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Showing posts with label Resveratrol. Show all posts
Showing posts with label Resveratrol. Show all posts

Monday 16 August 2021

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?

 


Adult-sized people with autism can cause property damage and much worse.


I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.

 

PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 

 

Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

 

Or just look up the old posts in this blog:- 


https://epiphanyasd.blogspot.com/search/label/PPAR%CE%B3


PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.

 

“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder


It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.

 

Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.

 

Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 

 

Conclusion

Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.

 

I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.





Thursday 7 February 2019

Pterostilbene for Neuromodulation – worth a look?

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Blueberries

A common criticism of this blog is that it is mainly about prescription drugs rather than OTC supplements.
Today’s post is about a supplement that is highly regarded by our reader Ling.
Pterostilbene is like a super potent version of resveratrol.  

Resveratrol is quite well known and has long been put forward as having some potentially highly beneficial health effects, but in practise it is just too poorly absorbed to have much effect in humans.
Pterostilbene is found in blueberries.  Also found in blueberries is Anthocyanin, which is worth a mention in this post, it is what gives blueberries their colour; very often it is the colour in a food that underlies part of its health benefit. This is why eating a mixed colour diet is a wise idea.
Aronia is extremely rich in anthocyanins and Aronia juice is very common where I live. We even have a bottle of the dark coloured juice in the kitchen.
The purple colour in beetroot is betanin, a so-called betacyanin and may well have anti-Alzheimer’s effects, inhibiting plaque formation.
Anthocyanin is put forward as one reason certain Japanese who eat large amounts of purple sweet potato do not suffer much cancer or dementia and live a very long time.


Today we are mainly looking at pterostilbene, but if you want Anthocyanins, to avoid dementia, just eat blue and purple coloured fruit and vegetables on a very regular basis.
Ling has proposed pterostilbene as a PDE4 inhibitor, but as is often the case, it has numerous other effects, so it would be hard to know which is the main reason it might be therapeutic.  


Known biological effects of Pterostilbene                                                                                   
Here is an excellent graphic that highlights many of the effects of Pterostilbene, other than on PDE4.





The regular readers of this blog will note that the great majority of the above signalling molecules are implicated in autism.

The proposed effects on the brain are highlighted in the next graphic





The source paper is here: -  

           

Based on the evidence presented, PTE (Pterostilbene) is more bioavailable and better at evoking molecular and functional events than RES (Resveratrol) in vivo

Although clinical trials are underway to assess the effects of RES in diseases such as dementia and AD, pre-clinical and clinical studies on PTE have yet to be conducted. Furthermore, the biological effects of many of the structural analogues of RES and PTE are unknown, and no studies have identified the metabolites of RES or PTE in brain tissues. There is a need for future studies to identify means of enhancing the efficacy and bioavailability of these compounds and to analyse the metabolites of these compounds in thebrain. Altogether, the evidence from a variety of studies strongly suggests the potential of RES and PTE as promising bioactive agents to improve brain health and prevent neurodegeneration

Most research, but not all, concerns aging and dementia. 


Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.

Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer's disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

Low-dose pterostilbene, but not resveratrol, is apotent neuromodulator in aging and Alzheimer's disease.

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene                                                                                                        


Effect of resveratrol and pterostilbene on aging and longevity.

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms.

One area of autism research concerns targeting mTOR signalling. This is covered in the paper below


and was the subject of this blog post from 2015


Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.


Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.


And finally, PDE4
Inhibiting PDE4 has some very useful anti-inflammatory benefits. It may also improve myelination and indeed cognition.  PDE4 inhibitors are currently used to treat severe asthma and in clinical trials for Multiple Sclerosis (MS) and cognitive enhancement.
There are different sub-types of PDE4.
Inhibiting one of the subtypes has the tendency to make you want to vomit.  This is currently the drawback that limits the use of PDE4 inhibiting drugs.
A selective PDE4 inhibitor is required.
As Ling has found, research does indeed show that pterostilbene is a PDE4 inhibitor.

The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.

The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2',3,5',5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.


Conclusion
Based on Ling’s recommendation, I have ordered some Pterostilbene and I am curious to see its effects. It is another substance that might be helpful for older adults, if not for your case of autism.
It is clear that in most cases resveratrol is a substance whose effect is limited to the test tube rather than humans. As a “super-resveratrol” we should take a closer look at Pterostilbene.
Eating large amounts of fruits, vegetables and berries with anthocyanins and betacyanins is going to do you no harm and does look a way to possibly secure a long healthy future, like those Japanese centenarians in Okinawa.







Tuesday 14 March 2017

Leptin Signaling and JAK Inhibitors in Early Onset Autism - perhaps RORα and Adiponectin?


A future baldness therapy (a JAK inhibitor) to treat some autism?

Today’s rambling post has been pending for some time. It got left on one side, but is interesting and can be applied.
As we know there are distinct sub-types of autism and fortunately so does Paul Ashwood at the UC Davis MIND Institute. He often splits his findings into regressive vs early onset autism. 


There is evidence of both immune dysregulation and autoimmune phenomena in children with autism spectrum disorders (ASD). We examined the hormone/cytokine leptin in 70 children diagnosed with autism (including 37 with regression) compared with 99 age-matched controls including 50 typically developing (TD) controls, 26 siblings without autism, and 23 children with developmental disabilities (DD). Children with autism had significantly higher plasma leptin levels compared with TD controls (p<.006). When further sub-classified into regression or early onset autism, children with early onset autism had significantly higher plasma leptin levels compared with children with regressive autism (p<.042), TD controls (p<.0015), and DD controls (p<.004). We demonstrated an increase in leptin levels in autism, a finding driven by the early onset group.

A second study also found elevated leptin levels. 


Results: We found decreased levels of resistin, increased levels of leptin and unaltered levels of adiponectin in plasma from ASD subjects in comparison with controls. There was also a negative correlation between the levels of adiponectin and the severity of symptoms as assessed by the SRS. Conclusion: There are significant changes in the plasma levels of adipokines from patients with ASDs. They suggest the occurrence of systemic changes in ASD and may be hallmarks of the disease.


So today's post is really investigating what high levels of leptin in early onset autism might mean.  Is this just another abnormality produced by autism, or is it something to be fixed?  It appears to be the latter.



In my simplification of classic autism one of my four broad categories is neuroinflammation. These four categories interrelate, so a problem with one may affect all four. There are all kinds of mechanisms involved in chronic inflammation and this is why there are so many types of treatment for arthritis, IBS, IBD etc.
Recall all those posts about the activated microglia, the brain’s main form of active immune defence, and how in autism the body’s “immunostat” is somehow stuck on maximum.
So there is a long list of immune-modulating therapies that might help autism.  There is already a long list for conditions like arthritis. 
What works wonders for a few, like the TSO parasite worms, fails to help the majority when a larger clinical trial is carried out. 
One mechanism involved in the immune response is leptin signaling, the subject of today’s post.
It should be most relevant to people with unusually high levels of leptin that includes obese people and people with early onset autism.
So we have a hormone (leptin) driving inflammation. We saw in an earlier post how an imbalance in testosterone/estrogen connects with an ion channel dysfunction (KCC2/NKCC1) via ROR. So the hormone dysfunction is making the channelopathy worse.  Not so surprisingly we will see how high leptin associates with high testosterone (and hence low aromatase/estrogen).  The α4 subunit of ROR appears to drive leptin production.
We then have the choice of blocking the negative effects of high levels of leptin or we can go back to RORα and again consider treating autism like aromatase deficiency.  Aromatase is the enzyme that converts testosterone to estrogen in males.


We saw in autism a lack of estrogen receptors and a lack of aromatase, this then resulted in a lack of the neuroprotective effects of estrogen, which protects females from developing autism.
So if we increase estradiol not only do we  affect neurolin2 to produce more KCC2 and so lower intracellular chloride, but via  RORα we should produce less leptin in adipose (body fat) tissue.

Option A
Use JAK inhibitors to block the negative inflammatory effect of excess leptin.  There are potent inhibitors approved for arthritis and it looks like milder ones will be approved for treating some kinds of hair loss.

Option B
Deal with the proposed Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis, by increasing estradiol and hope that via RORα, and more precisely RORα4, leptin levels reduce.
We know that high testosterone is associated with high leptin.
Since we want to solve as many of the damaging abnormalities found in autism, using the smallest number of therapies, Option B seems attractive.


Option C
Use a drug that reduces leptin.
Some PPAR gamma agonists are known to reduce leptin, including the thiazolidinedione Rosiglitazone. Some others do not.
PPAR gamma agonists have been used in autism for other reasons.

A natural PPAR gamma agonist is tangeritin/sytrinol.
There is a relationship between PPAR and RORα that is not yet understood in the literature.
Some readers of this blog are already using Option C.

Option D
Use a drug that raises adiponectin. Adiponectin is another hormone made in your fat cells and it reduces leptin. In some studies, low levels of Adiponectin are found in autism and that is not good for your wider health.
There is naturally some overlap with the therapies in option C.
Ways known to increase Adiponectin include:-

·        PPAR-γ agonists like rosiglitazone

·        PPAR- α agonists, like fibrates

·        ACE inhibitors, like Trandolapril

·        some statins (not simvastatin)

·        Niacin

·        renin-angiotensin-aldosterone system blockers

·        some calcium channel blockers, like Verapamil

·        mineralocorticoid receptor blockers,

·        new β-blockers

·        vanadyl sulfate (VS)

·        natural compounds; resveratrol has a modest effect, also reported in research are curcumin, capsaicin, gingerol, and catechins
  
What is Leptin?
Leptin is the satiety hormone and ghrelin is the hunger hormone.  They act together to regulate appetite.  In obese people leptin resistance occurs and they become desensitized to leptin.
People with obesity tend to have high levels of leptin, but it does them no good.
Unfortunately leptin has other functions unrelated to regulating how much you eat.  This is another example of evolution reusing the same substance for entirely different purposes.

Leptin plays a key role in the immune system and the regulation of the inflammatory response.
Leptin is a member of the cytokine superfamily and resembles IL-6, Autism’s public enemy #1. 
Chronically elevated leptin levels are associated not only with obesity but inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease.   It is speculated that leptin responds specifically to adipose (body fat) derived inflammation.  Adipose tissue (body fat) produces hormones such as leptin, estrogen, resistin, and the cytokine TNFα.
Leptin also affects the HPA axis, which regulates the interactions among three endocrine glands, the hypothalamus, the pituitary gland and the adrenal.
The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, insomnia, post-traumatic stress disorder, borderline personality disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism  

Leptin and testosterone levels? 

This study demonstrates a close association between serum levels of testosterone and leptin in males which has not been described previously. Serum testosterone levels could be an important contributor to the known gender difference in serum leptin levels which can be found even after correction for body composition.

The Leptin-JAK-STAT pathway
We can now jump forward in sophistication to the Leptin-JAK-STAT pathway.  This is the signaling pathway that lies behind much of what is going on with leptin.  It explains the comorbidities that people with high leptin may experience.
The pathway only makes full sense if you know a bit about the relevance of things like PKC, AKT etc. These pathways underlie how your body is regulated.  They are mainly being studied to understand all the types of cancer, but are equally relevant to the molecular understanding of autism. 
Tamoxifen, recently shown to reverse autism in a SHANK3 mouse model, is a PKC inhibitor. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type 2 diabetes and cancer. PKC (and PKA) are reduced in regressive autism.

In general terms the Leptin-JAK-STAT pathway leads to inflammation and so it is a target for therapies to treat inflammatory disease like arthritis on inflammatory bowel disease.
You can reduce leptin signaling by inhibiting JAK.





After leptin binds to the long isoform of the leptin receptor (OB-Rb), Jak2 is activated at the box1 motif, resulting in the autophosphorylation of tyrosine residues and phosphorylation of tyrosines that provide docking sites for signaling proteins containing src homology 2 (SH2) domains. The autophosphorylated Jak2 at the box 1 motif can phosphorylate insulin receptor substrate1/2 (IRS1/2) that leads to activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Akt can regulate a wide range of targets including FOXO1 and NF-κB. Activation of NF-κB after leptin binding has been shown to induce Bcl-2 and Bcl-XL expressions. Leptin binding to OB-Rb can also activate the phospholipase C (PLC) for stimulation of c-jun N-terminal protein kinase (JNK) via protein kinase C (PKC).

Both Tyr1077 and Tyr1138 bind to STAT5, whereas only Tyr1138 recruits STAT1 and STAT3. STAT3 proteins form dimers and translocate to the nucleus to induce expression of genes such as c-fos, c-jun, egr-1, activator protein-1 (AP-1) and suppressors of cytokine signaling 3 (SOCS3). SOCS3 negatively regulates signal transduction by leptin by binding to phosphorylated tyrosines on the receptor, to inhibit the binding of STAT proteins and the SH2 domain-containing phosphatase 2 (SHP2). SHP2 activates the mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase (ERK1/2), p38 MAPK and p42/44 MAPK through an interaction with the adaptor protein growth factor receptor-bound protein 2 (GRB2), to induce cytokine and chemokine expression in immune cells. SOCS2 binds to Tyr1077 and might interfere with STAT5 binding. After stimulation with leptin, Src associated in mitosis protein 68 (Sam68) can form a complex with activated STAT3, leading to its dissociation from RNA. Sam68 can also be directly activated by Jak2 to phosphorylate IRS1/2 for Akt activation.



Leptin is a hormone whose central role is to regulate endocrine functions and to control energy expenditure. After the discovery that leptin can also have pro-inflammatory effects, several studies have tried to address - at the molecular level - the pathways involved in leptin-induced modulation of the immune functions in normal and pathologic conditions. The signaling events influenced by leptin after its binding to the leptin receptor have been under scrutiny in the past few years, and considerable experimental work has elucidated the consequences of leptin effects on immune cells. This review examines the biochemistry, function and regulation of leptin signaling in view of possible intervention on this molecule for a better management and therapy of immune-mediated diseases.


Janus kinase inhibitors/ JAK inhibitors
Janus kinase inhibitors, also known as JAK inhibitors inhibit the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway
The currently approved drugs are:-
  • Ruxolitinib against JAK1/JAK2 for psoriasis, myelofibrosis, and rheumatoid arthritis.
  • Tofacitinib against JAK3 for psoriasis and rheumatoid arthritis.
  •  Oclacitinib against JAK1 for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs

Both aspirin and Metformin have some related effects, but do not appear to be JAK inhibitors. 



JAK inhibitors for baldness?

Much of modern medicine is stumbled upon.  This has happened at least twice in the search for treatments for hair loss.  Merck developed Proscar based on the observation of a tribe that never had enlarged prostates, and then they found their new drug caused hair growth as a side effect, so they marketed a low dose version as Prospecia. Researchers at Columbia were treating a man with psoriasis using the JAK inhibitor Tofacitinib. He regrew a full head of hair within seven months.  He had a type of hair loss called Alopecia Areata.
Since haircare is a huge business, new JAK inhibitors are being developed for hair loss, both oral and topical.
Perhaps less potent JAK inhibitors than used for arthritis may be enough for people with autism and high leptin?


Natural JAK Inhibitors
We can also look in nature for potential JAK inhibitors.
By chance, before deciding to complete this post that been unfinished, I did look at some other unfinished once.  One that was all about the medicinal benefits of Nigella sativa, often called black cumin.
At least one reader of this blog is already a fan of Nigella sativa.
It turns out that one constituent of Nigella sativa is Thymoquinone. We know that Thymoquinone affects STAT3 in the complicated diagram above.  It is known to have anti-inflammatory and anticancer properties, but does it affect higher up the pathway at JAK?
For example, another natural product Cucurbitacin B, used in Chinese herbal medicine, is a dual inhibitor of the activation of both JAK2 and STAT3.
Brevilin A, a novel natural product, inhibits Janus Kinase Activity and blocks STAT3 Signaling. 






Back to Option B - RORα 


Here we show that gene expression of the nuclear receptor RORalpha is induced during adipogenesis, with RORalpha4 being the most abundantly expressed isoform in human and murine adipose tissue. Over-expression of RORalpha4 in 3T3-L1 cells impairs adipogenesis as shown by the decreased expression of adipogenic markers and lipid accumulation, accompanied by decreased free fatty acid and glucose uptake. By contrast, mouse embryonic fibroblasts from staggerer mice, which carry a mutation in the RORalpha gene, differentiate more efficiently into mature adipocytes compared to wild-type cells, a phenotype which is reversed by ectopic RORalpha4 restoration.

Previous studies have identified a role for RORa in cerebellum development, immune function and circadian rhythmicity. Recent reports have also outlined a function for RORa in cholesterol and lipid metabolism. In the present study we show that the RORa1 and RORa4 genes are expressed in adipose tissue and that RORa increases upon differentiation of preadipocytes into adipocytes, identifying RORa4 as the principal isoform in adipose tissue. Moreover, RORa4 over-expression in 3T3-L1 cells inhibits adipocyte differentiation, impairs fatty acid and glucose uptake and reduces expression of genes known to be involved in both adipocyte differentiation (including PPARc, CEBPa and aP2) and function (such as FAS, PEPCK, and the fatty acid and glucose transporters FATP, CD36 and Glut-4).

Although our experiments did not address the molecular mechanism(s) involved in the RORa-mediated inhibition of adipogenesis, several hypotheses can be put forward. Inhibition of adipocyte differentiation may occur principally through inhibition of positive regulators such as PPARc or CEBPa, or through the induction of inhibitory factors like GATA, KLF2, CHOP or Wnt signaling [3]. Alternatively, RORa may regulate other factors known

to inhibit adipocyte differentiation, for instance, through induction of p21CYP1/Waf1 leading to growth arrest. Along this line, Rev-erba acts as a p21 repressor in hepatic cells [27], and RORc induces p21 in liver. Thus, RORa might act, at least in part, by up-regulating p21 transcription in adipose cells. Another possible explanation may lie in the recent observation that Rev-erba represses PPARc2 gene expression during adipocyte differentiation [6]. The fact that RORa induces Rev-erba gene transcription ([28] and this report, not shown) may constitute an additional potential mechanism for adipogenesis inhibition by RORa.

Although future studies are necessary to further delineate RORa-regulated pathways in adipose cells, our findings clearly identify RORa4 as novel negative modulator of adipocyte differentiation and function.



Option C – reduce Leptin

Thiazolidinediones/glitazones
Thiazolidinediones also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2.

Thiazolidinediones act by activating PPARs (peroxisome proliferator-activated receptors with greatest specificity for PPARγ.
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:


PPARgamma agonist have been trialed with some success in autism.


These results indicate that antidiabetic thiazolidinediones down-regulate leptin gene expression with potencies that correlate with their abilities to bind and activate PPARgamma.


The thiazolidinedione BRL 49653 and the thiazolidinedione derivative CGP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proliferator-activated receptor gamma (PPARgamma) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid receptor-related orphan receptor alpha (RORA) and exhibits potent antiarthritic activity. Both receptors belong to the superfamily of nuclear receptors and are structurally related transcription factors. We tested BRL 49653 and CGP 52608 for receptor specificity on PPARgamma, RORA, and retinoic acid receptor alpha, a closely related receptor to RORA, and compared their pharmacological properties in in vitro and in vivo models in which these compounds have shown typical effects. BRL 49653 specifically induced PPARgamma-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both compounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, elevated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in rats, whereas CGP 52608 exhibited steroid-like effects on triglyceride levels and body weight in this model. In contrast, potent antiarthritic activity in rat adjuvant arthritis was shown for CGP 52608, whereas BRL 49653 was nearly inactive. Our results support the concept that transcriptional control mechanisms via the nuclear receptors PPARgamma and RORA are responsible at least in part for the different pharmacological properties of BRL 49653 and CGP 52608. Both compounds are prototypes of interesting novel therapeutic agents for the treatment of non-insulin-dependent diabetes mellitus and rheumatoid arthritis.

BRL-49653 became the drug Rosiglitazone
CGP 52608 was not commercialized.



In our study, activation of PPAR𝛾 also negatively regulates leptin signaling. PPAR𝛾 and its agonist ciglitazone downregulate leptin, and its receptor mRNA expression, inhibit leptin-induced STAT3 phosphorylation and activation and increase STAT3 inhibitor SOCS3 expression. These findings indicate that PPAR𝛾 and leptin signaling pathways are mutually regulated in growth plate chondrocytes. The imbalance between the levels of PPAR𝛾 and leptin may facilitate the dysfunction of the growth plate observed in obese children.


Option D – Increase Adiponectin

Adiponectin restrains leptin-induced signalling

Another hormone you may not of heard of is Adiponectin; is it secreted from the same adipose tissue that produces leptin.
Whereas the high levels of leptin found in classic autism appear to be bad for you, it is the low levels of Adiponectin found in autism, and indeed ADHD, that may be bad for. Low levels of Adiponectin are associated with many conditions ranging from NAFLD to type 2 diabetes.
Another way to reduce leptin signaling is to increase the level of Adiponectin.
Much is known about ways to increase adiponectin and many readers of this blog are actually already doing it. Ways to increase it include:-

·        PPAR-γ agonists like rosiglitazone

·        PPAR- α agonists, like fibrates

·        ACE inhibitors, like Trandolapril

·        some statins (not simvastatin)

·        Niacin

·        renin-angiotensin-aldosterone system blockers

·        some calcium channel blockers, like Verapamil

·        mineralocorticoid receptor blockers,

·        new β-blockers

·        vanadyl sulfate (VS)

·        natural compounds; resveratrol has a modest effect, also reported in research are curcumin, capsaicin, gingerol, and catechins
Combining an ACE inhibitor with the calcium channel blocker verapamil has an even bigger effect on Adiponectin levels.


Reduced levels of adiponectin are found in some Autism studies  


The neurobiological basis for autism remains poorly understood. We hypothesized that adipokines, such as adiponectin, may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of adiponectin are altered in subjects with autism. We measured serum levels of adiponectin in male subjects with autism (n = 31) and age-matched healthy male subjects (n = 31). The serum levels of adiponectin in the subjects with autism were significantly lower than that of normal control subjects. The serum adiponectin levels in the subjects with autism were negatively correlated with their domain A scores in the Autism Diagnostic Interview—Revised, which reflects their impairments in social interaction. This study suggests that decreased levels of serum adiponectin might be implicated in the pathophysiology of autism.  

Autism is a neurodevelopmental disorder with pathogenesis not completely understood. Although a genetic origin has been recognized, it has been hypothesized a role for environmental factors, immune dysfunctions, and alterations of neurotransmitter systems. In young autistic patients we investigated plasma leptin and adiponectin levels over a year period. Thirty-five patients, mean age at the basal time 14.1 ± 5.4 years, were enrolled. Controls were 35 healthy subjects, sex and age matched. Blood samples were withdrawn in the morning at the baseline and 1 year after. In patients leptin concentrations significantly increased, while adiponectin did not significantly change. Leptin values in patients were significantly higher than those found in controls at each time; adiponectin values did not differ at each time between patients and controls. Since patients were not obese, we could hypothesize that leptin might participate to clinical manifestations other than weight balance. The role of adiponectin in autism is still debatable.


Modulation of adiponectin as therapy
In many conditions it is already considered wise to modulate adiponectin as a therapy.  Examples are diabetes and cardiovascular disease.  The subject is quite well studied.

Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.

  
The Secretome of human adipose tissue

The genome, the epigenome and the microbiome, we now have the secretome. Human body fat is an endrocrine organ producing more than 600 different proteins; the first one, leptin, was identified only in 1994.

Adipokines: A treasure trove for the discovery of biomarkers for metabolic disorders

So clearly scientists have a very long way to go to understand how the human body works.




Conclusion
It is odd how in this blog we keep coming back to drugs that are helpful for diabetes and high cholesterol. Obesity also recurs as a theme.
Interesting present day options seem to be:-
·        JAK inhibitors (Ruxolitinib, Tofacitinib)

·        Estradiol, my hunch with some evidence

·        PPAR gamma agonists Rosiglitazone (Avandia) or lots of Tangeretin/Sytrinol

·        ACE inhibitors, some statins, verapamil, fibrates and niacin 

I think some people will benefit from the following, but perhaps not due reduced leptin signaling

·        Low dose aspirin

·        Metformin, in human use for more than 50 years to treat type 2 diabetes the molecular mechanism of metformin is incompletely understood

·        Nigella sativa / Thymoquinone