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Showing posts with label Simvastatin. Show all posts
Showing posts with label Simvastatin. Show all posts

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.







Monday 17 November 2014

Tuning Wnt Signaling for more/fewer hairs and to optimize Dendritic Spine Morphology in Autism




Today’s post is about another example of how evolution can play jokes on us.  It really is the case that a signaling pathway that controls hair growth is the same that determines the number and shape of dendritic spines in the brain.

This is good news not just for Homer Simpson but for people interesting in perking up behavior and cognitive function in autism.

The post also connects several subjects that we have previously encountered - dendritic spines which are abnormal in autism, Wnt signaling which is implicated in cancer (and autism), statins, Ivermectin, CAPE found in some propolis and verapamil.  There is plenty of research to back all these connections, but strangely nobody seems to be applying them to develop any practical therapies.

I introduced dendritic spines in an earlier post.  Each neuron in your brain has hundreds of protruding spines.
Dendritic Spines in Autism – Why, and potentially how, to modify them

In that post I reported that PAK1, the gene NrCAM and the protein MTOR were all implicated in the dysfunction in both shape and number of these spines.

It now seems that there may be one even more critical pathway involved – Wnt. There are links between Wnt and PAK1, that appeared in several earlier posts.

You may recall that dendritic spines are constantly changing shape.  Their shape affects their function.  In many disorders, both the number and shape of the spines is dysfunctional.  It appears that the morphology (shape) can be modified, which implies you could affect behavior, memory, and cognitive function.







My follow up post of dendritic spines has yet to materialize, but here is a sneak preview, showing the progression of autism, schizophrenia and Alzheimer’s in terms of the number of dendritic spines.









Dendritic Spines and Wnt Signaling

Dendritic spines are constantly changing their shape and certain psychiatric disorders are characterized by different morphologies (shapes) of these spines.  It is not just the number of spines, but their shape which affects cognitive function, memory and behavior.

The Wnt signaling pathway also lies behind hair growth.

What is more, we know that Wnt signaling is dysfunctional in autism and we even now which the genes are that likely trigger of this dysfunction.

Wnt dysfunction is also involved in many types of cancer and therefore has been subject of much research.

The surprise came when I read that attempts are underway to “tune” Wnt signaling to control hair growth.  Why not autism?

This post is about tuning Wnt signaling to improve cognitive function and behavior.  This appears just as plausible as controlling hair growth.



The Wnt Signaling Pathways

Here is the Wikipedia explanation.

Wnt signaling pathway



The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. All three Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved, which means they are similar across many species from fruit flies to humans.[1][2]
Wnt signaling was first identified for its role in carcinogenesis, but has since been recognized for its function in embryonic development. The embryonic processes it controls include body axis patterning, cell fate specification, cell proliferation, and cell migration. These processes are necessary for proper formation of important tissues including bone, heart, and muscle. Its role in embryonic development was discovered when genetic mutations in proteins in the Wnt pathway produced abnormal fruit fly embryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.
The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, and others.[3][4]


The Canonical Wnt pathway is dysfunctional in Autism

It is the canonical Wnt pathway that is dysfunction in autism and it is this same pathway plays a role in dendrite growth and suboptimal Wnt activity negatively affects the dendritic arbor.

A very thorough review of all the genetic evidence is provided in the following study:



Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms.


The review highlights that, as we have seen before, some people with autism are hypo and some people are hyper; this means some people need Wnt signaling to be inhibited and other people need the opposite therapy.  The author points out that you really need some test to check which way you need your Wnt “tuned”.  

It sounds a bit like tuning the timing of the sparks inside your car engine, in the days before it was all electronic and self-tuning.  In theory you needed to measure the timing of the sparks with a special strobe light; but if you knew what you were doing you could just use your ears.  So in the same vein, you could make a small change to inhibit Wnt and see the result, if it made matters worse you just stop and go the other way.  As you will see later in this post, some of us are already tuning Wnt without even realizing it.

We have exactly the same issue with mGluR5, where you might need a positive/negative allosteric modulator to optimize brain performance.  Different variants of “autism” would be located either left or right of “top dead center”.

In that post we learnt that at MIT they are suggesting that errors in synaptic protein synthesis are behind several types of autism and that these errors can be corrected using either positive or negative stimulators of the receptor mGluR5.









For a more detailed understanding of Wnt signaling, see the paper below:-





For Homer Simpson and others wanting more hair




Abnormal hair development and regeneration has been implicated in diseases of the skin (ie., hirsutism, alopecia, etc) or in open wounds when hair follicles are completely eliminated. To manage these clinical conditions, it is important to understand molecular pathways which regulate the number, size, growth and regeneration of hair follicles. Wnt signaling plays a fundamental role in this process. We need a deeper understanding so we can reliably adjust Wnt levels in existing follicles. This studies reviewed here have future translational value for skin regeneration following severe wound injuries or in the context of tissue engineering. Tuning the levels of Wnt ligands can directly modulate the number and growth of hairs. Using this new knowledge, we now know that Wnt activity can be modulated by adjusting the secretion of Wnt ligands, altering binding of ligands to receptors, inhibiting β-catenin translocation, or by regulating extra-follicular dermal Wnt and Wnt inhibitors.



How to tune Dendritic Spine Morphology

We have already encounter Brain-Derived Neurotropic Factor  (BDNF) in an earlier post.  You could think of BDNF as brain fertilizer.



“Older people and anyone with Retts Syndrome are likely to benefit from more NGF (Nerve Growth Factor).  In autism it appears possible that there was too much NGF and BDNF at a very early age, with levels then changing.  High levels of NGF and BDNF look a bad idea.  A lot more research is needed to understand what determines  NGF and BDNF levels.  It appears that BDNF may stay high in autism, but NGF levels.”

It has been shown that BDNF and Wnt signaling together regulate dendritic spine formation.

So, since in autism we have excess BDNF as the brain is developing, this might explain there are too many dendritic spines in autistic brains.  Too many spines and the wrong morphology (shape) would explain very many issues that have gone “wrong” in autistic brains.




Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.
BDNF overexpression rapidly and robustly increases primary dendrite formation in cortical neurons (Horch et al., 1999; McAllister et al., 1997; Wirth et al., 2003). We reproduced this finding, and found that this increase was not blocked by overexpression of the Wnt inhibitors (Fig. S2), indicating that some aspects of BDNF modulation of dendrites remain intact in the presence of Wnt inhibitors. To further assess whether expression of the Wnt inhibitors impaired the signaling ability of BDNF, we analyzed autocrine induction of c-Fos expression by BDNF overexpression. c-Fos is an immediate early gene whose transcription is rapidly upregulated by BDNF (Calella et al., 2007; Gaiddon et al., 1996). We found that BDNF induced c-Fos expression was not reduced in neurons overexpressing any of the four Wnt inhibitors, suggesting that the ability of the inhibitors to interfere with BDNF-induced spine formation and spine head width expansion was not a result of decreased levels of BDNF signaling (Fig. S3).

Wnt2 overexpression is sufficient to increase cortical dendrite length. (A) Representative cortical neurons expressing either EV or Wnt2. Quantification of the total dendrite length per neuron (B) and the number of dendritic endpoints per neuron (C) for ...
Wnt2 overexpression increases dendritic protrusion density and influences spine shape on cortical neurons. (A) Representative dendritic segments of cortical neurons expressing either EV or Wnt2. (B) Quantification of dendritic protrusion density. (C) ...


Wnt inhibition and dendritic spine maturation

We found that a series of different Wnt signaling inhibitors were able to block BDNF-induced increases in dendritic spine density and dendritic spine head width


I think all this existing science really tells us a lot.


Back in the slow lane

In cancer research, decades have already been spent investigating Wnt signaling.




Drugs that Enhance Wnt Signaling

Back in my world, with a little help from Google scholar, I rapidly find that drugs already exist that affect Wnt signaling.  Some very familiar names pop up.




SummaryStatins improve recovery from traumatic brain injury and show promise in preventing Alzheimer disease. However, the mechanisms by which statins may be therapeutic for neurological conditions are not fully understood. In this study, we present the initial evidence that oral administration of simvastatin in mice enhances Wnt signaling in vivo. Concomitantly, simvastatin enhances neurogenesis in cultured adult neural progenitor cells as well as in the dentate gyrus of adult mice. Finally, we find that statins enhance Wnt signaling through regulation of isoprenoid synthesis and not through cholesterol. These findings provide direct evidence that Wnt signaling is enhanced in vivo by simvastatin and that this elevation of Wnt signaling is required for the neurogenic effects of simvastatin. Collectively, these data add to the growing body of evidence that statins may have therapeutic value for treating certain neurological disorders.Simvastatin rescues cerebrovascular and memory-related deficits in mouse models of Alzheimer disease (AD) (Li et al., 2006; Tong et al., 2009, 2012), and recent meta-analysis of clinical studies concluded that statins provide a slight benefit in the prevention of AD and all-type dementia (Wong et al., 2013). While these effects have been attributed to reduction of inflammation, reduced oxidative stress, upregulated PI3K/AKT signaling, and enhanced neurogenesis, the mechanisms by which statins are beneficial in neurological disorders are not fully understood.Simva is under investigation for its potential therapeutic effects outside of hyperlipidemia treatment. While statins have been reported to enhance Wnt signaling in vitro, it was heretofore not known whether statins can enhance this pathway in vivo and in the context of neurogenesis. Here we provide evidence that oral simva treatment enhances Wnt signaling in the mammalian adult hippocampus. This is significant in that aside from lithium, no other clinically approved compound has been demonstrated to enhance Wnt signaling in the brain


You will find the element Lithium in your smart phone battery, but it is also a drug.

Lithium is useful in the treatment of bipolar disorder. Lithium salts may also be helpful for related diagnoses, such as schizoaffective disorder and cyclic major depression. The active part of these salts is the lithium ion Li+.

But, not surprisingly, Lithium has other effects, like activating Wnt signaling.





Drugs that inhibit Wnt Signaling

There are drugs with the opposite effect, inhibiting Wnt signaling.


Abstract
In past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. FRZB, a soluble antagonist of Wnt signaling, has been studied in osteoarthritis (OA) animal models and OA patients as a modulator of Wnt signaling. We screened for FDA-approved drugs that induce FRZB expression and suppress Wnt/β-catenin signaling. We found that verapamil, a widely prescribed L-type calcium channel blocker, elevated FRZB expression and suppressed Wnt/β-catenin signaling in human OA chondrocytes. Expression and nuclear translocation of β-catenin was attenuated by verapamil in OA chondrocytes. Lack of the verapamil effects in LiCl-treated and FRZB-downregulated OA chondrocytes also suggested that verpamil suppressed Wnt signaling by inducing FRZB. Verapamil enhanced gene expressions of chondrogenic markers of ACAN encoding aggrecan, COL2A1 encoding collagen type II α1, and SOX9, and suppressed Wnt-responsive AXIN2 and MMP3 in human OA chondrocytes. Verapamil ameliorated Wnt3A-induced proteoglycan loss in chondrogenically differentiated ATDC5 cells. Verapamil inhibited hypertrophic differentiation of chondrocytes in the explant culture of mouse tibiae. Intraarticular injection of verapamil inhibited OA progression as well as nuclear localizations of β-catenin in a rat OA model. We propose that verapamil holds promise as a potent therapeutic agent for OA by upregulating FRZB and subsequently downregulating Wnt/β-catenin signaling.








AbstractConstitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.


Previous studies have revealed that its anti-tumor function could be attributed to its ability to suppress the abnormal Wnt/β-catenin signaling pathway


What about hair loss/gain?

To quote from  the previous study on hair loss gain:-

“Using this new knowledge, we now know that Wnt activity can be modulated by adjusting the secretion of Wnt ligands, altering binding of ligands to receptors, inhibiting β-catenin translocation, or by regulating extra-follicular dermal Wnt and Wnt inhibitors.”

We have now learnt that the drug Verapamil is thought to be a Wnt inhibitor.  So it would be fair to assume that hair loss would be reported as a side effect of using Verapamil.  Indeed it is.

Dermatologic side effects have included rash (up to 1.4%). Diaphoresis has been reported with intravenous verapamil. Arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, and erythema multiforme have been reported during open trials/postmarketing experience.


What about Statins and hair?

So many millions of people take statins, of course somebody would claim it causes hair loss (alopecia).  I think it should cause hair gain.  As with Verapamil the effect on the hair growth would be much greater if it was applied to the skin and not taken orally.  Maybe older people would not go to the doctor to complain about hair gain?




Summary

·        As hair loss is a generally accepted male characteristic, drug-induced alopecia may be mistaken as part of a natural process and therefore under reported.
·        There have been reports of alopecia associated with the use of all UK licensed statins but there is insufficient data to confidently attribute hair loss to statin use.
·        Case studies suggest an association but as yet there is insufficient information to suggest a mechanism, make comparisons of the individual incidence of alopecia between the various statins or propose a class effect.
·        The greatest number of reports of alopecia is for simvastatin but this may be related to a greater market share or length of time on market.


It would seem that enough people lose hair from Verapamil for it to be a published side effect.  The same is not true for statins and I think hair loss may be coincidental.


But, maybe too much and too little Wnt signaling cause hair loss ?

Recall earlier in this post that Hans Otto Kalkman suggested that both too much and too little Wnt might cause similar behavioral and cognitive symptoms.  Perhaps the same is true with hair growth.

The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms.

For optimal hair growth perhaps there is an optimal amount of Wnt signaling? 

That might explain why a small number of people find Wnt inhibitors (Verapamil) and drugs that enhance Wnt (statins) cause hair loss.

That might mean that people with very full hair have optimal Wnt signaling?

So advise Homer Simpson to find out whether his Wnt signaling is hyper or hypo.  Then he might find either simvastatin or verapamil brings back his full head of hair.



Wnt signaling and Diabetes

Yet again we find another connection between Diabetes and autism.

In the pancreas  β-cells produce insulin. In diabetics these β-cells get destroyed.  It appears that Wnt signaling is involved in controlling these β-cells.  It has been proposed that they could be protected via this pathway.


Role of Wnt signaling in the development of type 2 diabetes.

 

Abstract

Type 2 diabetes is characterized by insulin resistance, insulin deficiency, and hyperglycemia. Susceptibility to type 2 diabetes has been linked to Wnt signaling, which plays an important role in intestinal tumorigenesis. Carriers of variants of the transcription factor 7-like 2 gene, an important component of the Wnt pathway, are at enhanced risk for developing type 2 diabetes. The modulation of proglucagon expression by Wnt activity may partially explain the link between Wnt signaling and diabetes, and one of the transcriptional and processing products of the proglucagon gene, the glucagon-like peptide-1 (GLP-1), exhibits a wide variety of antidiabetogenic activities. GLP-1 stimulates Wnt signaling in pancreatic beta cells, enhancing cell proliferation; thus, positive feedback between GLP-1 and Wnt signaling may result in increased proliferation, and suppressed apoptosis, of pancreatic cells. Since beta-cell protection is a potential treatment for type 2 diabetes, stimulation of Wnt activity may represent a valid therapeutic approach.




Here, we review emerging new evidence that Wnt signaling influences endocrine pancreas development and modulates mature β-cell functions including insulin secretion, survival and proliferation. Alterations in Wnt signaling might also impact other metabolic tissues involved in the pathogenesis of diabetes, with TCF7L2 proposed to modulate adipogenesis and regulate GLP-1 production. Together, these studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, highlighting the importance of further investigation of this pathway to develop new therapies for this disease.





As with autism and cancer, the people with diabetes are also perhaps not benefiting from the latest science.



Oral verapamil administration prevents β-cell apoptosis and STZ-induced diabetes.





The End.