Thursday, 13 September 2018

Ginseng, as a GABAb Antagonist, as an "Add-on Therapy" for some Autism? Also Homotaurine and Acamprosate

Rather like negotiating with North Korea, today’s post does rather meander. It does in the end up with some interesting options for some people. 

Korea - the centre of Ginseng research
This post was prompted by research highlighted by our reader Ling, which suggested that bumetanide responders (i.e. people with high intracellular chloride) might benefit from a GABAB antagonist. 
There has been quite a lot of coverage in this blog about agonists of GABAB receptors, like Baclofen and Arbaclofen. Some people with an autism diagnosis do indeed seem to benefit, ranging from some with Fragile-X to others with Asperger’s. Russian-developed GABAB agonists like Phenibut and Pantogam are widely used by adults self-treating their behavioural/emotional disturbances.
Some Aspies have commented in this blog that far from helping, Baclofen made them feel worse; perhaps the opposite therapy might help? (the Goldilocks scenario, from the previous post) 
The paper below shows how a GABAB antagonist (the opposite of Baclofen) might benefit some with autism.

GABAB receptors are G-protein-coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABAB receptor forms part of larger signaling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABAA receptor in mature neurons. Using biochemical, molecular, and functional studies in rodent hippocampus, we show that activation of GABAB receptors results in a decrease in KCC2 function, which is associated with a reduction in the protein at the cell surface. These findings reveal a novel "crosstalk" between the GABA receptor systems, which can be recruited under conditions of high GABA release and which could be important for the regulation of inhibitory synaptic transmission.

SIGNIFICANCE STATEMENT Synaptic inhibition in the brain is mediated by ionotropic GABAA receptors (GABAARs) and metabotropic GABAB receptors (GABABRs). To fully appreciate the function and regulation of these neurotransmitter receptors, we must understand their interactions with other proteins. We describe a novel association between the GABABR and the potassium-chloride cotransporter protein, KCC2. This association is significant because KCC2 sets the intracellular chloride concentration found in mature neurons and thereby establishes the driving force for the chloride-permeable GABAAR. We demonstrate that GABABR activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABAAR. Our data therefore support an additional mechanism by which GABABRs are able to modulate fast synaptic inhibition.

In bumetanide-responsive autism, neurons remain immature because the “GABA switch“ never flipped and so NKCC1 is overexpressed and KCC2 is underexpressed, chloride levels remain high and the neurotransmitter GABA works backwards (excitatory, rather than inhibitory).
Bumetanide partially counters the over-abundance of NKCC1 transporters that carry chloride into neurons, but is a partial solution.
The above research suggests that blocking GABAB receptors might increase the flow of chloride ions exiting through KCC2.
All very complicated sounding, but in effect it means that a GABAB antagonist might boost the effect of bumetanide.

Which GABAB antagonist?
This was Ling’s question.
Saclofen is a competitive antagonist for the GABAB receptor. This drug is an analogue of the GABAB agonist baclofen.
Phaclofen/phosphonobaclofen, is a selective antagonist for the GABAB receptor.
Since these “–aclofens” are not accessible we are left with a choice of homotaurine (developed to treat Alzheimer’s) or Ginsenosides from Korean/Panax ginseng.
Both homotaurine and Ginsenosides have various other effects beyond GABAB.
Since Ling is in Scandinavia, homotaurine is an option. It seems to be banned in the US, though it is approved in Canada and sold in Europe.
Ginseng is very widely used, indeed it is the most widely consumed herbal nutritional product in the world, with sales of $400 million in 2012.
I was surprised that there actually is research in both humans and animal models using Ginseng in autism and indeed ADHD.
N-Acetyl homotaurine,  a derivative of homotaurine, is a registered drug called Acamprostate. It is used to treat alcohol dependence. It affects both NMDA and GABA receptors. Acamprostate has been shown to benefit Fragile-X, as has bumetanide. A drug that affects GABAB will inevitably also affect NMDA receptors.
This was covered in this post from 2015.

which highlighted this paper:

Homotaurine has been reported as a GABA antagonist as well as a GABA agonist. In vitro studies have found that homotaurine is a GABAA partial agonist as well as a GABAB receptor partial agonist with low efficacy, becoming an antagonist and a displacing full agonist of GABA or baclofen at this receptor.[15] In a study in rats, homotaurine reversed the catatonia induced by baclofen (the prototypical GABAB agonist),[16] and was able to produce analgesia via the GABAB receptor, an effect that was abolished when CGP 35348, a GABAB receptor antagonist was applied.[17][18] 
One study suggests Homotaurine increases dopamine levels.[19]

One study in rats showed that homotaurine suppressed ethanol-stimulated dopamine release, as well as ethanol intake and preference in rats in a way similar to the N-acetyl derivative of homotaurine, acamprosate.[20] Acamprosate was approved by the FDA in 2004 to treat alcohol dependence.[3]

Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission.
Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.

Back to Ginseng
Autism spectrum disorder (ASD) is heterogeneous neurodevelopmental disorders that primarily display social and communication impairments and restricted/repetitive behaviors. ASD prevalence has increased in recent years, yet very limited therapeutic targets and treatments are available to counteract the incapacitating disorder. Korean Red Ginseng (KRG) is a popular herbal plant in South Korea known for its wide range of therapeutic effects and nutritional benefits and has recently been gaining great scientific attention, particularly for its positive effects in the central nervous system.


Thus, in this study, we investigated the therapeutic potential of KRG in alleviating the neurobehavioral deficits found in the valproic acid (VPA)-exposed mice models of ASD.


Starting at 21 days old, VPA-exposed mice were given daily oral administrations of KRG solution (100 or 200 mg/kg) until the termination of all experiments. From P28, mice behaviors were assessed in terms of social interaction capacity, locomotor activity, repetitive behaviors, short-term spatial working memory, motor coordination, and seizure susceptibility.


VPA-exposed mice showed sociability and social novelty preference deficits, hyperactivity, increased repetitive behavior, impaired spatial working memory, slightly affected motor coordination, and high seizure susceptibility. Remarkably, long-term KRG treatment in both dosages normalized all the ASD-related behaviors in VPA-exposed mice, except motor coordination ability.


As a food and herbal supplement with various known benefits, KRG demonstrated its therapeutic potential in rescuing abnormal behaviors related to autism caused by prenatal environmental exposure to VPA.

In the trial below the dose appears very low at 250mg. In the more encouraging study in ADHD the dose was 1000mg twice a day.

Autism is a pervasive developmental disorder, with impairments in reciprocal social interaction and verbal and nonverbal communication. There is often the need of psychopharmacological intervention in addition to psychobehavioral therapies, but benefits are limited by adverse side effects. For that reason, Panax ginseng, which is comparable with Piracetam, a substance effective in the treatment of autism, was investigated for possible improvement of autistic symptoms. There was some improvement, which suggests some benefits of Panax ginseng, at least as an add-on therapy.
Three male outpatients (age range 18.4–22.2 years; mean=21.3 years; SD =4.1 years) meeting ICD-10 criteria for autistic disorder participated in our observation. IQs ranged from 54 to 82 (68 +/− 14), which were obtained from the Wechsler Intelligence Scale. At least two child and adolescent psychiatrists independently diagnosed the subjects for autistic disorder. All subjects had no additional medical or neurological illnesses. They had been treated with either methylphenidate, or neuroleptics before entry into the study, without any positive effect (nonresponder). One patient’s language consisted of monosyllabic utterances, second patient’s language consisted of single words(10-word vocabulary),and the third patient spoke in sentences. Parents and mentors’ (i.e., the person who takes care of the patient in daily life, and supports the patient’s educational efforts) rated instruments included weekly ratings by means of the Aberrant Behavior and Symptom Checklist. Clinician ratings consisted of the Global Assessment Scale, Psychiatric Rating Scale (CPRS), and Clinical Global Improvement. Panax ginseng (oral administration of tablets containing 250-mg alcoholic Panax ginseng berry extract, pure encapsulations) was administered for 4 weeks (dosage: 250 mg daily). Patients were free of medication for at least 4 weeks before the beginning of the study. During that time, there were no changes in the symptoms of the patients. Subjects continued to receive educational and behavioral interventions, which were not altered substantially in any of the patients during their participation in the study. The means of parent and mentor ratings were averaged over the 4-week treatment period. Clinician and mentor ratings were made at the beginning of the treatment period and then weekly up to the end of the treatment. Ratings were compared by paired t-test.

Panax ginseng slightly improved the ratings on the ABC factors: irritability (before treatment, 13.2 +/− 5.9; after treatment, 11.3 +/− 6.2; p =.41), hyperactivity (before treatment, 20.6+/−12.4;     after,18.4+/− 9.4; p = .33), inadequate eye contact (before treatment, 8.6 +/− 5.4; after, 7.5 +/− 3.2; p .35), and inappropriate speech (before treatment, 6.1+/−2.2;after, 4.3 +/− 3.6; p = .41). The symptom checklist scores revealed a slight increase in drowsiness (before treatment, 1.6 +/− 2.2; after, 2.9+/−4.2; p =.31) and decreased activity (before treatment, 2.5 +/− 3.3; after, 4.4 +/− 3.1; p = 0.40). None of the clinician ratings showed significant improvement. This may result from different impressions of clinical visits and daily life observations of caregivers. Panax ginseng has some moderate sedative effect with effects especially on daily life, a fact that also makes it effective in the treatment of attention deficit/hyperactive disorders. None of the subjects appeared to have headaches or stomach aches, although report of such side effects was limited by the expressive language and social skills of these subjects. Medication was continued after the observation period. We did not see any significant changes in symptoms.

Although this was a very small study (n = 3), which revealed very modest therapeutic effect of Panax ginseng in the management of autistic patients in some of the subjects (which might be due to the small sample size), it may be mentioned that its role in the management of these symptoms in patients with autistic disorder may be limited, especially because of its risk for estrogen-associated problems in females (Papapetropoulos, 07). Since there does not seem to be any significant improvement caused by Panaxginseng, its effect as an add-on therapy remains completely open and requires further investigation. Before knowing its efficacy for adults, Panax ginseng should not be recommended for treating children suffering from autism.

Ginseng for ADHD? 

Objective: There is evidence that Korean red ginseng (KRG) can reduce the production of the adrenal corticosteroids, cortisol, and dehydroepiandrosterone (DHEA), and thus may be a viable treatment for attention-deficit/hyperactivity disorder (ADHD). The present randomized double-blind placebo-controlled clinical trial tested the effect of KRG on children with ADHD symptoms.
Methods: Subjects 6–15 years, who satisfied the inclusion criteria and had ADHD symptoms, were randomized into a KRG group (n=33) or a control group (n=37). The KRG group received one pouch of KRG (1g KRG extract/pouch) twice a day, and the control group received one pouch of placebo twice a day. At the 8 week point, the primary outcomes were the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for inattention and hyperactivity scale scores, which were measured at baseline and 8 weeks after starting treatment. Secondary outcomes were quantitative electroencephalography theta/beta ratio (QEEG TBR) (measured at baseline and week 8) and salivary cortisol and DHEA levels (measured at baseline and at 4 and 8 weeks).
Results: The baseline characteristics of the KRG and control groups were not statistically different. The mean ages of the KRG and control groups were 10.94±2.26 and 10.86±2.41, respectively. The KRG group had significantly decreased inattention/hyperactivity scores compared with the control group at week 8 (least squared means of the differences in inattention adjusted for baseline scores: −2.25 vs. −1.24, p=0.048; hyperactivity: −1.53 vs. −0.61, p=0.047). The KRG group had significantly decreased QEEG TBR compared with the control group (least squared means of the differences: −0.94 vs. −0.14, p=0.001). However, neither the KRG group nor the control group exhibited significant differences in salivary cortisol or DHEA levels at week 8 compared with the baseline levels. No serious adverse events were reported in either group.
Conclusions: These results suggest that KRG extract may be an effective and safe alternative treatment for children with inattention and hyperactivity/ impulsivity symptoms. Further studies to investigate the efficacy and safety of KRG are warranted. 
Although medications to treat psychiatric disorders for children and adolescents have been widely researched and several are on the market, natural products may also be effective in these patients while inducing fewer significant adverse effects. The present randomized controlled trial was performed to assess whether KRG, a well-known traditional medicine plant that is used particularly frequently in Eastern Asia, can improve the adrenal function and inattention/hyperactivity symptoms of chronically stressed children with ADHD symptoms. KRG extract significantly improved the inattention and hyperactivity of the subjects and had a good safety profile. However, the KRG extract did not have significant effects on cortisol or DHEA levels

Clinical Significance
To our knowledge, this is the first randomized controlled trial to investigate the efficacy and safety of Korean red ginseng extract for children with ADHD. The stimulant medications for ADHD have demonstrated not only clinical efficacy, but also significant adverse events such as poor growth, tics, and psychosis. Although KRG extract did not affect the salivary cortisol or DHEA, it significantly improved ADHD symptoms and QEEG TBR. And the safety profile of KRG extract was good. The results imply that KRG extract is a possible effective alternative medication for ADHD children.


A combination herbal product containing American ginseng extract, Panax quinquefolium, (200 mg) and Ginkgo biloba extract (50 mg) (AD-FX; CV Technologies, Edmonton, Alta.) was tested for its ability to improve the symptoms of attention-deficit hyperactivity disorder (ADHD). 


Open study. 


36 children ranging in age from 3 to 17 years who fit the diagnostic criteria for ADHD. 


AD-FX capsules were taken twice a day on an empty stomach for 4 weeks. Patients were instructed not to change any other medications during the study. 


At the beginning of the study, after 2 weeks, and then at the end of the 4-week trial, parents completed the Conners' Parent Rating Scale--revised, long version, a questionnaire that assesses a broad range of problem behaviours (and was used as an indication of ADHD symptom severity). 


After 2 weeks of treatment, the proportion of the subjects exhibiting improvement (i.e., decrease in T-score of at least 5 points) ranged from 31% for the anxious-shy attribute to 67% for the psychosomatic attribute. After 4 weeks of treatment, the proportion of subjects exhibiting improvement ranged from 44% for the social problems attribute to 74% for the Conners' ADHD index and the DSM-IV hyperactive-impulsive attribute. Five (14%) of 36 subjects reported adverse events, only 2 of which were considered related to the study medication. 


These preliminary results suggest AD-FX treatment may improve symptoms of ADHD and should encourage further research on the use of ginseng and Ginkgo biloba extracts to treat ADHD symptoms.

Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.


1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site. 2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding.

3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding.
4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

very detailed paper

Also (Ling) note that there is an effect on ERbeta

A ginseng-derived oestrogen receptor beta (ERbeta) agonist, Rb1 ginsenoside, attenuates capillary morphogenesis.

 Ginseng extracts contain a variety of active ingredients and have been shown to promote or inhibit angiogenesis, depending on the presence of different ginsenosides that exert opposing effects on blood vessel growth. Leung et al. in this issue of the British Journal of Pharmacology report that Rb1, a ginsenoside that constitutes only 0.37–0.5% of ginseng extracts (depending on manufacturing and processing methods), blocks tube-like network formation by endothelial cells in vitro. At the molecular level, Rb1 binds to the oestrogen receptors and stimulates the transcription of pigment epithelium-derived factor that, in turn, inhibits matrix-driven capillary morphogenesis.

Ginseng, the root of Panax ginseng and related species, has been a key component of traditional medicine in the Far East for over a thousand years. The genus name Panax means ‘cure all' in Greek; it, thus, comes as no surprise that ginseng has been described as beneficial in many different ailments (Huang, 1999; Kiefer and Pantuso, 2003; Ng, 2006). Perhaps the most studied biological actions of ginseng extracts and constituents are those relating to its inhibitory effects on solid tumour growth (Yun, 2001). The main active ingredients in ginseng-based herbal preparations are thought to be the ginsenosides, comprising 3–6% of ginseng extracts (Huang, 1999). 

Reviewed here is the existing evidence for the effects of ginseng extracts and isolated ginsenosides relevant to cognition in humans. Clinical studies in healthy volunteers and in patients with neurological disease or deficit, evidence from preclinical models of cognition, and pharmacokinetic data are considered. Conditions under which disease modification may indirectly benefit cognition but may not translate to cognitive benefits in healthy subjects are discussed. The number of chronic studies of ginseng effects in healthy individuals is limited, and the results from acute studies are inconsistent, making overall assessment of ginseng's efficacy as a cognitive enhancer premature. However, mechanistic results are encouraging; in particular, the ginsenosides Rg3 , Rh1 , Rh2 , Rb1 , Rd, Rg2 , and Rb3 , along with the aglycones protopanaxadiol and protopanaxatriol, warrant further attention. Compound K has a promising pharmacokinetic profile and can affect neurotransmission and neuroprotection. Properly conducted trials using standardized tests in healthy individuals reflecting the target population for ginseng supplementation are required to address inconsistencies in results from acute studies. The evidence summarized here suggests ginseng has potential, but unproven, benefits on cognition.

Ginseng is the most widely consumed herbal nutritional product in the world. According to the most recent data available, ginseng had a total world export value in 2010 of over US$350 million, which was expected to rise to more than US$400 million in 2012

The survey had 54 respondents and 4 (8.5%) used Ginseng.

There is a long list of substances shown to have a benefit in some autism. Today we can add the Asian type of Ginseng and also Acamprosate (at least for Fragile-X).
It would be interesting to see the effect of Phaclofen and Saclofen which may be more selective for GABAB receptors.
Ginseng has so many effects there is no way to know which is the one that benefited autism and ADHD in today’s highlighted posts.
We also have the problem with natural substances that there is natural variation and that supplement companies are known to cheat with ingredients. Ginseng roots are not cheap and apparently ginseng is known to get adulterated.  Drug companies are usually much more reliable.
If anyone tries out homotaurine or ginseng, let us all know the result.
Homotaurine was originally developed as an Alzheimer’s drug, but did not work well enough, its developer then tried to sell it as a supplement called Vivimind, but it was rejected by the FDA. It is sold in Canada and Europe. 
For our Aspie readers, here is a link for them:-

Thursday, 6 September 2018

Ketones and Autism Part 4 – Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1β

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD earlier on in this blog, before I knew all the nitty-gritty of the science. (no re-editing required)

Inflammasome Inhibition: Putting Out the Fire                                                                                                                       

There is more than one anti-inflammatory mechanism involved in the ketogenic diet (KD); in Part 3 we covered Niacin Receptor HCA2, today in Part 4 we look at NLRP3 and CtBP.
The reason I am going into all this detail is because if you knew why someone responds to ketones in a favourable way, there might actually be an even more potent therapy using an entirely different substance.
CtBP represses the transcription of certain tumour supressing genes and some other genes involved in the development of cancer, i.e. they promote tumorigenesis.  CtBP is often overexpressed in certain cancers and indicates a worse prognosis. In these cancers you would want to inhibit CtBP.
Just to complicate matters, CtBP also supresses the activity of certain inflammatory genes. So, in certain diseases like diabetes you might benefit from keeping CtBP permanently in its active state. In particular, this would apply to when the microglia are activated, which is the case in much autism.
The coconut oil doctors have the idea that the key problem in autism is activated microglia in the brain.  Microglia mediate immune responses in the central nervous system, clearing cellular debris and dead neurons via a process called phagocytosis. These doctors propose coconut oil to calm the microglia.
Microglia can be in a resting or activated state, the research suggests that in much autism the microglia are permanently activated.
Some research suggests that microglia act like an “immunostat” reflecting not just what is going on in the brain, but elsewhere in the body.  I favour this view.
A small trial using a drug to calm the microglia did not impact autism.
Personally, I believe that microglia being activated is not a good thing, but that it is part of a much more complex picture than the coconut doctors suggest. 
As we learn later in this post, to get the CtBP benefit to microglia, it appears that you need the kind of ketosis you achieve only in the full ketogenic diet, not the transient mild ketosis that you achieve from two heaped tablespoons of coconut oil, or any of the keto supplements. 

NLRP3 inflammasome
The complicated-sounding NLRP3 inflammasome relates to diseases where the proinflammatory cytokine IL-1β is elevated; this includes Alzheimer’s, MS, Inflammatory Bowel Disease (IBD) and often autism.
For the details of how NLRP3 works see below; the important thing to note is that the result is elevated levels of IL-1β, which, at least in blood, is easy to measure.  It is an open question whether this represents the level inside the brain.  If your child has elevated IL-1β then it is worth studying NLRP3.

Schematic illustration of the NLRP3 inflammasome activation. Upon exposure to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), Toll-like receptors (TLRs) are phosphorylated and subsequently activate NF-κB. In the nucleus, NF-κB promotes the transcription of NLRP3, proIL-1β, and proIL-18, which, after translation, remain in the cytoplasm in inactive forms. Thus, this signal (depicted in red as “Signal 1”) is a priming event. A subsequent stimulus (shown as “Signal 2” in black) activates the NLRP3 inflammasome by facilitating the oligomerization of inactive NLRP3, apoptosis-associated speck-like protein (ASC), and procaspase-1. This complex, in turn, catalyzes the conversion of procaspase-1 to caspase-1, which contributes to the production and secretion of the mature IL-1β and IL-18. Three models have been proposed to describe the second step of inflammasome activation: (1) Extracellular ATP can induce K+/potassium efflux through a purogenic P2X7-dependent pore, which, leads to the assembly and activation of the NLRP3 inflammasome. Calcium flux is also involved in this process. (2) PAMPs and DAMPs trigger the generation of ROS that promote the assembly and activation of the NLRP3 inflammasome. (3) Phagocytosed environmental irritants form intracellular crystalline or particulate structures leading to lysosomal rupture (magenta box) and release of lysosomal contents like cathepsin B. These induce NLRP3 inflammasome assembly and activation. In addition, other factors and mechanisms have been implicated in the assembly and activation of the NLRP3 inflammasome, including mitochondrial damage, autophagic dysfunction, and thioredoxin-interacting protein (TXNIP).

Proinflammatory cytokine IL-1β 
My public enemy number 1 cytokine is actually IL-6, today we primarily look at IL-1β, which for many people with a neurological disorder is a big part of their problem. IL-6 and IL-1β are actually interrelated, as we see later.
For a summary of the role of this cytokine in autism, I will leave it to Paul Ashwood:-  

Interleukin (IL)-1B

IL-1Β is an inflammatory cytokine expressed very early in immune responses. In tissue, IL-1Β propagates inflammation by activating local immune cells and the vascular endothelium. Systemically, IL-1Β stimulates IL-6 production and eventually an acute phase response in the liver. Systemic IL-1Β can cross the blood brain barrier and stimulate its own expression in the hypothalamus, which leads to neuroendocrine changes associated with fever and sickness behavior . IL-1Β receptors are structurally related to toll-like receptors (TLRs), and signaling is achieved through NF-κB and MAP kinase (MAPK) signaling cascades. IL-1Β belongs to an evolutionarily conserved family of proteins that function beyond immunity. It shares structural homology with fibroblast growth factors, which are critical in embryonic neurodevelopment, and are implicated in autism and schizophrenia.
Genes for IL-1Β, its receptor, and its receptor-associated proteins are associated with intellectual disability, schizophrenia, and autism. Children and adults with autism have increased plasma IL-1Β and skewed cellular IL-1Β responses following stimulation. Compared to controls, monocytes from children with ASD produce excessive IL-1Β following LPS exposure, and lower levels following exposure to TLR 9 agonists. The IL-1 antagonist, IL-1ra, is also increased among ASD subjects. IL-1ra reduces inflammation by competing for the IL-1Β receptor, and increased levels may represent an attempt to counteract inflammation in ASD. Postmortem brains from ASD subjects had normal IL-1Β levels, but given that peripheral IL-1Β can enter the brain, increased systemic levels could directly impact neurological processes
IL-1Β disruption can have a variety of neurological consequences relevant to autism. The cytokine and its receptors are found throughout the nervous system during critical developmental periods. IL-1Β induces neural progenitor cell proliferation in some CNS regions, while inhibiting it in others. This could contribute to the region-specific overgrowth and undergrowth observed in the ASD brain. Excitatory synapse formation is partially mediated by the IL-1 receptor and receptor-associated proteins.
Altering these proteins can tip the balance between excitatory and inhibitory signaling, which might underlie neurological features of autism. Increased IL-1ra in autism suggests an attempt to counterbalance IL-1Β and may or may not be beneficial. Following brain injury, IL-1ra upregulation serves a neuroprotective role by dampening excessive inflammation. However, if administered during critical windows of neurodevelopment, IL-1ra can negatively impact neurogenesis, brain morphology, memory consolidation, and behavior. This shows that some level of IL-1B signaling is essential during development. In adulthood, IL-1Β is implicated in CNS disorders like Alzheimer’s disease and the advancement of amyloid-containing plaques. While excessive IL-1B contributes to pathology in some cases, it may have a protective role in others. For example, IL-1Β limits neuronal damage following excitotoxic exposures, and mice lacking IL-1Β fail to undergo remyelination following experimental autoimmune encephalitis (EAE) induction. IL-1Β is involved in higher order brain processes and is induced in the hippocampus during learning processes, and is critical for maintenance of long-term potentiation (LTP) Both over expression and under expression of IL-1 beta are associated with impairments in memory and learning.

At the table in the kitchen, there were three bowls of porridge.  Goldilocks was hungry.  She tasted the porridge from the first bowl.
"This porridge is too hot!" she exclaimed.
So, she tasted the porridge from the second bowl.
"This porridge is too cold," she said
So, she tasted the last bowl of porridge.
"Ahhh, this porridge is just right," she said happily and she ate it all up. 

In summary, IL-1Β participates in neurological processes, and appears to have a role in both CNS pathology and healing. Normal, homeostatic levels of IL-1Β and its antagonist IL-1ra are necessary for proper brain development and function. This “Goldilocks” state is typical of many cytokines, where too much or too little is not desirable. Alterations in IL-1Β systems due to genetic mechanisms or environmental exposures may contribute to autism. 

CtBP (C-terminal-binding protein) 
In 2017 research led by Dr Raymond Swanson, a professor of neurology at the University of California, San Francisco, suggested CtBP as an additional possible mechanism by which the ketogenic diet can reduce brain inflammation.   CtBP activation turns off key inflammatory genes.
In the case of CtBP, I doubt that the very partial ketosis achieved with BHB and C8 supplements will be enough, I think you would need the full ketogenic diet. 
Restricting the glucose metabolism with the ketogenic diet lowers the NADH/NAD+ ratio which activates CtBP. There is no direct role played by ketones in this process, it is just the presence of large amounts of ketones reduces the role of glucose.

Factors that reduce glucose flux through glycolysis, such as reduced glucose availability or glycolytic inhibitors, reduce NADH levels and thereby reduce NADH:NAD+ ratio, whereas factors that inhibit oxidative metabolism, such as hypoxia and mitochondrial inhibitors, have the opposite effect. Glutamine provides ketone bodies (α-ketoglutarate) to fuel mitochondrial ATP production in the absence of glycolysis. Lactate dehydrogenase (LDH) maintains the lactate:pyruvate ratio in equilibrium with the cytosolic NADH:NAD+ ratio.

BHB is not directly a CtBP activator.
A drug that acts as an CtBP activator would be great for diabetes and anyone with brain inflammation.
Using BHB and C8 you would need to create enough ketones in your blood to reduce the glucose metabolism substantially, not by a trivial amount.
The easy to read version:- 

New research uncovers and replicates the mechanism by which a ketogenic diet curbs brain inflammation. The findings pave the way for a new drug target that could achieve the same benefits of a keto diet without having to actually follow one.

A keto state lowers brain inflammation
A keto diet changes the metabolism, or the way in which the body processes energy. In a keto diet, the body is deprived of glucose derived from carbs, so it starts using fat as an alternative source of energy.

In the new study, Dr Swanson and his colleagues recreated this effect by using a molecule called 2-deoxyglucose (2DG).
The 2DG molecule stopped glucose from metabolizing and created a ketogenic state in rodents with brain inflammation as well as in cell cultures. Levels of inflammation were drastically reduced - almost to healthy levels - as a result.
"We were surprised by the magnitude of our findings," said Dr Swanson. "Inflammation is controlled by many different factors, so we were surprised to see such a large effect by manipulating this one factor. It reinforces the powerful effect of diet on inflammation."
The restricted glucose metabolism lowered the so-called NADH/NAD+ ratio
"Cells convert NAD+ to NADH, as an intermediary step in generating energy from glucose, and thus increase the NADH/NAD+ ratio," he added.
When this ratio is lowered, the CtBP protein gets activated and attempts to turn off inflammatory genes. As Dr. Swanson told us, "CtBP is a protein that senses the NADH/NAD ratio and regulates gene expression depending on this ratio."
So, the scientists designed a molecule that stops CtBP from being inactive. This keeps the protein in a constant "watchful" state, blocking inflammatory genes in an imitation of the ketogenic state. Dr. Swanson said, "Our findings show that it is [...] possible to get the anti-inflammatory effect of a ketogenic diet without actually being ketogenic
The findings could apply to other conditions that are characterized by inflammation. In diabetes, for example, the excessive glucose produces an inflammatory response, and the new results could be used to control this dynamic.
"[The] ultimate therapeutic goal would be to generate a [drug] that can act on CtBP to mimic the anti-inflammatory effect of [the] ketogenic diet," Dr. Swanson concluded. 

Full Paper:- 

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

One way that CtBP regulates gene transcription is through interactions with the histone acetyltransferase HDAC1. 

Taken together, our findings indicate that metabolic influences that alter the cytosolic NADH:NAD+ ratio regulate NF-κB transcriptional activity through an NADH-dependent effect on CtBP dimerization. Conditions that reduce glycolytic flux, such as ketogenic diet and caloric restriction, can thereby suppress NF-κB activity, while conditions that increase glycolytic flux may increase it. These interactions provide a mechanism for the suppressive effects of ketogenic diet and caloric restriction on brain inflammation after brain injury. By extension, these interactions may also contribute to the pro-inflammatory states associated with diabetes mellitus and metabolic syndrome. 

Inhibiting NLRP3 and/or activating CtBP

You do not need to be a genius to see that inhibiting NLRP3 and/or activating CtBP, using the ketogenic diet, is likely to benefit some people with autism.
On the flipside, someone with colon cancer, where CtBP is over-expressed to the point where the cancer depends on it for growth, certainly would not want the ketogenic diet.
This cancer flipside we have seen before, antioxidants like NAC and Sulforaphane (via activating the redox switch Nrf2) are chemoprotective for healthy people, but bad for you if you have developed cancer.  Oxidative stress is very damaging to cancer cells and so it becomes a good thing. Some people who develop cancer then choose to improve their diet to include new healthy foods, sadly for some people this may actually be counterproductive.
Estrogen is another case in point, it has many positive effects and has been suggested to be one reason why women like longer than men. If you develop estrogen positive breast cancer, more estrogen is the last thing you would want.  

Other NLRP3 inhibitors 


Coll et al. (2015) discovered that MCC950, a diarylsulfonylurea-containing compound known to inhibit caspase-1-dependent processing of IL-1β, also inhibits both canonical and non-canonical activation of the NLRP3 inflammasome. MCC950 inhibits secretion of IL-1β and NLRP3-induced ASC oligomerization in mouse and human macrophages. It reduces secretion of IL-1β and IL-18, alleviating the severity of EAE and CAPS in mouse models. Coll et al. (2015) further showed that MCC950 acts specifically on the NLRP3 inflammasome

Note that MCC950 is the new name for a drug Pfizer originally called CP-456773 or CRID3, which was not successful as a treatment for arthritis, but now has a second chance

Youm et al. (2015) discovered that the ketone metabolite β-hydroxybutyrate (BHB), but not acetoacetate or the short-chain fatty acids butyrate and acetate, reduced IL-1β, and IL-18 production by the NLRP3 inflammasome in human monocytes. Like MCC950, BHB appears to block inflammasome activation by inhibiting NLRP3-induced ASC oligomerization. Their in vivo experiments showed that BHB or a ketogenic diet alleviate caspase-1 activation and caspase-1-mediated IL-1β production and secretion, without affecting the activation of NLRC4 or AIM2 inflammasomes. BHB inhibits NLRP3 inflammasome activation independently of AMP-activated protein kinase, ROS, autophagy, or glycolytic inhibition. These studies raise interesting questions about interactions among ketone bodies, metabolic products, and innate immunity. BHB levels increase in response to starvation, caloric restriction, high-intensity exercise, or a low-carbohydrate ketogenic diet. Vital organs such as the heart and brain can exploit BHB as an alternative energy source during exercise or caloric deficiency. Future studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency 
Although both MCC950 and BHB inhibit NLRP3 inflammasome activation, their mechanisms differ in key respects. BHB inhibits K+ efflux from macrophages, while MCC950 does not. MCC950 inhibits both canonical and non-canonical inflammasome activation, while BHB affects only canonical activation. Nevertheless both inhibitors represent a significant advance toward developing therapies that target IL-1β and IL-18 production by the NLRP3 inflammasome in various diseases. 

Type I Interferon (IFN) and IFN-β

In contrast to these newly described, NLRP3-specific inflammasome inhibitors, type I interferons (IFNs), including IFN-α and IFN-β, have been used for some time to inhibit the NLRP3 and other inflammasomes in various auto-immune and auto-inflammatory diseases. These diseases include multiple sclerosis, systemic-onset juvenile idiopathic arthritis caused by gain-of-function NLRP3 mutations, rheumatic diseases and familial-type Mediterranean fever.

These studies highlight the efficacy of type I IFN therapy and the need for future studies to elucidate the mechanisms of NLRP3 inflammasome inhibition. This work may improve clinical approaches to treating multiple sclerosis and other auto-immune and auto-inflammatory diseases.

Other Kinds of NLRP3 Inflammasome Inhibitors
Several additional ways for inhibiting the NLRP3 inflammasome have opened up in recent years. Autophagy, a self-protective catabolic pathway involving lysosomes, has been shown to inhibit the NLRP3 inflammasome, leading researchers to explore the usefulness of autophagy-inducing treatments  

Cannabinoid receptor 2 (CB2R) is an already demonstrated therapeutic target in inflammation-related diseases (Smoum et al., 2015). Work from our own laboratory (Shao et al., 2014) has shown that autophagy induction may help explain why activation of the anti-inflammatory CB2R leads to inhibition of NLRP3 inflammasome priming
Thus CB2R agonists similar to the HU-308 used in our work may become an effective therapy for treating NLRP3 inflammasome-related diseases by inducing autophagy.
Several other microRNAs have been reported to be involved in the activation of the NLRP3 inflammasome, including microRNA-155, microRNA-377, and microRNA-133a-1. Reducing the levels of these factors may be useful for treating inflammasome-related disease 

Conclusion regarding NLRP3 inhibitors

At this point in time BHB is clearly the best choice; at some point it would be expected that Pfizer will commercialize MCC950. 

 Further relevant papers: 

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors. 

NLRP3-inflammasome activates caspase-1 and processes pro-IL-1β and pro-IL-18 into the active cytokines. Two recent studies describe specific inhibitors of NLRP3 inflammasome that inhibit IL-1β release and inflammation. The specificity and potency of these compounds gives hope that a targeted approach to inhibit NLRP3-driven inflammation may be just around the corner

Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer’s disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targeting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS + Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function. 

Scientists say new treatments for inflammatory diseases could be on the way

New treatments for inflammatory diseases could be on the way thanks to a significant discovery made by an international group of scientists, including some at Trinity College Dublin. 
The treatments could be used for a whole range of inflammatory disease including arthritis, Alzheimer's, multiple sclerosis, Parkinson's, gout, asthma and Muckle-Wells syndrome.

The researchers have found that a molecule, previously developed and then abandoned by a multinational pharmaceutical company, can block one of the key drivers of a plethora of inflammatory conditions.
The molecule, MCC950, was produced by Pfizer two decades ago as a possible treatment for arthritis.
However, the company discontinued its efforts to bring the drug to market, and the intellectual property rights on it subsequently lapsed.
Around eight years ago, scientists at Trinity's Biomedical Sciences Institute led by Professor of Biochemistry Luke O'Neill came across the compound and began to explore its potential uses.
They subsequently discovered that it could effectively block the NLRP3 inflammasome.
Inflammasomes are a complex of molecules that trigger inflammation when exposed to infection or stress.
They have been identified as promising therapeutic targets for researchers in recent years.
The NLRP3 inflammasome has been found to be a common activator of a key process in certain inflammatory diseases.
The discovery by the research team, details of which are published in the journal Nature Medicine, confirms that all inflammatory diseases share a common process, although the part of the body which experiences the inflammation might differ.
The scientists subsequently carried out trials on mice and found that the molecule stopped the progression of multiple sclerosis and sepsis.
They also carried out testing on samples taken from humans with Muckle-Wells syndrome, a rare auto-inflammatory disorder, and discovered it was equally effective.
The scientists also say that it is likely the drug could produce fewer common side-effects, such as susceptibility to infection, than other anti-inflammatory drugs, and could prove cheaper and capable of being administered orally.
The next stage will involve testing the compound on humans and a wider group of diseases.
The researchers say for certain conditions, like Muckle-Wells syndrome and asthma, such trials could take place as early as two to three years from now, as the drug had already undergone some human testing by Pfizer.
However, even if the trials prove the drug is safe and effective, they stress that it could be ten-15 years before it could be fully approved for use in humans for the treatment of more complex diseases like multiple sclerosis or Alzheimer's.
They also stress that while the molecule could become an effective treatment, it will not be a cure, though it is possible it could be effective in undoing some of the damage done by well progressed cases of certain diseases.
Prof O'Neill and his team now plan to form a company to further develop and test the compound.
MCC950 is also currently being tested on mice in the US for anti-ageing properties, as there is a growing school of thought that inflammation is responsible for much of the ageing process - a theory which has come to be known as "inflammaging".
The study, part funded by Science Foundation Ireland and the European Research Council, was carried out by a collaboration of six institutions, including the Universities of Queensland, Michigan, Massachusetts and Bonn. 


I am amazed at all the potentially good things that ketones and KD can do for many people’s health and it is all based on science from very serious institutions.