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Thursday, 5 March 2015

Gingerols and Statins (as Farnesyltransferase inhibitors) for RASopathies and Some Autism

Today’s post was driven by another attempt not to take a statin.


Statins are among the world’s most prescribed, and yet most maligned, drugs.  Hundreds of millions of people take a statin drug every day to lower their cholesterol, but a small, vocal minority complain about muscle pains, memory loss and even type 2 diabetes.

Since my Polypill is evidently a therapy, and not a cure, for autism, the odds are that it will be needed life-long.  Regardless of the apparent lack of side-effects, nobody should be taking drugs/supplements that are not really needed.  Atorvastatin (Lipitor/Sortis) is part of my Polypill for the type of autism affecting Monty, aged 11, with ASD.

Every time I stop the statin part of my Polypill therapy, I end up starting it again after only a one day break.  I notice all sorts of little behavioral changes that I really do not want to see.   

These changes involve loss of initiative, flexibility and motivation.  I really do not see how these would be measured in any existing behavioral assessment of autism.  These little changes make a big difference in daily life, so-called adaptive behavior.

In case you are wondering, the types of people with autism that I think might benefit from statins, have high cholesterol and some of the following:-

·        Non-verbal, or people who are slightly verbal, but choose not to speak
·        Poor ability to generalize skills already mastered in 1:1 therapy
·        Great difficulty in separating
·        Great difficulty in coping with change

As with some other elements of the Polypill, there are numerous reasons why statins could/should help in autism.  Today I found yet another one and an interesting non-drug alternative.


Why Statins?

I originally choose statins as a possible therapy, based on their ability to control pro-inflammatory cytokines (e.g. cytokine storms), and their known neuro-protective properties (e.g. reduce mortality after a traumatic brain injury).

I then noted they also affect some autism target genes, such as PTEN and BCL-2.

I did also note that statins were being researched to treat Neurofibromatosis, a single gene condition that is frequently comorbid with an “autism” diagnosis.

Today’s post is really about why statins should help in Neurofibromatosis and what else shares the same mechanism of action. 

Putting aside cytokines, PTEN and BCL-2, this new mechanism (excessive RAS/ERK signaling) might also be active in broader autism and Intellectual Disability / MR.

The other recent development was a study at UCLA that looked at a rare condition called Noonan Syndrome.  Noonan Syndrome and Neurofibromatosis are members of a group of conditions called RASopathies.


The RASopathies are developmental syndromes caused by mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinases that control signal transduction.


Drawing upon Silva’s previous research on neurofibromatosis 1, another Ras-influenced disease, the UCLA team treated the mice with lovastatin, an FDA-approved statin drug currently in wide clinical use.

When adult mice with Noonan were treated with lovastatin in the UCLA study, the drop in Ras activity dramatically improved their memory and ability to remember objects and navigate mazes.

We were amazed to see that statin treatment restored the adult animals’ cognitive functions to normal. Traditionally, science assumes that therapy needs to start in the fetal stage to be effective,” explained Silva. “Our research suggests that the leading gene mutation responsible for Noonan syndrome plays critical roles not only in fetal development, but also in how well the adult brain functions.”

According to Silva, UCLA’s approach could help the estimated 35 million Americans who struggle with learning disabilities

The paper itself:-





RAS/ERK Inhibitors

For those of you more interested in the implications, rather than the science, here they are.

Known RAS inhibitors include:-


·        Statins, the popular cholesterol reducing drugs.  The “lipophilic” statins (Simvastatin, Lovastatin, Atorvastatin) can cross the blood brain barrier

·        Farnesyltransferase inhibitors, these are mainly anti-cancer research compounds, but one is the flavonoid Gingerol


Gingerol, is the active constituent of fresh ginger.  It is normally found as a pungent yellow oil, but also can form a low-melting crystalline solid.
Cooking ginger transforms gingerol into zingerone, which is less pungent and has a spicy-sweet aroma. When ginger is dried, gingerol undergoes a dehydration reaction forming shogaols, which are about twice as pungent as gingerol. This explains why dried ginger is more pungent than fresh ginger.
Ginger also contains 8-gingerol, 10-gingerol, and 12-gingerol.

Physiological effects

Gingerol seems to be effective in an animal model of rheumatoid arthritis.

Gingerol has been investigated for its effect on cancerous tumors in the bowel, breast tissue, ovaries, the pancreas, among other tissues, with positive results.



Neurofibromatosis, Behavioral dysfunction and RAS signaling

Neurofibromatosis Type 1: Modeling CNS Dysfunction


Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest CNS abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights into RAS and cAMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation.

Working memory, which, like attention, depends on intact prefrontal circuitry, is also impaired in both Nf1+/− mice and in individuals with NF1. Functional imaging studies showed that the working memory impairments of NF1 subjects correlated with hypoactivation in the prefrontal cortex, which may reflect increased GABA-mediated inhibition in prefrontal cortical circuits of Nf1+/− mice. Remarkably, a dose of a GABA receptor inhibitor (picrotoxin), which caused deficits in working memory in control mice, rescued the working memory deficits of Nf1+/− mice, a result consistent with the hypothesis that increased inhibition is at the root of the working memory deficits associated with NF1.

Increases in RAS/ERK signaling in Nf1+/− mice have been implicated in the working memory, attention, and spatial learning deficits of these mice. Genetic and pharmacological manipulations that target the RAS/ERK signaling pathway were shown to rescue the physiological and behavioral deficits of Nf1+/− mice. Importantly, pharmacological manipulations that impair the isoprenylation of RAS (statins, farnesyl transferase inhibitors), and therefore decrease the levels of RAS/ERK signaling, also rescue key electrophysiological and behavioral phenotypes of Nf1+/− mice. Indeed, at concentrations that do not affect signaling, physiology, or behavior of wild-type controls, statins reverse the signaling, electrophysiological, attention, and spatial learning deficits of Nf1+/− mice. Prompted by these findings, clinical studies are currently underway to test the efficacy of statins as a treatment for the behavioral and cognitive deficits in individuals with NF1.

Similar to individuals with NF1, Nf1 mutant mice also show attention deficits. These deficits are thought to be key contributors to academic and social problems in children with NF1. Using an additional Nf1 GEM strain to study attention, in which the Nf1+/− mutation is combined with Cre-driven homozygous Nf1 gene deletion in GFAP-expressing cells (Nf1 OPG mouse), it was found that reduced striatal dopamine was responsible for the observed attention deficits. Treatment with methylphenidate (but not with drugs that affect RAS) reversed the attention deficits of these Nf1 OPG mutants, suggesting that defects in brain catecholamine homeostasis contribute to the attention deficits observed. These results suggest that, in addition to drugs that affect RAS/ERK signaling, drugs that manipulate dopaminergic function could also be used to treat the cognitive deficits associated with NF1.

Treatments and future directions

With the availability of genetically engineered mouse models for NF1-associated CNS pathology, it now becomes possible to envision a pipeline in which fundamental basic science discoveries lead to the identification of new cellular and molecular targets for therapeutic drug design, culminating in preclinical evaluation before testing in patients with NF1. First, the success of Nf1 mouse model implementation has already resulted in the clinical evaluation of lovastatin in children with NF1-associated learning deficits and rapamycin analogs for the treatment of glioma. Second, mouse models afford an opportunity to envision specific features of NF1 as distinct diseases defined by the timing of NF1 gene inactivation or the particular cell of origin. Similar to other cancers, the identification of molecular or cellular subtypes of NF1-associated nervous system tumors or learning/behavioral problems may result in more individualized treatments with a higher likelihood of success. Third, as we further exploit these powerful preclinical models, additional cellular and molecular targets may emerge as candidates for future therapeutic drug design. In this regard, one could envision more effective therapies resulting from the combined use of targeted inhibition of multiple growth control pathways regulated by neurofibromin in the neoplastic cell (NF1-deficient neuroglial precursor) or dual targeting of non-neoplastic (microglia) and neoplastic cells within NF1-associated CNS tumors.


RASopathies & Autism



Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.


This systematic study offers empirical support that autism traits are associated with developmental Ras/MAPK pathway dysregulation. It suggests that individuals affected by RASopathies should be evaluated for social communication challenges and offered treatment in these areas. This is the first strong evidence that multiple members of a well-defined biochemical pathway can contribute to autism traits. Future studies could explore potential modifying or epistatic factors contributing to variation within the RASopathies and the role of Ras/MAPK activation in idiopathic ASDs.



RAS/ERK Inhibitors

Inhibition of Ras for cancer treatment: the search continues



Discussion

Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer.

Conclusions

Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.




Conclusion

In some people with “autism” statins are an effective therapy.  Higher doses of statin are associated with side effects.  By knowing the principal mode of action of statins in autism, we might be able to develop a more potent therapy – STATIN PLUS.

On the basis of today’s post, investigating Farnesyltransferase inhibitors, as inhibitors of RAS signalling, looks an interesting option.

Gingerol is available as an inexpensive, supposedly standardized, productGinger itself has been safely used in traditional medicine for thousands of years.

Perhaps Gingerol is the PLUS and for people unwilling to use a statin, perhaps Gingerol could be the statin?


The current medical view on ginger:-


Recent preliminary results in animals show some effect in slowing or preventing tumor growth. While these results are not well understood, they deserve further study. Still, it is too early in the research process to say whether ginger will have the same effect in humans.



  
Note on Intellectual Disability / MR

Regular readers may recall, I have commented that not only are many types of autism partially treatable, but so should be some types of Intellectual Disability / MR.  This same theme about treating cognitive dysfunction is raised in the paper below.

In the days when most readers of this blog were at school, 30-50% of people with an autism diagnosis were also diagnosed with Intellectual Disability / MR.  This is no longer the case; as autism diagnoses have skyrocketed in Western countries, diagnosis of Intellectual Disability / MR has not followed it.

People born today with what used to be called autism, often suffer from epilepsy and impaired cognitive function.  They do now tend to get rather sidelined by the much wider scope of the “autism” diagnosis used today, mainly in Anglo-Saxon countries (where most research is carried out).

The point where this matters is in clinical trials, since many of the milder autisms (now even being called “quirky autism”) may be caused by entirely different dysfunctions.  The observational diagnosis of “autism” is enough to enter most trials, but as we have seen in this blog, autism is not a true diagnosis; it is merely a description of symptoms.  It is like going to the doctor and saying “I think I might have a head ache” and after some questions, the doctors sits back and says “yes, you have a headache”.  You want to know why you have a head ache and how to make it go away.



A fraction of the cases of intellectual disability is caused by point mutations or deletions in genes that encode for proteins of the RAS/MAP Kinase signaling pathway known as RASopathies. Here we examined the current understanding of the molecular mechanisms involved in this group of
genetic disorders focusing in studies which provide evidence that intellectual disability is potentially treatable and curable. The evidence presented supports the idea that with the appropriate understanding of the molecular mechanisms involved, intellectual disability could be treated pharmacologically and perhaps through specific mechanistic-based teaching strategies.







5 comments:

  1. Atorvastatin had a tremendous impact on my 6 year old daughter with Asperger (I have the same condition). I started with what I considered a low dose (2mg) and after about 3-4 hours she was significantly worse (peak blood concentration?), bad temper mostly. A few hours later however, about 6 hours after administration, she was transformed, very happy, she had a lot more initiative, she was “abnormally” sociable , talking loudly and with confidence instead of mumbling or not saying anything. She was more articulated and her speech patterns were also improved. She started role playing again with her preferred stuffed toys, something she stopped doing when she regressed at around 4 and then did on and off depending on how well her autism was controlled. I use it a bit as a barometer for her condition. I noticed similar improvements in her behaviors in the past with other supplements (ginger extract among others) but they rarely lasted or reached that level of effectiveness. I hope this one lasts.

    I think the negative initial effect is due to her “main problem” which is an excessive immune reaction to almost anything she eats, it causes regression lasting from a few hours to 2 or 3 days depending on the offending food type (a very restricted diet is helping a lot). I suppose Atorvastatin triggers the same reaction but eventually the beneficial effect takes over. I tried a higher dosage (2.5mg) but the negative side effects lasted almost all day so I am now trying to find the lowest possible dosage and will probably split it in 2, leaning towards maybe 0.7g twice a day.



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    Replies
    1. That is good to hear, but the short term negative effects are a surprise. Autism is very specific to the individual and a problem in one area can impact the effectiveness of another therapy.

      I think many people's autism is driven by what is going on in their intestines. This is not the case in my son, who can eat anything and everything.

      Many things can reduce gut permeability, which might be an issue. Sodium butyrate is interesting but there are many therapies that might help (melatonin, L.reuteri ...).

      Let us know how things progress.

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    2. I've been using atorvastatin for my 9yo son for a few months on and off with caution. 2,5 mg is the current dose and he's on other drugs possibly influencing statins metabolism. Initiative was the most easy to describe effect, noticed by others.

      Behaviours shortly after food intake are reported in children with autism. It also used to happen in my son .
      I have two ideas about it, the first is GI mast cell driven reaction. Sodium cromoglicate (Nalcrom) helped my son with that.

      I also think that post meal insulin spike inducing potassium shift into the cells can drive similar effects as are described in hypokalemic periodic paralysis, but with regard to sensory issues (if a child is prone to hypokalemic sensory overload). Then low glycemic index diet would help or using potassium to high carb meals, like they do in hypoKPP. My son drinks potassium supplement with meals, but this is because of Bumetanide.
      Atorvastatin tablet would not cause insulin spike of course.

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    3. Christi,
      Your daughter's cholesterol level is normal high or low? You tried atorvastatin after testing cholesterol level or without testing it? Thank you.

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    4. I never had her tested. however she is very much like me (Asperger) and my cholesterol has always been low.

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