent behavioral dysfunction in the Alzheimer disease (AD) rat model. Rat AD models were established by an operation (OP) in which rats were treated with a one-time intra-cerebroventricuIar injection of amyloid β-protein (Aβ) and continuous gavage of aluminum chloride every day for 4 weeks. GRE was administered intra-gastrically to rats. After 35 days, learning and memory were assessed in all of the rats. Brain sections were processed for immunohistochemistry and Hematoxylin & Eosin (H&E) and Nissl staining. The latency to show significant memory deficits was shorter in the group that received OP with a high dose of GRE (HG)(OP+HG) than in the groups that received OP with a low or moderate dose of GRE (LG, MG)(OP+LG, OP+MG) (p<0.05). The expression of superoxide dismutase (SOD) and catalase (CAT) in the OP+MG and OP+LG groups was up-regulated compared to the OP+HG groups (p<0.05). The rats in the OP+HG groups had lower levels of nuclear factor-κB (NF-κB), interleukin-1β (IL-1β), and malondialdehyde (MDA) expression than the rats in the OP+MG and OP+LG groups (p<0.05). This experiment demonstrates that the administration of GRE reverses behavioral dysfunction and prevents AD-like symptoms in our rat model.

[6]-Gingerolattenuates β-amyloid-induced oxidative cell death via fortifying cellularantioxidant defense system

 Abstract

β-Amyloid (Aβ) is involved in the formation of senile plaques, the typical neuropathological marker for Alzheimer’s disease (AD) and has been reported to cause apoptosis in neurons via oxidative and/or nitrosative stress. In this study, we have investigated the neuroprotective effect and molecular mechanism of [6]-gingerol, a pungent ingredient of ginger against Αβ_25–35-induced oxidative and/or nitrosative cell death in SH-SY5Y cells. [6]-Gingerol pretreatment protected against Aβ_25–35-induced cytotoxicity and apoptotic cell death such as DNA fragmentation, disruption of mitochondrial membrane potential, elevated Bax/Bcl-2 ratio, and activation of caspase-3. To elucidate the neuroprotective mechanism of [6]-gingerol, we have examined Aβ_25–35-induced oxidative and/or nitrosative stress and cellular antioxidant defense system against them. [6]-Gingerol effectively suppressed Aβ_25–35-induced intracellular accumulation of reactive oxygen and/or nitrogen species and restored Aβ_25–35-depleted endogenous antioxidant glutathione levels. Furthermore, [6]-gingerol treatment up-regulated the mRNA and protein expression of antioxidant enzymes such as γ-glutamylcysteine ligase (GCL) and heme oxygenase-1 (HO-1), the rate limiting enzymes in the glutathione biosynthesis and the degradation of heme, respectively. The expression of aforementioned antioxidant enzymes seemed to be mediated by activation of NF-E2-related factor 2 (Nrf2). These results suggest that [6]-gingerol exhibits preventive and/or therapeutic potential for the management of AD via augmentation of antioxidant capacity.

Cancer

NAC interferes with some anti-cancer actions, be careful if self treating

6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, andGADD 153 expression

Abstract

Ginger, the rhizome of Zingiber officinale, is a traditional medicine with anti-inflammatory and anticarcinogenic properties. This study examined the growth inhibitory effects of the structurally related compounds 6-gingerol and 6-shogaol on human cancer cells. 6-Shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] inhibits the growth of human cancer cells and induces apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 6-shogaol-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. Up-regulation of Bax, Fas, and FasL, as well as down-regulation of Bcl-2 and Bcl-X_L were observed in 6-shogaol-treated COLO 205 cells. N-acetylcysteine (NAC), but not by other antioxidants, suppress 6-shogaol-induced apoptosis. The growth arrest and DNA damage (GADD)-inducible transcription factor 153 (GADD153) mRNA and protein is markedly induced in a time- and concentration-dependent manner in response to 6-shogaol.

Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol,[10]-gingerol and [6]-shogaol

Results

In the antioxidant activity assay, [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol exhibited substantial scavenging activities with IC₅₀ values of 26.3, 19.47, 10.47 and 8.05 μM against DPPH radical, IC₅₀ values of 4.05, 2.5, 1.68 and 0.85 μM against superoxide radical and IC₅₀ values of 4.62, 1.97, 1.35 and 0.72 μM against hydroxyl radical, respectively. The free radical scavenging activity of these compounds also enhanced with increasing concentration (P < 0.05). On the other hand, all the compounds at a concentration of 6 μM have significantly inhibited (P < 0.05) f-MLP-stimulated oxidative burst in PMN. In addition, production of inflammatory mediators (NO and PGE₂) has been inhibited significantly (P < 0.05) and dose-dependently.

Conclusions

6-Shogaol has exhibited the most potent antioxidant and anti-inflammatory properties which can be attributed to the presence of α,β-unsaturated ketone moiety. The carbon chain length has also played a significant role in making 10-gingerol as the most potent among all the gingerols. This study justifies the use of dry ginger in traditional systems of medicine.

Growth Inhibition of Human Non-Small Lung Cancer Cells H460 By Green Tea and Ginger Polyphenols

Conclusion: The study reports the antiproliferative and apoptosis-mediated cytotoxic effects of green tea and ginger polyphenolic extracts on human H460 cell line, indicating their promising chemopreventive effect against lung cancer.

Conclusion

Ginger certainly does look to be good for you, but it has to be uncooked, otherwise you lose those gingerols.

I expect in ten years’ time we will know whether RAS signaling does underlie the autism of a wider group of people than those with currently identified RASopathies.

If you are impatient to know the answer you have a few choices:-

·        Statins

·        Gingerols

·        Other farnesyltransferase inhibitors (FTIs), a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in cancer.