PAK inhibitors and potentially treating some Autism using Grandpa’s Medicine Cabinet

I wrote several posts about why PAK1 inhibitors should be beneficial in some autism and indeed some schizophrenia.

We also saw that PAK1-blocking drugs could be potentially useful for the treatment of neurofibromatosis type 2, in addition to RAS-induced cancers and neurofibromatosis type 1.

One problem with drugs developed for cancer is that, even if they finally get approved, they tend to be ultra-expensive.  Production volumes are low because even if they “work” they do not prolong life for so long and cancer has numerous sub-types.

Cheap drugs are ones used to treat common chronic conditions like high blood pressure, high cholesterol and indeed treatment of male lower urinary tract symptoms (LUTS), like benign prostatic hyperplasia (BPH).

A small number of readers of this blog have confirmed the beneficial effect of PAK inhibitors in their specific sub-types of autism.  The problem is that there are no potent PAK1 inhibitors suitable for long term use that are readily available.

The anti-parasite drug Ivermectin is an extremely cheap PAK1 inhibitor, but cannot be used long term, due to its other effects.

Propolis containing CAPE (Caffeic Acid Phenethyl Ester) is a natural PAK1 inhibitor, but may not be sufficiently potent as is reported by people with neurofibromatosis.

You would think somebody would just synthesize CAPE (Caffeic Acid Phenethyl Ester) artificially and then higher doses could be achieved.

PAK Inhibitors and Treatment of Prostate Enlargement

I was rather surprised that research has recently been published suggesting that PAK inhibitors could be used to treat the prostate enlargement, common in most older men. 

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

Abstract

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α₁-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.

It looks like a PAK inhibitor could potentially solve both the key problems in BPH and so replace the current therapies.

Existing Drugs for LUTS/BPH

Undoubtedly someone is going to wonder whether existing drugs for LUTS/BPH might improve autism.  This is actually possible, but totally unrelated to PAK1 inhibition and RASopathies.

Existing drugs are in two classes, 5α-reductase inhibitors and α₁-adrenoceptor antagonists.

α-adrenoceptor antagonists

Alpha blockers relax certain muscles and help small blood vessels remain open. They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure.

Because alpha blockers also relax other muscles throughout the body, these medications can help improve urine flow in older men with prostate problems.

Selective α₁-adrenergic receptor antagonists are often used in BPH because it is the α₁-adrenergic receptor that is present in the prostate.

 α ₂-adrenergic receptors are present elsewhere in the body

Alpha-2 blockers are used to treat anxiety and post-traumatic stress disorder (PTSD). They decrease sympathetic outflow from the central nervous system. Post-traumatic stress disorder is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system.

Alpha-2 receptor agonists for the treatment of post-traumatic stress disorder

So a nonselective alpha blocker, like one given to an older man with high blood pressure and BPH, might well have an effect on some kinds of anxiety.

You would think that a selective alpha 2 blocker might be interesting, how about Idazoxan?

Idazoxan is a drug which is used in research. It acts as both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in schizophrenia. Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, a brain area thought to be involved in the pathogenesis of schizophrenia.

Mirtazapine is a cheap generic drug used at high doses for depression.  It happens to be a selective alpha 2 blocker, but it has numerous other effects as well.  One reader of this blog does respond very well to Mirtazapine.

So realistically in Grandpa’s medicine cabinet there might a selective alpha 1 agonist or a non-selective alpha agonist, it is the latter type that might have an effect on some kinds of autism.

5α-reductase inhibitors

The pharmacology of 5α-reductase inhibition involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone.

Beyond being a catalyst in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC).

In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function.

These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABA_A receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT.

This, in turn, results in slight elevations in testosterone and estradiol levels. 

In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.

A new look at the 5alpha-reductase inhibitor finasteride

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.

This would suggest that a 5α-reductase inhibitor, like finasteride, that might be among Grandpa’s tablets might very well have an effect on someone with GABAa dysfunction, this includes very many people with autism, schizophrenia and Down Syndrome.

Whether the effect will be good or bad is hard to say, and may well depend on whether other drugs that target GABA or NMDA receptors are being used. Due to their other effects, 5α-reductase inhibitors are usually only used in adults.

Merck developed a lower dose form of finasteride, called Prospecia to treat baldness, usually in men.  It is 20% the normal potency used for BPH.

Side effects

The current BPH drugs cause side effects in some people.  PAK1 inhibitors may also have some side effects.

Conclusion

Going back in the days of living with your extended family might make treating many people’s autism much simpler.  It looks like many older people’s drugs can be repurposed for some types of autism (ion channel modifying diuretics, calcium channel blockers, statins, even potentially intranasal insulin in some).  Because older people’s drugs are so widely used they are well understood and inexpensive.  

Clearly the research on PAK inhibitors for LUTS/BPH is at an early stage, but there is a huge potential market.   A widely available PAK1 inhibitor might be a big help to some people with autism, neurofibromatosis, other RASopathies, not just Grandpa’s prostate.

In addition to FRAX486 and IPA3, why doesn’t someone try synthetic CAPE, i.e. without the bees, as a PAK inhibitor?

Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.

There is far more chance of a PAK1 inhibitor coming to market for LUTS/BPH, or certain cancers than for autism.  That is a fact of life.

As for 5α-reductase inhibitors, like finasteride, we know from Hardan’s study on Pregnenolone at Stanford that this hormone can have a positive effect and we know that various natural steroid metabolites will modulate GABA subunits.  So it is quite likely that finasteride is going have a behavioral effect.  Perhaps Hardan would like to trial finasteride 5mg and 1mg (Prospecia) in some adults with autism. I suspect it will make some people “worse” and others somewhat “better”; so please do not report the “average” response, highlight the nature of the positive responders.

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.

.

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.