Choose your Statin with Care in FXS, NF1 and idiopathic Autism

There are several old posts in this blog about the potential to treat some autism using statins; this has nothing to do with their ability to lower cholesterol. 

Statins are broadly anti-inflammatory but certain statins do some other particularly clever things. This led me to use Atorvastatin and Fragile-X researchers to use Lovastatin.

Fragile X is suggested by an elongated face and big/protruding ears; 

other features include MR/ID and autism.

I was recently forwarded a Scottish study showing why Simvastatin does not work in Fragile X syndrome, but Lovastatin does.

Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E (see chart below). In people with Fragile X, they lack the FMR1 protein. Boys are worse affected than girls, because females have a second X chromosome and so a "spare" copy of the gene.

         Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.

So  ? = Does NOT inhibit

The researchers in Scotland did not test Atorvastatin in their Fragile X study.

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

RASopathies have been covered in this blog. Too much of the Ras protein is a common feature of much ID/MR. Investigating RAS took me to PAK1 inhibitors and the experimental drug FRAX486. This drug was actually developed to treat Fragile X; it is now owned by Roche. At least one person is using FRAX486 to treat autism.

You might wonder why the researchers do not just try Lovastatin in humans with Fragile X.  Unfortunately, Lovastatin was never approved as a drug in Scotland, or indeed many other countries.  Some researchers just assumed they could substitute Simvastatin, which on paper looks a very similar drug and one that crosses the blood brain barrier better than Lovastatin.

Lovastatin, not simvastatin, corrects core phenotypes in the fragile X mouse model

The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1-/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1-/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX.  

Although we propose the beneficial effect of lovastatin stems from the inhibition of ERK1/2-driven protein synthesis, it is important to note that statins are capable of affecting several biochemical pathways. Beyond the canonical impact on cholesterol biosynthesis, statins also decrease isoprenoid intermediates including farnesyl and geranylgeranyl pyrophosphates that regulate membrane association for many proteins including the small GTPases Ras, Rho and Rac [18, 46, 48, 49]. The increase in protein synthesis seen with simvastatin could be linked to altered posttranslational modification of these or other proteins. Indeed, although we see no change in mTORC1-p70S6K signaling, other studies have shown an activation of the PI3 kinase pathway that could be contributing to this effect [32]. However, our comparison of lovastatin and simvastatin shows that there is a clear difference in the correction of pathology in the Fmr1-/y model, suggesting that the impact on ERK1/2 is an important factor in terms of pharmacological treatment for FX.  There are many reasons why statins would be an attractive option for treating neurodevelopmental disorders such as FX. They are widely prescribed worldwide for the treatment of hypercholesterolemia and coronary heart disease [50], and safely used for longterm treatment in children and adults [46]. However, our study suggests that care should be taken when considering which statin should be trialed for the treatment of FX and other disorders of excess Ras. Although the effect of different statins on cholesterol synthesis has been well documented, the differential impact on Ras-ERK1/2 signaling is not well established. We show here that, contrary to lovastatin, simvastatin fails to inhibit the RasERK1/2 pathway in the Fmr1-/y hippocampus, exacerbates the already elevated protein synthesis phenotype, and does not correct the AGS phenotype. These results are significant for considering future clinical trials with lovastatin or simvastatin for FX or other disorders of excess Ras. Indeed, clinical trials using simvastatin for the treatment of NF1 have shown little promise, while trials with lovastatin show an improvement in cognitive deficits [28-30]. We suggest that simvastatin could be similarly ineffective in FX and may not be a suitable substitute for lovastatin in further clinical trials.

Conclusion

If you are treating Fragile X, best to start with Lovastatin and see if it helps.  In theory it might also help NF1 (Neurofibromatosis Type 1).

It looks to me that Atorvastatin also inhibits the relevant pathway and does much more besides that (PTEN, BCL2 etc)

Atorvastatin inhibits insulin synthesis by inhibiting the Ras/Raf/ERK/CREB pathway in INS-1 cells

What is Roche doing with FRAX486?

Ketones and Autism Part 6 - Capric Acid (C10) for Mitochondrial Disease, in Particular Complex 1, plus more on Metformin

Capric Acid (C10) is so named because it smells like a goat (Goat in Latin = Caper)

Photographer: Armin Kübelbeck, CC-BY-SA, Wikimedia Commons

Rather than Goaty acid, C10 is called Capric acid, or indeed Decanoic acid (after its 10 carbon atoms). Today’s post is indirectly again about ketones, because if you eat a Ketogenic Diet (KD) you are likely to consume a fair amount of Capric acid (C10).

I have written a lot in this blog about mitochondria, even though I do not think my son has mitochondrial dysfunction. Clearly many people with autism do have a lack of one or more of the critical mitochondrial enzyme complexes that allow glucose to be converted to ATP (usable energy), by the clever process OXPHOS (Oxidative phosphorylation).

The “rate limiting” enzyme is usually Complex 1, meaning that is the one it is most important not to be short of.

Another favourite, but obscure, subject of this blog is PPAR gamma.

Peroxisome proliferator-activated receptors (PPARs) are a group of proteins that function as transcription factors regulating the expression of certain genes. Transcription factors are particularly important because they trigger numerous effects.

PPAR gamma plays a key role in fat storage and glucose metabolism, but has other functions. 

Activation of PPAR-gamma by Capric acid (C10) has been shown to increase the number of mitochondria, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase. 

So, if you have autism and impaired mitochondrial function, C10 may well give a benefit because it can increase the peak power available to your brain.

The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells

The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

Capric Acid (C10) as a PPARγ agonist

As shown in the above study the mechanism by which C10 benefits the mitochondria is via PPARγ agonism.

Here is another study confirming that C10 is indeed a PPARγ agonist.

Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferator-activated Receptors

Background: Mechanism of action of medium chain fatty acid remains unknown.

Results: Our results show that decanoic acid (C10) binds and activates PPARγ.

Conclusion: Decanoic acid acts as a modulator of PPARγ and reduces blood glucose levels with no weight gain.

Significance: This study could lead to design of better type 2 diabetes drugs.

Other PPARγ agonists

PPARγ agonists have been covered previously in this blog and we know that glitazones, a class of drugs for diabetes, do improve some types of autism. Glitazones are PPARγ agonists.

Metformin, a very widely used drug for type 2 diabetes, works differently to Glitazones, but I did suggest a while back it should help some types of autism. Last year it was indeed found to be beneficial in Fragile X.

Diabetes drug may help symptoms of autism-associated condition

 "Basically, it's something like a wonder drug," Sonenberg said.

The study suggests that metformin might also be used to treat other autism spectrum disorders, said Ilse Gantois, a research associate in Sonenberg's lab at McGill.

"We mostly looked at the autistic form of behaviour in the Fragile X mouse model," explained Gantois, who is co-lead author with McGill researchers Arkady Khoutorsky and Jelena Popic. "We want to start testing other mouse models to see if the drug could also have benefits for other types of autism."

Metformin is very cheap and has been used in humans for 60 years. It is another example of re-purposing a drug from Grandpa’s medicine cabinet to treat Grandson’s autism. 

Metformin has been trialled to combat obesity in idiopathic autism caused by antipsychotics. It did help with weight gain, but no comments were made about behavioural improvements, but then those studied were on antipsychotic drugs, which might mask such effects. 

Glitazone-type drugs appear more problematic than Metformin.

There are natural PPAR gamma agonists and they are often used to lower cholesterol, lower blood sugar and improve insulin sensitivity.

Sytrinol, a product containing flavanols tangeretin and nobiletin does indeed have a positive effect on some people’s autism, but for most people (but not all) the effect is lost after a few days.

Our doctor reader Maja, did suggest combining it with a PPARα agonist to see if the effect might be maintained.

This combination has indeed been researched for type 2 diabetes.               

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.

There actually is another natural substance that is an agonist of both PPARγ and PPARα, Berberine, the alkaloid long used in Chinese medicine.

In the research it is suggested that “BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK”, which is not what you would want. But this may not be correct.

People who like supplements might want to follow up on Berberine.

Berberine is used by many people with diabetes and a few with autism, for all kinds of reasons, from mercury to GI problems.

Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.

Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.

Berberine activates peroxisome proliferator-activated receptor gamma to increase atherosclerotic plaque stability in Apoe^-/- mice with hyperhomocysteinemia.

                                                                                                                                     

Sources of Capric Acid (C10)

Goat milk is a good source of capric acid.

Capric acid is 8-10% of coconut oil and 4% of palm kernel oil

Capric acid is a large component (about 40%) of the less expensive MCT oil supplements.

http://cdn.intechopen.com/pdfs/39464/InTech-The_effect_of_fatty_acids_in_goat_milk_on_health.pdf

1.2. Fatty acid composition in goat milk fat Average goat milk fat differs in contents of its fatty acids significantly from average cow milk fat, being much higher in butyric (C4:0), caproic (C6:0), caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0), palmitic (C16:0), linoleic (C18:2), but lower in stearic (C18:0), and oleic acid (C18:1) (Table 1). Three of the medium chain fatty acids (caproic, caprylic, and capric) have actually been named after goats, due to their predominance in goat milk. They contribute to 15% of the total fatty acid content in goat milk in comparison to 5% in cow milk (Haenlein, 1993). The presence of relatively high levels of medium chain fatty acids (C6:0 to C10:0) in goat milk fat could be responsible for its inferior flavour (Skjevdal, 1979). 

             

Conclusion

If someone responds well to coconut oil or cheaper MCT oil the reason may have more to do with PPAR gamma and improved mitochondrial function than anything to do with ketones and what they do.

Cheaper MCT oils are mainly a mixture of C8 and C10. To maximize the production of the ketone BHB you really want just C8, but if what you really need is a PPAR gamma agonist, to perk up your mitochondria, it is the C10 you need.

You may indeed benefit from both ketones and agonizing PPAR gamma, in which case you either follow the Ketogenic Diet, or supplement BHB, C8 and C10.

I think this explains why some people with autism reportedly respond well to teaspoon-sized doses of cheaper MCT oil or small amounts of coconut oil.

If you have Complex 1 mitochondrial dysfunction then a dose of Capric acid (C10) is likely to help.

Berberine may, or may not be, as effective as C10. I doubt we will ever know. I think C10 is the better option. 

I wonder when the Canadian researchers will publish their results showing whether Metformin is beneficial beyond Fragile X syndrome. They do not really know why it helps, but that is a repeating theme in medicine.  It is a cheap safe drug, so it would be a pity to waste time finding out if it could be repurposed for some autism.

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 GABA_B antagonist. 

There has been quite a lot of coverage in this blog about agonists of GABA_B 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 GABA_B 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 GABA_B antagonist (the opposite of Baclofen) might benefit some with autism.

Neuronal Chloride Regulation via KCC2 Is Modulated through a GABA_B Receptor Protein Complex.

GABA_B receptors are G-protein-coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABA_B receptor forms part of larger signaling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABA_B receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABA_A receptor in mature neurons. Using biochemical, molecular, and functional studies in rodent hippocampus, we show that activation of GABA_B 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 GABA_A receptors (GABA_ARs) and metabotropic GABA_B receptors (GABA_BRs). 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 GABA_BR 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 GABA_AR. We demonstrate that GABA_BR activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABA_AR. Our data therefore support an additional mechanism by which GABA_BRs 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 GABA_B receptors might increase the flow of chloride ions exiting through KCC2.

All very complicated sounding, but in effect it means that a GABA_B antagonist might boost the effect of bumetanide.

Which GABA_B antagonist?

This was Ling’s question.

Saclofen is a competitive antagonist for the GABA_B receptor. This drug is an analogue of the GABA_B agonist baclofen.

Phaclofen/phosphonobaclofen, is a selective antagonist for the GABA_B 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 GABA_B.

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 GABA_B will inevitably also affect NMDA receptors.

This was covered in this post from 2015.

NMDAR hypo-function causing E/I imbalance in Autism and Schizophrenia – Baclofen, Sodium benzoate and Cinnamon (again)

which highlighted this paper:

GABA_B-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction

Homotaurine 

Homotaurine has been reported as a GABA antagonist as well as a GABA agonist. In vitro studies have found that homotaurine is a GABA_A partial agonist as well as a GABA_B 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 GABA_B agonist),^[16] and was able to produce analgesia via the GABA_B receptor, an effect that was abolished when CGP 35348, a GABA_B 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]

Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome.

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

 Supplementation of Korean Red Ginseng improves behavior deviations in animal models of autism

Background

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.

Objectives

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.

Design

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.

Results

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.

Conclusion

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.

First preliminary results of an observation of Panax ginseng treatment in patients with autistic disorder.

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.

RESULTS

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.

DISCUSSION 

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? 

Effects of Korean Red Ginseng Extract on Behavior in Children with Symptoms of Inattention and Hyperactivity/Impulsivity: A Double-Blind Randomized Placebo-Controlled Trial

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.

Effect of the herbal extract combination Panax quinquefolium and Ginkgo biloba on attention-deficit hyperactivity disorder: a pilot study.

OBJECTIVE:

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). 

DESIGN:

Open study. 

PATIENTS:

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

INTERVENTIONS:

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. 

OUTCOME MEASURES:

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). 

RESULTS: 

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. 

CONCLUSIONS:

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.

Abstract

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.

Emerging signals modulating potential of ginseng and its active compounds focusing on neurodegenerative diseases

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). 

Effects and mechanisms of ginseng and ginsenosides on cognition. 

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

A survey of Korean medicine doctors’ clinical practice patterns for autism spectrum disorder: preliminary research for clinical practice guidelines

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

Conclusion

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 GABA_B 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:-

https://www.reddit.com/r/phenibut/comments/5ii692/homotaurine_gabab_antagonist_tolerance_reversal/

More Support for the use of Statins in some Autism

Monty, aged 12 with ASD, has been taking Atorvastatin for two years, with a clear cognitive improvement from day one.  

This improvement is lost when this therapy is interrupted.

There are several posts in this blog giving the scientific basis why statins might be beneficial in some autism, these included the genes/proteins RAS, PTEN and BCL2.  In addition, statins possess potent anti-inflammatory properties.

Following a flood of visits to this blog to read about statins and autism, I did a quick check and in recent weeks at least three papers have been published suggesting the potential for statins to improve some autism.

I include the word “some” because with 800 currently identified autism genes, and I expect eventually it will be thousands, what works for one person’s “autism” may not help the next person’s “autism” and might even make it worse.

The first paper is the one getting the media coverage, it is from the University of Edinburgh, plus Mark Bear et al from MIT.  Mark Bear’s lab has featured in this blog several times, particularly relating to Fragile-X.  Lovastatin is being already trialed in humans with Fragile-X.

I use Atorvastatin (Lipitor) because it has best side effect profile.  Lovastatin and Simvastatin will have the same effect.  In some countries these drugs are available cheaply OTC.

Their therapeutic effect in autism, based on my sample of one, is from the first pill.

Over to the "experts":-

Cholesterol drug could aid autism sufferers

Intellectual disabilities and autism spectrum disorders could share similar defects although their genetic causes are different, according to Scottish scientists.

A study of two models of intellectual disability in mice by Edinburgh University has found that they share similar disease mechanisms.

Researchers also found that treatment with a statin drug called Lovastatin, which is often used to treat high cholesterol, can correct high levels of protein production in the brain linked to the conditions.

The findings suggest that different types of intellectual disabilities may benefit from common therapeutic approaches, the researchers say.

Professor Peter Kind, Director of the University of Edinburgh’s Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities, said: “Statins, such as lovastatin, are already used widely for treating people, including children, for high cholesterol with minimal side effects.

“Further studies are needed to determine whether these existing medications could also help people with intellectual disabilities.”

The study has been published in the Journal of Neuroscience

The full paper is here:-

Convergence of Hippocampal Pathophysiology in Syngap+/− and Fmr1−/y Mice

Abstract

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap^+/− and Fmr1^−/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap^+/− hippocampal slices. Super-resolution microscopy reveals that Syngap^+/− and Fmr1^−/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras–ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.

SIGNIFICANCE STATEMENT As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap^+/− mice phenocopy Fmr1^−/y mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu₅ receptor–ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1^−/y mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.

The other two papers are from 2015 Society for Neuroscience annual meeting in Chicago.

  

Experimental cancer drug eases autism symptoms in mice

A drug that blocks a cancer-related pathway normalizes neuron number and prevents behavior problems in mice that lack a copy of the autism-linked chromosomal region 16p11.2. Researchers presented the unpublished results yesterday at the 2015 Society for Neuroscience annual meeting in Chicago.

Loss of 16p11.2 results in intellectual disability, enlarged head, obesity and, often, autism. This region spans 27 genes — including one called ERK1, part of a signaling cascade that regulates cell growth. The cascade, called the RAS pathway, is hyperactive in some types of cancer and in four rare autism-linked neurodevelopmental disorders, collectively dubbed ‘RASopathies.’ The proteins encoded by ERK1 and the related ERK2 gene carry out many of the molecular consequences of RAS pathway activation.

Paradoxically, the ERK proteins are hyperactive in mice lacking a copy of 16p11.2¹. This hyperactivation coincides with a period of intense neuron development in the mouse embryo. The animals also have too few neurons in some parts of the cerebral cortex, the brain’s outer layer, and too many neurons in others.

“Because of this aberrant ERK hyperactivity, we were thinking that we can potentially try to bring the levels down by using a specific ERK inhibitor,” says Joanna Pucilowska, a postdoctoral fellow in Gary Landreth’s lab at Case Western Reserve University in Cleveland, Ohio.

Sniffing clues:

Pucilowska and her colleagues used an experimental drug that blocks activation of the ERK proteins. They injected the drug into pregnant mice to investigate its effects on neuron development in mouse embryos.

Treating mice with the drug prenatally for five days stabilizes ERK activity, the researchers found. It also normalizes neuron numbers in the cerebral cortex.

The treatment has lasting effects on behavior, too. Unlike untreated mice that lack a copy of 16p11.2 — which are underweight, hyperactive and have memory problems — the treated mice resemble those that do not have the chromosomal deletion.

The researchers discovered for the first time that mice lacking 16p11.2 are quicker than those without the deletion to sniff out a hidden snack in their cage, suggesting they have a highly acute sense of smell, like some people missing 16p11.2. Female mice with the deletion are also faster to retrieve pups that stray from the safety of their nest, an innate maternal behavior. The drug treatment normalizes both behaviors.

Pucilowska says she and her colleagues would like to test the drug in cells derived from people missing a copy of 16p11.2. If it works in human cells the same way it does in mice, then it might be possible to treat people with the deletion using cholesterol-lowering drugs called statins, which are also known to block signaling in the RAS pathway. “This can potentially lead to the first treatment for children with 16p11.2 deletion,” Pucilowska says.

Autism model reveals brain processes behind ‘super’ skills

Structural changes in the connections between neurons may underlie the enhanced learning and motor skills seen in mice with an extra copy of the autism-linked gene MeCP2. Blocking these changes with a drug blunts the animals’ performance.

The findings, presented yesterday at the 2015 Society for Neuroscience annual meeting in Chicago, point to neural mechanisms underlying the restricted interests and, in some cases, exceptional learning abilities seen in people with autism.

“This could lead to enhanced learning and enhanced performance in constrained behaviors, like in autistic savants,” says Ryan Ash, a graduate student in Stelios Smirnakis’ lab at Baylor College of Medicine in Houston. “Maybe they can’t iteratively refine those kinds of behaviors over time, so they get stuck in a behavior, which can be exceptional in certain cases but then impaired in others.”

People carrying an extra copy of MeCP2 often have autism. Mice with the same duplication have autism-like symptoms, such as avoiding social interactions with other mice.

“But they also have a super-learner phenotype,” Ash says. They perform better than controls do on a test of motor skill learning that involves balancing on a rotating rod. Typical mice fall off the rod as its speed increases, but mice with the duplication learn to coordinate their feet so that they can stay on about 30 seconds longer.

When mice learn a motor task, new synapses, connections between neurons, form in the brain¹. The researchers suspected that the superior learning abilities of the mice carrying the extra MeCP2 might stem from alterations in the formation and stability of these neuronal links.

To test this hypothesis, the researchers used microscopy to image neurons in the brain that connect to the spinal cord and control movement. They took pictures of the same neurons before and after the mice practiced the rotating rod test for four days, and again after the animals had four days of rest.

Spine support:

As expected, training spurred neurons in typical mice to form new signal-receiving projections, called dendritic spines. About half of these spines remained after four days of rest, suggesting the formation of stable memories. Mutant mice form more spines than controls do, and more of them stay put after the mice take a break.

The stable spines tend to cluster. Enhanced performance on the rod tracks with a greater number of clustered spines remaining after the rest period.

“We think this is important because spines that are near each other can drive the cell more strongly when they get activated at the same time,” Ash says.

Training stimulates greater activation of a signaling cascade called the RAS pathway in the mutant mice than it does in controls. Activation of this pathway is known to strengthen clustered spines².

Blocking the activation of this pathway with an experimental drug called SL327 lowers the mutants’ performance on the rotating rod back to the normal range. And the spines in these animals also look more like those of typical mice.

The findings suggest that spine formation and stability underlie the enhanced learning abilities of the mutant mice. Both processes appear to depend on the activation of the RAS pathway.

The drug the researchers used lasts only for a few hours, so it is not likely to help people with autism, Ash says. But cholesterol-lowering drugs called statins block activation of the same pathway by a different mechanism. “Maybe you could do a more chronic treatment with a statin, but we haven’t tried that yet,” he says.

Other mouse models of autism show enhanced performance on the rotating rod test. These include mice with a duplication in chromosomal region 15q11-13 and with mutations in the CNTNAP2, NLGN3 and NRXN1 genes, Ash says.

Interestingly, mice that lack a copy of MeCP2 — the gene mutated in the autism-linked disorder Rett syndrome — have impaired performance on the same test, and show reduced spine stability. “I would hypothesize that all of these things are actually the opposite in the Rett mice,” Ash says.