Showing posts with label Kudzu. Show all posts
Showing posts with label Kudzu. Show all posts

Wednesday, 10 January 2018

A RORα Agonist for Autism?

Today’s post is again about RORα, which was suggested to be a nexus where different biological dysfunctions that lead to autism may converge. I think you can consider RORα like a dimmer switch on your lights, you need to adjust the brightness to give the effect you want.

Fine tuning RORα to tune autism gene expression

I recently came across some research where the scientist clearly has the same idea. He has been working on a synthetic RORα/γ agonist for some years and has investigated its use as both a cancer therapy and an autism therapy.
I have become rather interested in cancer therapies because there are so many overlaps between what can lead to cancer and what exists in autism. The big research money is of course in cancer research.
Tumor suppressor genes/proteins like PTEN and p53 have been shown to be disturbed in autism, as is Bcl-2. The Bcl-2 family of proteins regulate cell death (apoptosis); some members induce cell death and other inhibit it; the balance is important.
Generally it seems that most people with autism might benefit from more PTEN and Bcl-2. 

Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes. Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORα target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORα may be a method for treatment of autism. 
The RORs have been linked to autism in human in several studies. In 2010, Nguyen and co-workers reported that RORα protein expression was significantly reduced in the brains of autistic patients and this decrease in expression was attributed to epigenetic alterations in the RORA gene. Additional work from this group demonstrated that multiple genes associated with autism spectrum disorder are direct RORα target genes and suggested that reduction of RORα expression results in reduced expression of these genes associated with the disorder leading to the disease. Independently, Devanna and Vernes demonstrated that miR-137, a microRNA implicated in neuropsychiatric disorders, targets a number of genes associated with autism spectrum disorder including RORA. There are also additional links between RORα and autism. Deficiency of Purkinje cells is one of the most consistently identified neuroanatomical abnormalities in brains from autistic individuals, and RORα is critical in development of the Purkinje cells. Significant circadian disruptions have also been recognized in autistic patients, and RORs play a critical role in regulation of the circadian rhythm., Additionally, the staggerer mouse displays behaviors that are associated with autism including abnormal spatial learning, reduced exploration, limited maze patrolling, and perseverative behavior relative to wt mice.

SR1078 is a relatively low potency compound with limited RORα efficacy (3–5 μM EC50Emax 40%), but the efficacy compares favorably to other classes of compounds that have been optimized such as a 38% decrease in the same model induced by the mGluR5 allosteric modulator GRN-529 and a 47% reduction by the mGluR5 antagonist MPEP. Both of these compounds have been optimized and display high potency (single digit nanomolar range at mGluR5) and strong efficacy., Thus, we believe that focused optimization of RORα ligands will provide compounds that will have improved efficacy in this model. It should also be noted that SR1078 has both RORα and RORγ agonist activity and a RORα selective agonist has not yet been developed. Thus, it is possible that the RORγ activity of this compound may also play a role in its efficacy in this model of autism. In summary, we have demonstrated that a synthetic RORα/γ agonist is able to increase the expression of key genes whose decrease in expression is associated with ASD both in cell culture and in vivo. Furthermore, the agonist decreases repetitive behavior in an animal model of autism suggesting that it is possible that ROR agonists may hold utility in treatment ASD. 

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.  

Results showed that levels of Bcl-2 decreased by 38% and 36% in autistic superior frontal and cerebellar cortices, respectively when compared to control tissues. By the same token, levels of P53 increased by 67.5% and 38% in the same brain areas in autistic subjects vs. controls respectively. Calculations of ratios of Bcl-2/P53 values also decreased by 75% and 43% in autistic frontal and cerebellar cortices vs. controls respectively. The autistic cerebellar values were significantly reduced (p < 0.08) vs. control only. There were no significant differences in levels of β-actin between the two groups. Additionally, there were no correlations between Bcl-2, P53, and β-actin concentrations vs. age or PMI in either group.
These results confirm and extend previous data that levels of Bcl-2 and P53 are altered in three important brain tissues, i.e. frontal, parietal, and cerebellar cortices of autistic subjects, alluding to deranged apoptotic mechanisms in autism.  

Increasing PTEN and Bcl-2 is already part of my Polypill, via the use of Atorvastatin.
There are of course many other genes miss-expressed in autism and we cannot give a drug for each one. We need to identify a handful of nexus, where multiple anomalies can be resolved with a single intervention.
It is good that Thomas Burris, the lead researcher, has been working on SR1078 for at least 6 years, let’s hope he continues to persevere.
I think it highly likely that some types of autism will need the opposite therapy, a RORα antagonist.
My method of attempting to modulate RORα will be different. I come back to my earlier gross simplification of autism :- 

As we have seen in earlier posts, the hormonal dysfunction, this time the balance between testosterone and estradiol, has a direct effect on RORα (and vice versa).

The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.

androgen receptor = AR 

estrogen receptor = ER

As you might know, many hormones are interrelated, so what are thought of as male/female sex hormones have much wider effects. They impact growth hormones and play a big role in calcium metabolism. They also affect serotonin.
We know that in most autism aromatase is reduced, estradiol is reduced and that there is reduced expression of estrogen receptor beta.
In the ideal world it might indeed be best to use an agonist or antagonist to fine tune RORα.
We have a chicken and the egg situation. Is RORα out of tune in autism because the hormones are disturbed, or vice versa?
We do know that hormones generally have feedback loops, but we also know that increasing a hormone like estradiol via obesity is not fully matched by a corresponding reduction in aromatase. So it looks highly plausible that you can tune RORα via estradiol, and that this could be a long term strategy, not just a short term strategy.
In the case of people with low T3 thyroid hormone centrally (in the brain), giving exogenous T3 may help initially, but in the long term it does not because feedback loops to the thyroid will reduce production of the pro-hormone T4. In the extreme you will make the thyroid gland shut down, this does happen to people using thyroid hormones for depression and even weight loss. 
T3 is quite commonly prescribed by alternative practitioners in the US for autism and also for depression in older people. In Europe this hormone is rarely even available. 
Many phytoestrogens are used as OTC autism therapies. These are dietary estrogens that are structurally similar to the human hormone estradiol and so produce estrogen-like effects. They include soy products, fenugreek, kudzu, EGCG etc.