Showing posts with label Lovastatin. Show all posts
Showing posts with label Lovastatin. Show all posts

Wednesday, 24 October 2018

Choose your Statin with Care in FXS, NF1 and idiopathic Autism

There are several old posts in this blog about the potential to treat some autism using statins; this has nothing to do with their ability to lower cholesterol. 

Statins are broadly anti-inflammatory but certain statins do some other particularly clever things. This led me to use Atorvastatin and Fragile-X researchers to use Lovastatin.

Fragile X is suggested by an elongated face and big/protruding ears; 
other features include MR/ID and autism.

I was recently forwarded a Scottish study showing why Simvastatin does not work in Fragile X syndrome, but Lovastatin does.
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E (see chart below). In people with Fragile X, they lack the FMR1 protein. Boys are worse affected than girls, because females have a second X chromosome and so a "spare" copy of the gene.

         Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.

So  ? = Does NOT inhibit

The researchers in Scotland did not test Atorvastatin in their Fragile X study.
The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

RASopathies have been covered in this blog. Too much of the Ras protein is a common feature of much ID/MR. Investigating RAS took me to PAK1 inhibitors and the experimental drug FRAX486. This drug was actually developed to treat Fragile X; it is now owned by Roche. At least one person is using FRAX486 to treat autism.
You might wonder why the researchers do not just try Lovastatin in humans with Fragile X.  Unfortunately, Lovastatin was never approved as a drug in Scotland, or indeed many other countries.  Some researchers just assumed they could substitute Simvastatin, which on paper looks a very similar drug and one that crosses the blood brain barrier better than Lovastatin.

The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1-/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1-/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX.  

Although we propose the beneficial effect of lovastatin stems from the inhibition of ERK1/2-driven protein synthesis, it is important to note that statins are capable of affecting several biochemical pathways. Beyond the canonical impact on cholesterol biosynthesis, statins also decrease isoprenoid intermediates including farnesyl and geranylgeranyl pyrophosphates that regulate membrane association for many proteins including the small GTPases Ras, Rho and Rac [18, 46, 48, 49]. The increase in protein synthesis seen with simvastatin could be linked to altered posttranslational modification of these or other proteins. Indeed, although we see no change in mTORC1-p70S6K signaling, other studies have shown an activation of the PI3 kinase pathway that could be contributing to this effect [32]. However, our comparison of lovastatin and simvastatin shows that there is a clear difference in the correction of pathology in the Fmr1-/y model, suggesting that the impact on ERK1/2 is an important factor in terms of pharmacological treatment for FX.  There are many reasons why statins would be an attractive option for treating neurodevelopmental disorders such as FX. They are widely prescribed worldwide for the treatment of hypercholesterolemia and coronary heart disease [50], and safely used for longterm treatment in children and adults [46]. However, our study suggests that care should be taken when considering which statin should be trialed for the treatment of FX and other disorders of excess Ras. Although the effect of different statins on cholesterol synthesis has been well documented, the differential impact on Ras-ERK1/2 signaling is not well established. We show here that, contrary to lovastatin, simvastatin fails to inhibit the RasERK1/2 pathway in the Fmr1-/y hippocampus, exacerbates the already elevated protein synthesis phenotype, and does not correct the AGS phenotype. These results are significant for considering future clinical trials with lovastatin or simvastatin for FX or other disorders of excess Ras. Indeed, clinical trials using simvastatin for the treatment of NF1 have shown little promise, while trials with lovastatin show an improvement in cognitive deficits [28-30]. We suggest that simvastatin could be similarly ineffective in FX and may not be a suitable substitute for lovastatin in further clinical trials.

If you are treating Fragile X, best to start with Lovastatin and see if it helps.  In theory it might also help NF1 (Neurofibromatosis Type 1).

It looks to me that Atorvastatin also inhibits the relevant pathway and does much more besides that (PTEN, BCL2 etc)

What is Roche doing with FRAX486?

Thursday, 12 November 2015

More Support for the use of Statins in some Autism

Monty, aged 12 with ASD, has been taking Atorvastatin for two years, with a clear cognitive improvement from day one.  

This improvement is lost when this therapy is interrupted.

There are several posts in this blog giving the scientific basis why statins might be beneficial in some autism, these included the genes/proteins RAS, PTEN and BCL2.  In addition, statins possess potent anti-inflammatory properties.

Following a flood of visits to this blog to read about statins and autism, I did a quick check and in recent weeks at least three papers have been published suggesting the potential for statins to improve some autism.

I include the word “some” because with 800 currently identified autism genes, and I expect eventually it will be thousands, what works for one person’s “autism” may not help the next person’s “autism” and might even make it worse.

The first paper is the one getting the media coverage, it is from the University of Edinburgh, plus Mark Bear et al from MIT.  Mark Bear’s lab has featured in this blog several times, particularly relating to Fragile-X.  Lovastatin is being already trialed in humans with Fragile-X.

I use Atorvastatin (Lipitor) because it has best side effect profile.  Lovastatin and Simvastatin will have the same effect.  In some countries these drugs are available cheaply OTC.

Their therapeutic effect in autism, based on my sample of one, is from the first pill.

Over to the "experts":-

Intellectual disabilities and autism spectrum disorders could share similar defects although their genetic causes are different, according to Scottish scientists.

A study of two models of intellectual disability in mice by Edinburgh University has found that they share similar disease mechanisms.

Researchers also found that treatment with a statin drug called Lovastatin, which is often used to treat high cholesterol, can correct high levels of protein production in the brain linked to the conditions.

The findings suggest that different types of intellectual disabilities may benefit from common therapeutic approaches, the researchers say.

Professor Peter Kind, Director of the University of Edinburgh’s Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities, said: “Statins, such as lovastatin, are already used widely for treating people, including children, for high cholesterol with minimal side effects.

“Further studies are needed to determine whether these existing medications could also help people with intellectual disabilities.”

The study has been published in the Journal of Neuroscience

The full paper is here:-

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap+/− and Fmr1−/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap+/− hippocampal slices. Super-resolution microscopy reveals that Syngap+/− and Fmr1−/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras–ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.
SIGNIFICANCE STATEMENT As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap+/− mice phenocopy Fmr1−/y mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu5 receptor–ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1−/y mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.

The other two papers are from 2015 Society for Neuroscience annual meeting in Chicago.


A drug that blocks a cancer-related pathway normalizes neuron number and prevents behavior problems in mice that lack a copy of the autism-linked chromosomal region 16p11.2. Researchers presented the unpublished results yesterday at the 2015 Society for Neuroscience annual meeting in Chicago.
Loss of 16p11.2 results in intellectual disability, enlarged head, obesity and, often, autism. This region spans 27 genes — including one called ERK1, part of a signaling cascade that regulates cell growth. The cascade, called the RAS pathway, is hyperactive in some types of cancer and in four rare autism-linked neurodevelopmental disorders, collectively dubbed ‘RASopathies.’ The proteins encoded by ERK1 and the related ERK2 gene carry out many of the molecular consequences of RAS pathway activation.

Paradoxically, the ERK proteins are hyperactive in mice lacking a copy of 16p11.21. This hyperactivation coincides with a period of intense neuron development in the mouse embryo. The animals also have too few neurons in some parts of the cerebral cortex, the brain’s outer layer, and too many neurons in others.

“Because of this aberrant ERK hyperactivity, we were thinking that we can potentially try to bring the levels down by using a specific ERK inhibitor,” says Joanna Pucilowska, a postdoctoral fellow in Gary Landreth’s lab at Case Western Reserve University in Cleveland, Ohio.

Sniffing clues:

Pucilowska and her colleagues used an experimental drug that blocks activation of the ERK proteins. They injected the drug into pregnant mice to investigate its effects on neuron development in mouse embryos.

Treating mice with the drug prenatally for five days stabilizes ERK activity, the researchers found. It also normalizes neuron numbers in the cerebral cortex.
The treatment has lasting effects on behavior, too. Unlike untreated mice that lack a copy of 16p11.2 — which are underweight, hyperactive and have memory problems — the treated mice resemble those that do not have the chromosomal deletion.
The researchers discovered for the first time that mice lacking 16p11.2 are quicker than those without the deletion to sniff out a hidden snack in their cage, suggesting they have a highly acute sense of smell, like some people missing 16p11.2. Female mice with the deletion are also faster to retrieve pups that stray from the safety of their nest, an innate maternal behavior. The drug treatment normalizes both behaviors.

Pucilowska says she and her colleagues would like to test the drug in cells derived from people missing a copy of 16p11.2. If it works in human cells the same way it does in mice, then it might be possible to treat people with the deletion using cholesterol-lowering drugs called statins, which are also known to block signaling in the RAS pathway. “This can potentially lead to the first treatment for children with 16p11.2 deletion,” Pucilowska says.

Structural changes in the connections between neurons may underlie the enhanced learning and motor skills seen in mice with an extra copy of the autism-linked gene MeCP2. Blocking these changes with a drug blunts the animals’ performance.
The findings, presented yesterday at the 2015 Society for Neuroscience annual meeting in Chicago, point to neural mechanisms underlying the restricted interests and, in some cases, exceptional learning abilities seen in people with autism.
“This could lead to enhanced learning and enhanced performance in constrained behaviors, like in autistic savants,” says Ryan Ash, a graduate student in Stelios Smirnakis’ lab at Baylor College of Medicine in Houston. “Maybe they can’t iteratively refine those kinds of behaviors over time, so they get stuck in a behavior, which can be exceptional in certain cases but then impaired in others.”
People carrying an extra copy of MeCP2 often have autism. Mice with the same duplication have autism-like symptoms, such as avoiding social interactions with other mice.
“But they also have a super-learner phenotype,” Ash says. They perform better than controls do on a test of motor skill learning that involves balancing on a rotating rod. Typical mice fall off the rod as its speed increases, but mice with the duplication learn to coordinate their feet so that they can stay on about 30 seconds longer.
When mice learn a motor task, new synapses, connections between neurons, form in the brain1. The researchers suspected that the superior learning abilities of the mice carrying the extra MeCP2 might stem from alterations in the formation and stability of these neuronal links.
To test this hypothesis, the researchers used microscopy to image neurons in the brain that connect to the spinal cord and control movement. They took pictures of the same neurons before and after the mice practiced the rotating rod test for four days, and again after the animals had four days of rest.
Spine support:
As expected, training spurred neurons in typical mice to form new signal-receiving projections, called dendritic spines. About half of these spines remained after four days of rest, suggesting the formation of stable memories. Mutant mice form more spines than controls do, and more of them stay put after the mice take a break.
The stable spines tend to cluster. Enhanced performance on the rod tracks with a greater number of clustered spines remaining after the rest period.
“We think this is important because spines that are near each other can drive the cell more strongly when they get activated at the same time,” Ash says.
Training stimulates greater activation of a signaling cascade called the RAS pathway in the mutant mice than it does in controls. Activation of this pathway is known to strengthen clustered spines2.
Blocking the activation of this pathway with an experimental drug called SL327 lowers the mutants’ performance on the rotating rod back to the normal range. And the spines in these animals also look more like those of typical mice.
The findings suggest that spine formation and stability underlie the enhanced learning abilities of the mutant mice. Both processes appear to depend on the activation of the RAS pathway.
The drug the researchers used lasts only for a few hours, so it is not likely to help people with autism, Ash says. But cholesterol-lowering drugs called statins block activation of the same pathway by a different mechanism. “Maybe you could do a more chronic treatment with a statin, but we haven’t tried that yet,” he says.
Other mouse models of autism show enhanced performance on the rotating rod test. These include mice with a duplication in chromosomal region 15q11-13 and with mutations in the CNTNAP2, NLGN3 and NRXN1 genes, Ash says.

Interestingly, mice that lack a copy of MeCP2 — the gene mutated in the autism-linked disorder Rett syndrome — have impaired performance on the same test, and show reduced spine stability. “I would hypothesize that all of these things are actually the opposite in the Rett mice,” Ash says.

Monday, 27 April 2015

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:


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.

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.
• 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
• 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:-

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

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,

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

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. 


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


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-agonistinduced 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.


“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

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.


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


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.

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

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.


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.


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.


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 Αβ25–35-induced oxidative and/or nitrosative cell death in SH-SY5Y cells. [6]-Gingerol pretreatment protected against Aβ25–35-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 Aβ25–35-induced oxidative and/or nitrosative stress and cellular antioxidant defense system against them. [6]-Gingerol effectively suppressed Aβ25–35-induced intracellular accumulation of reactive oxygen and/or nitrogen species and restored Aβ25–35-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.


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


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-XL 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.

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.
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.

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.


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.