Acid-sensing Ion Channels (ASICs) and Autism – Acid in the Brain

Acid sensing ion channels (ASICs) are another emerging area of science where much remains known.  It would seem that ASICs have evolved for a good reason, when pH levels fall they trigger a reaction to compensate.  (The lower the pH the higher is the acidity)  In some cases, like seizures, this seems to work, but in other cases the reaction produced actually makes a bad situation worse.

Research is ongoing to find inhibitors of ASICs to treat specific conditions raging from MS (Multiple Sclerosis), Parkinson’s and Huntington’s to depression and anxiety. Perhaps autism should be added to the list.

NSAIDs like ibuprofen are inhibitors of ASICs.

The complicated-looking chart below explains the mechanism.  The ASIC is on the left, also present is a voltage-gated calcium channel (VGCC) and an NMDA receptor. We already know that VGCCs can play a key role in autism and mast cell degranulation. Similarly we know that in autism there is very often either too much or too little NMDA signaling. Here we have all three together.

  

The role of ASICs is to sense reduced levels of extracellular pH (i.e. acidity outside the cell) and result in a response from the neuron. Under increased acidic conditions, a proton (H+) binds to the channel in the extracellular region, activating the ion channel and opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions.

All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization.

Voltage-gated Ca²⁺ channels are then activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released.

NMDA receptors are also activated and this results in more influx of calcium into the cell.

This calcium inflow then triggers further reactions via CaMKII (calmodulin-dependent protein kinase II).

The overall effect is likely to damage the cell.

There is also an important effect on dendritic spines:-

“ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca²⁺]_i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures”

In general the research is looking to inhibit ASICs to improve a variety of neurological conditions.

Acid in the Brain

ASICs only become activated when there is acidity (low pH).  When the pH is more than 6.9 they do nothing at all.

Unfortunately, in many neurological disorders pH is found to be abnormally low and that includes autism.

ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca²⁺permeability and an inward flow of Ca²⁺. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death.

However in the case of epilepsy, ASIC1a channels can be helpful.  Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. 

Increased brain acidity in psychiatric disorders

Changes in the brain pH level have been considered an artifact, therefore substantial effort has been made to match the tissue pH among study participants and to control the effect of pH on molecular changes in the postmortem brain. However, given that decreased brain pH is a pathophysiological trait of psychiatric disorders, these efforts could have unwittingly obscured the specific pathophysiological signatures that are potentially associated with changes in pH, such as neuronal hyper-excitation and inflammation, both of which have been implicated in the etiology of psychiatric disorders. Therefore, the present study highlighting that decreased brain pH is a shared endophenotype of psychiatric disorders has significant implications on the entire field of studies on the pathophysiology of mental disorders.

This research raises new questions about changes in brain pH. For example, what are the mechanisms through which lactate is increased and pH is decreased? Are specific brain regions responsible for the decrease in pH? Is there functional significance to the decrease in brain pH observed in psychiatric disorders, and if so, is it a cause or result of the onset of the disorder?. Further studies are needed to address these issues.

The following paper is mainly by Japanese researchers and is very thorough; it will likely make you consider brain acidosis as almost inevitable in your case of autism. 

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

Lower pH is a well-replicated finding in the post-mortem brains of patients with schizophrenia and bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding  reflects a primary feature of the diseases or is a result of confounding factors such as medication, post-mortem interval, and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies.  In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar  disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then  utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis  that lower brain pH exists in these brains compared to controls due to the underlying pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific  calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and  one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same post-mortem interval and agonal state at death. Upon post-mortem examination, we observed  significantly lower pH and higher lactate levels in the brains of model mice relative to controls. There was a significant negative correlation between pH and lactate levels. These results suggest that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather than mere artefacts.

A number of postmortem studies have indicated that pH is lower in the brains of patients with schizophrenia and bipolar disorder. Lower brain pH has also been observed in patients with ASD. In general, pH balance is considered critical for maintaining optimal health, and low pH has been associated with a number of somatic disorders. Therefore, it is reasonable to assume that lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of various psychiatric disorders.            

Researches have revealed that brain acidosis influences a number of brain functions, such as anxiety, mood, and cognition. Acidosis may affect the structure and function of several types of brain cells, including the electrophysiological functioning of GABAergic  neurons and morphological properties of oligodendrocytes. Alterations in these types of cells have been well-documented in the brains of patients with schizophrenia, bipolar disorder, and ASD and may underlie some of the cognitive deficits associated with these disorders. Deficits in GABAergic neurons and oligodendrocytes have been identified in the mouse models of the disorders, including Shn2 KO mice. Brain acidosis may therefore be associated with deficits in such cell types in schizophrenia, bipolar disorder, and ASD.

Interestingly, we observed that Wnt- and EGF-related pathways, which are highly implicated in somatic and brain cancers, are enriched in the genes whose expressions were altered among the  five mutant mouse strains.

These findings raise the possibility that elevated glycolysis underlies the increased lactate and pyruvate levels in the brains of the mouse models of schizophrenia, bipolar disorder, and ASD.

Dysregulation of the excitation-inhibition balance has been proposed as a candidate cause of schizophrenia, bipolar disorder, and ASD. A shift in the balance towards excitation would result in increased energy expenditure and may lead to increased glycolysis.

UI team develops new way to look at brain function

University of Iowa neuroscientist John Wemmie is interested in the effect of acid in the brain (not that kind of acid!). His studies suggest that increased acidity—or low pH—in the brain is linked to panic disorders, anxiety, and depression. But his work also indicates that changes in acidity are important for normal brain activity too.

“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, associate professor of psychiatry in the UI Carver College of Medicine. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.

“Brain activity is likely different in people with brain disorders such as bipolar or depression, and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day: Could this signal be abnormal or perturbed in human psychiatric disease? And if so, might it be a target for manipulation and treatment?”

Panic attacks as a problem of pH

An easy to read article from the Scientific American

Dendritic Spines and ASICS

ASIC2 Subunits Target Acid-Sensing Ion Channels to the Synapse via an Association with PSD-95

The present results and previous studies suggest that ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca²⁺]_i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures (Xiong et al., 2004; Yermolaieva et al., 2004; Gao et al., 2005; Friese et al., 2007; Ziemann et al., 2008). Interestingly, one previous report suggested increased ASIC2a expression in neurons surviving ischemia, although the functional consequence of those changes are uncertain (Johnson et al., 2001). Moreover, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation (Bernardinelli et al., 2007; Girirajan et al., 2007; Stone et al., 2007). Thus, we speculate that ASIC1a and ASIC2, working in concert, may regulate neuronal function in a variety of disease states  

ASICs in neurologic disorders

Disease	Role of ASICs
Parkinson’s disease	Lactic acidosis occurs in the brains of patients with PD.
	Amiloride helps protect against substantia nigra neuronal degeneration, inhibiting apoptosis.
	Parkin gene mutations result in abnormal ASIC currents.
Huntington’s disease	ASIC1 inhibition enhances ubiquitin-proteasome system activity and reduces huntingtin-polyglutamine accumulation.
Pain	ASIC3 is involved in: 1) primary afferent gastrointestinal visceral pain, 2) chemical nociception of the upper gastrointestinal system, and 3) mechanical nociception of the colon.
	Blocking neuronal ASIC1a expression in dorsal root ganglia may confer analgesia.
	NSAIDs inhibit sensory neuronal ASIC expression.
Cerebral ischemia	Neuronal ASIC2 expression in the hypothalamus is upregulated after ischemia.
	Blockade of ASIC1a exerts a neuroprotective effect in a middle cerebral artery occlusion model.
Migraine	Most dural afferent nerves express ASICs.
Multiple sclerosis	ASIC1a is upregulated in oligodendrocytes and in axons of an acute autoimmune encephalomyelitis mouse model, as well as in brain tissue from patients with multiple sclerosis.
	Blockade of ASIC1a may attenuate myelin and neuronal damage in multiple sclerosis.
Seizure	Intraventricular injection of PcTX-1 increases the frequency of tonic-clonic seizures.
	Low-pH stimulation increases ASIC1a inhibitory neuronal currents.
Malignant glioma	ASIC1a is widely expressed in malignant glial cells.
	PcTx1 or ASIC1a knock-down inhibits cell migration and cell-cycle progression in gliomas.
	Amiloride analogue benzamil also produces cell-cycle arrest in glioblastoma.

Source:   Acid-sensing ion channels: potential therapeutic targets for neurologic diseases

One logical question is whether the brain ASIC connection with autism connects to the common  gastrointestinal problems, some of which relate to acidity and are often treated with H2 antihistamines and proton pump inhibitors (PPIs).

Acid-Sensing Ion Channels in Gastrointestinal Function 

Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.

It looks like it is still early days in the research into ASICs and GI problems. Best look again in decade or two.  

Too Much Lactic Acid – Lactic Acidosis 

One theory is that panic attacks are cause by too much lactic acid.

In earlier posts of mitochondrial disease and OXPHOS, we saw that when the mitochondria have too little oxygen they can continue to produce ATP, but lactate accumulates and this leads to lactic acidosis.

So people with mitochondrial disease might have some degree of lactic acidosis that would reduce extracellular pH and activate ASICs.

So perhaps along with those prone to panic attacks, people with regressive autism and high lactate might benefit from an ASIC inhibitor?

Aerobic exercise is suggested to reduce excess lactate, although extreme exercise like running a marathon will actually make more.  Moderate exercise has the added advantage of stimulating the production of more mitochondria.

So moderate exercise for panic disorders and regressive autism (mitochondrial disease).   Moderate exercise is then an indirect ASIC inhibitor, because it should increase pH (less acidic). 

ASICs in panic and anxiety?

Localization and Behaviors in Null Mice Suggest that ASIC1 and ASIC2 Modulate Responses to Aversive Stimuli 

Acid sensing ion channels (ASICs) generate H⁺-gated Na⁺ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1^−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO₂ inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Recent genome-wide studies have associated SNPs near ASIC2 with autism (Stone et al., 2007), panic disorder (Gregersen et al., 2012), response to lithium treatment in bipolar disorder (Squassina et al., 2011) and citalopram treatment in depressive disorder (Hunter et al., 2013), and have implicated a copy number variant of ASIC2 with dyslexia (Veerappa et al., 2013). However, little is currently understood about whether ASIC2 is required for normal behavior.

The goals of this study were to better understand the role of ASIC2 in brain function. Thus our first aim was to localize ASIC2 subunits. Because ASIC2 subunits multimerize with ASIC1 subunits, we hypothesized that the distribution of the two subunits would show substantial overlap. In addition, given that ASIC channels in central neurons missing ASIC2 have altered trafficking and biophysical properties, we hypothesized that disrupting expression of ASIC2 would impact behavior. Therefore, we asked if mice missing ASIC2 would have altered behavioral phenotypes, and whether disrupting both ASIC1 and ASIC2 would have the same or greater behavioral effects than disrupting either gene alone. Because we found that ASIC2, like ASIC1, was highly expressed in brain regions that coordinate responses to threatening events, we focused on tests that evaluate defensive behaviors and reactions to stressful and aversive stimuli.

These results suggest that ASIC channels can influence synaptic transmission. We speculate that pH falls to the greatest extent with intense synaptic activity; the mechanism might involve release of the acidic contents of synaptic vesicles, transport of HCO₃⁻ or H⁺ across neuronal or glial cell membranes, and/or metabolism. The reduced pH could activate ASIC channels leading to an increased [Ca²⁺]_i (Xiong et al., 2004; Yermolaieva et al., 2004; Zha et al., 2006). In this scenario, the main function of ASIC channels would be to enhance synaptic transmission in response to intense activity. This would explain the pattern of abnormal behavior in ASIC null mice when the stimulus is very aversive.

Translating ASIC research into therapy

As you may have noticed in the first chart in this post, there already exist ways to inhibit ASICs, ranging from a diuretic called Amiloride to NSAIDs, like ibuprofen.  The process of translating science into medicine has already begun in multiple sclerosis, as you can see in the following study:-

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. 

Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. 

Agmatine and Spermine

In the graphic at the start of this post you might have noticed Agmatine and Spermine.  While ASICs are acid sensing and so activated by protons, they appear to be also activated by other substances.

The arginine metabolite agmatine may be an endogenous non-proton ligand for ASIC3 channels.

Extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.

However, other research shows spermine promotes autophagy and has been shown to ameliorate ischemia/reperfusion injury  (IRI) and suggests its use in children to prevent IRI .  

So nothing is clear cut.

It looks like spermine, spermidine and agmatine all promote autophagy.            

Agmatine gets converted to a polyamine called putrescene.

Personally, I expect polyamines will generally be found beneficial in autism, but there will always be exceptions.  

Conclusion

There is a case to be made for the use of the diuretic amiloride to treat MS and indeed panic disorders.

Will amiloride help autism? You would not want to use it if there is comorbid epilepsy, since ASICs are “seizure protective”. 

If your genetic testing showed an anomaly with the ASIC2 gene, which is known to occur in both autism and MR/ID, then amiloride would seem a logical therapy.

I think we should not be surprised if people with neurological conditions have lower pH brains than NT people, just like we should expect them to show signs of oxidative stress.

If you do indeed happen to have a rather acidic brain, as seems to be quite often the case, damping down the response from ASICs might make things better or worse, or in indeed a mixture of the two. You would hope, at least in some people, that ASICs provide some beneficial response on sensing low pH.

It would be useful if a researcher did a trial of amiloride in different types of autism, then we might have some useful data. You would think the Japanese researchers would be the ones to do this.

One good thing about amiloride is that it increases the level of potassium in your blood and there even is a combined bumetanide/amiloride pill.  Bumetanide has the side effect of lowering potassium.

Many people with autism find NSAIDs beneficial, either long term or for flare-ups. NSAIDs have many beneficial effects; just how important is ASIC inhibition is an open question.

Is the anxiety that many people with autism seem to suffer, sometimes related to ASICs?  Perhaps it is just a minor panic disorder and it relates to ASIC1 and ASIC2.  I think there are numerous different dysfunctions that produce what we might term “anxiety”, among the long list one day you may well find ASICs.

Science has a long way to go before there is a complete understanding of this subject.

Moderate exercise again appears as a simple therapy with countless biological benefits, in this case reducing lactate and thus reducing acidity (increasing pH).

Buy Arbaclofen for Autism? Perhaps try Pantogam Aktiv?

             

An Enantiomer is like a mirror image,

so there are two versions of the “same” molecule one called R- and one called  S-

Some people are still looking to obtain Arbaclofen to treat autism and Fragile-X, they regularly stumble upon this blog.

A couple of years ago there was a lot of interest in Arbaclofen (R-baclofen), a GABA_B drug, which is, in effect, a special version of a cheap existing drug called Baclofen.  Baclofen is generally used to treat spasticity, but also alcoholism and even hiccups.

As we saw in earlier posts, the drug Baclofen is a mixture of R-Baclofen and S-Baclofen. The research showed that their action is different and that S-Baclofen reduced the effect of R-baclofen.  So in some modes of action, pure R-Baclofen would have much greater effect than the regular Baclofen mixture.

If you use the "index by subject" on this blog, which is a tab at the top, you can find the posts that relate to Arbaclofen.

Arbaclofen

1.   4G and Autism - Glutamine, Glutamate, GABA & GAD

2.   Autism Clinical Trials, Arbaclofen (STX209), Curemark CM-AT and the Clever Chiropractor

3.   Human Growth Factors, Autism and the Centenarian Nobel Laureate

Arbaclofen Research in Autism/Fragile X

This very expensive episode was triggered by one child with autism being prescribed regular Baclofen, for an unrelated issue.  That child’s autism had dramatically improved, this then led to the interest of Seaside Therapeutics, who already had another prospective autism drug.

After tens of millions of dollars spent, everything stopped a couple of years ago.  The developer, Seaside Therapeutics, appears to have been shut down, although in its clinical trial a substantial minority found the drug was effective.  The way the trial had been structured, the drug did not achieve is “primary endpoint” and so Roche, the potential follow-on investor, deemed the trial a failure.

This led to many unhappy parents seeking alternative sources of R-Baclofen, which they believed had been effective.

Baclofen for Asperger’s?

At least one regular reader of this blog finds that Baclofen is very helpful for himself.

Yesterday before completing this post I had some exchanges with a UK pediatrician (spelled paediatrician in the UK) who is prescribing Baclofen to eight children with Asperger’s to treat anxiety. The results are very positive.  I do wonder is this a 100% response rate,  or are the eight a subset of all the children that have tried the drug?

One of our Australian readers of this blog is very interested in minimizing anxiety in his child with high functioning autism.  He did forward me some research, a while back,  that links GABA_B to Somatostatin, also called Growth Hormone Inhibiting Hormone (GHIH) .  The research from Carnegie Mellon shows that GHIH changes the way the brain functions. 

This does get very complicated the more you dig and, until today, I did not start to write up my findings.  This is just some initial thoughts/links for scientists.

Intermediary Neuron Acts as Synaptic Cloaking Device, Says Carnegie Mellon Study

“Furthermore, by silencing certain parts of the neuronal network, the activity of the somatostatin neurons also can change the way the brain functions, heightening some perceptual pathways and silencing others.” 

Neocortical Somatostatin Neurons Reversibly Silence Excitatory Transmission via GABAb Receptors

“If the levels of human growth hormone in circulation in the brain and the blood get too high, then special cells called somatostatin neurons detect this. These neurons then trigger the creation of more GHIH in the brain. This then in turn slows down the secretion of human growth hormone.”

Autism-linked gene guides growth of subtype of neurons

 “Mature interneurons from this brain region mainly express either parvalbumin or somatostatin, which serve as markers of these subtypes. Parvalbumin neurons tend to fire quickly in response to signals, whereas the somatostatin ones respond more slowly.

In control mice, the ratio of these two subtypes is about 50:50. By contrast, the mutant mice show a dramatic decrease in the number of interneurons expressing somatostatin. This results in an excess of abnormally large cells expressing parvalbumin.

Despite an overall loss of interneurons, the mice have more inhibitory signals than controls do, skewing the signaling balance to excitation.” 

We do know that the various growth factors in people with autism can be disturbed, but in different types of autism that disturbance varies, just to complicate things.

Various therapies based on this are under development (one uses IGF-1 and NNZ-256 is another).  We also know that many people with classic autism have accelerated growth (both body and head) in the first two years.  We also know that brain growth is also accelerated.

We know from the genetic research that many of the anomalies relate to GABA.

We know that targeting the GABA_A receptor can be hugely beneficial in classic autism (bumetanide and micro-dose clonazepam).  We can also fine tune the structure of the GABA_A receptor and potentiate it using allosteric modulators (like Pregnenolone or progesterone).  This also gets very complicated.

Baclofen for Classic Autism?

Baclofen is a spasticity drug:

Spasticity (from Greek spasmos-, meaning "drawing, pulling") is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles.

People with (classic) autism as opposed to Asperger’s can have all sorts of fine and gross motor issues, particularly as young children.

They can “toe walk”, walk with their feet pointing in different directions, they can have “claw hand”.  They can struggle to control a pencil and even when they learn, their handwriting can be very sloppy.

Are these spasticity issues?  I think they probably are.

When people’s autism flares up, an early sign is worsening handwriting.

When my son’s Polypill begins to wear off in spring/summer at school at around 11 am, the claw hand returns.

I did indeed try Baclofen about a year ago.  There is an effect - no claw hand.

The problem with Baclofen is tolerance, the more you use it the higher the effective dose becomes, just like benzodiazepines.

So I noted that there was an effect, but chose to move on.

Meanwhile over in Russia

For many years in Russia they have had their own GABA_B drug, similar to Baclofen, it is called Pantogam.  Pantogam has been used for years as a therapy for neurological conditions including autism.

Just as Baclofen is “racemic mixture” of left-baclofen and right-baclofen, so is Pantogam.  There is S-Pantogam and R-Pantogam.

Enantiomers

There is nothing strange about these left and right versions of a drug

Here is from Wikipedia:-

Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is sometimes a marked difference in the effects of two enantiomers on living beings. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for adverse effects.

Owing to this discovery, drugs composed of only one enantiomer ("enantiopure") can be developed to enhance the pharmacological efficacy and sometimes do away with some side effects. An example of this kind of drug is eszopiclone (Lunesta), which is enantiopure and therefore is given in doses that are exactly 1/2 of the older, racemic mixture called zopiclone. In the case of eszopiclone, the S enantiomer is responsible for all the desired effects, though the other enantiomer seems to be inactive; while an individual must take 2 mg of zopiclone to get the same therapeutic benefit as they would receive from 1 mg of eszopiclone, that appears to be the only difference between the two drugs.

Another good example is a common antihistamine:-

Levocetirizine (Xyzal) and cetirizine (Zyrtec)

Cetirizine, an effective H1-receptor antagonist, is a racemate mixture of two enantiomers: levocetirizine (R enantiomer) and dextrocetirizine (S enantiomer).  Chemically, levocetirizine is the active enantiomer of cetirizine. It is the L-enantiomer of the cetirizine racemate.

Cetirizine is sold as Zyrtec and Levocetirizine is sold as Xyzal.

If you prefer Claritin:

Claritin is loratadine.  The active half of this mixture is desloratadine.

So they have separated this out and produced a single-enantiomer drug made exclusively of desloratadine.  You can buy this as Clarinex/Aerius, depending on where you live.

In many cases the single-enantiomer drug works no better, it just costs more and may allow for a patent to be extended, which may mean billions of extra dollars.

Single-enantiomer drugs: elegant science, disappointing effects.

Abstract

Most new drugs are marketed as single enantiomers but many older agents are still available in racemic form. As these drugs reach the end of their patent life manufacturers become interested in marketing single enantiomer equivalents. This is called 'chiral switching' and it has been claimed that it will bring clinical benefits in terms of improved efficacy, more predictable pharmacokinetics or reduced toxicity. We reviewed the clinical evidence and prices for three recently marketed single enantiomer versions of widely used racemic drugs: escitalopram, esomeprazole and levosalbutamol. Claims of increased efficacy were based on comparisons of non-equivalent doses and any advantages seemed small and clinically unimportant. Prices of esomeprazole and levosalbutamol were higher than their racemic alternatives and we predict that these prices will remain high despite the market presence of generic versions of the racemates. Patent protection and a perception of superiority based on promotion rather than evidence will maintain price premiums for single enantiomer drugs that are not justified on the basis of clinical performance

Back to Russia

In Russia they have now marketed the single enantiomer drug of Pantogam, which is called Pantogam Aktiv.

Does Pantogam Aktiv work “better” than Pantogam, or does it just cost more?

Is Pantogam Aktiv equivalent to R-baclofen (arbaclofen)?

How would those eight kids with Asperger's in the UK fare on Pantogam Aktiv, as opposed to Baclofen?  Is tolerance an issue with Pantogam Aktiv? 

“Failed” Arbaclofen Trial

Rather than spend tens of millions of dollars on Arbaclofen, why did not someone just think of first trying Pantogam and Pantogam Aktiv on that very first child who responded to Baclofen?

When they closed the trial (and the company) why did they not suggest to those unhappy parents to try Pantogam and Pantogam Aktiv?

Pantogam Research

Most research is in Russian, but there is some in English.  Interestingly this drug affects both GABA_A and GABA_B.

While its main effect is on GABA_B. like Baclofen, it also has the effect of modulating the GABA_A response.  This effect means that when combined with benzodiazepines, where normally people build up a tolerance, and so the dose needs to be increased, no tolerance develops.  We saw this very effect on GABA_A with tiny doses of other drugs in earlier posts.

Attention Deficit Hyperactivity Disorder: Selection ofthe Optimum Duration of Medical Treatment

 A total of 32 children aged 6–12 years with attention deficit hyperactivity disorder (ADHD) were monitored during prolonged (6–8 months) treatment with Pantogam (homopantothenic acid) at daily doses of 500–1000 mg. Treatment results were assessed using the DSM-IV core ADHD symptom scales and the WFIRS-P (parental) scale every two months. Decreases in core symptoms on the DSM-IV core ADHD symptom scale were seen at two months of treatment. Significant changes on the WFIRS-P scale took longer: improvements in self-concept, socialization, and social activity were seen at four months and in behavior and schoolwork, basic life skills, along with decreases in risk-associated behavior, at six months. Thus, in contrast to regression of core ADHD symptoms, overcoming impairments in social-psychological adaptation required longer treatment periods.

Pantogam in daily psychiatric practice

Role of Combat Stress in the Formation of Chronic Pain Syndrome in Combatants and Its Treatment with Pantogam Active

Conclusion

Arbaclofen (R-Baclofen) failed its clinical trial, so it is no wonder drug for Fragile X and classic autism, but is was effective in a minority of people. 

It is possible that it would have been much more effective on people at the other end of the spectrum, those with Asperger’s – like the reader of this blog and the UK pediatrician using cheap Baclofen.

The people behind the Arbaclofen trial were super-brainy types from MIT, dig a bit deeper and I recall family links to Fragile-X.  So objectivity went out of the window, along with all those millions of dollars.

I do not suppose Pantogam and Pantogam Aktiv are autism wonder drugs, but they must help in some cases, otherwise the Russians would not be prescribing them. 

For those who found Arbaclofen really did help, why not try Pantogam and Pantogam Aktiv?  Just use Google:- “Buy Pantogam” in place of “Buy Arbaclofen”.

You would have thought someone smart at the US NIMH would have thought of this.  There are some very clever Russians and they do have autism over there too.

Biotin & Triglycerides - why perhaps Fish Oil and Niacin may actually help a little in Autism & Schizophrenia

Far back in this blog, I wrote a post about fish oil.  Omega 3 oils are definitely good for your general health, but do they help with autism?  They are also claimed to help with ADHD and improve your NT child’s cognitive performance.

On critical review of the evidence, it seemed that the benefit was far from conclusive.  There was one very positive study, that neither the authors nor anyone else could repeat.

The following review of the literature by the University of Maryland show that, as with autism, studies on fish oil in depression, ADHD, bipolar and schizophrenia show conflicting results.

Omega-3 fatty acids

Some of the “cognitive enhancing” fish oil products are extremely expensive and I showed that regular fish consumption was far cheaper and likely to be as effective.

There is an issue of just how big an effect you are looking for.  We can all imagine tiny effects, but you really want an effect that everyone else notices.

Monty, aged 11 with ASD, eats lots of fish, mainly because he loves it.  He is not at all put off by those little bones.

The effect of fish oil on Monty was not noticeable.

Biotin

A recent post contained a study from Greece, where they found a remarkably high proportion of kids with ASD with a biotin deficiency.  This had not shown up on the standard test, because the standard test is strangely not for biotin at all; it tests for biotinidase, a related enzyme.

Identifying a biotin deficiency is not easy, blood tests are not helpful and you have to look at certain compounds found in urine.  As a result your local laboratory may not offer a useful test for biotin.

Since supplementation with pharmacological doses of biotin is known to be harmless, the practical way forward is to try it.

In the midst of looking at the relative effect of different primary antioxidants, I was substituting one thiol antioxidant (ALA) for another (NAC) to see if there was any obvious difference.  I could give lots of reasons, with scientific papers to back them up, as to why 0.6g of ALA plus 1.8g of NAC might be “better” than 2.4g of NAC, but it is not.  If anything, it might be worse.

Then I tried Carnosine in combination with NAC and again I could see absolutely no effect.

Then I decided to go back to my original NAC regime and add the biotin that had been on the shelf since Christmas. Very surprisingly, the effect that I thought might show up with ALA, showed up with biotin.  

It was not a huge effect, but a small step forward, that Monty’s assistant at school also noticed.  He was more calm and altogether more "normal". 

Does this mean Monty has a biotin deficiency?  It is of course possible.  In the Greek study 4% of the kids were thought to have such a deficiency, far more than expected, and most did respond, in varying degrees, to biotin supplements.  Unfortunately they only gave the biotin to the 4%; I would like to know what would have happened to the remaining 96%.

Biotin lowers Triglycerides and Elevated Triglycerides are associated with Mood Disorders   

Biotin is a B vitamin, but very little is actually known about it.

Then I found the link I was looking for.

Biotin does not lower cholesterol, but it does reduce (in a big way) your Triglycerides.

Several studies have shown that elevated Triglycerides are associated with all kinds of disorders: bipolar, depression and schizophrenia.  These studies suggested a causal link between the mood disorder and the elevated triglyerides.

Other Effects on Mood

          Besides depression, high levels of triglycerides are also correlated with other affective disorders including bipolar disorder (manic depression), schizoaffective disorders, aggression and hostility. In fact, the poor nutritional status of many depressed persons, who often have diets high in fats, can be improved to lessen the depression, according to Charles Glueck, MD, medical director of the Cholesterol Center of Jewish Hospital in Cincinnati.

"We have shown that in patients with high triglycerides who were in a depressive state, the more you lower the triglycerides, the more you alleviate the depression," Glueck wrote in a 1993 article in Biological Psychiatry.

According to the U.S. Centers for Disease Control and Prevention (CDC), most Americans aren't aware of the role triglycerides play in physical and mental health. A five-year study of more than 5,000 Americans found that 33 percent of them had borderline high triglyceride levels.

Improvement in symptoms of depression and in an index of life stressors accompany treatment of severe hypertriglyceridemia.

In 14 men and nine women referred because of severe primary hypertriglyceridemia, our specific aim in a 54-week single-blind treatment (Rx) period was to determine whether triglyceride (TG) lowering with a Type V diet and Lopid would lead to improvement in symptoms of depression, improvement in an index of life stressors, change in locus of control index, and improved cognition, as serially tested by Beck (BDI), Hassles (HAS) and HAS intensity indices, Locus of Control index, and the Folstein Mini-Mental status exam. On Rx, median TG fell 47%, total cholesterol (TC) fell 15%, and HDLC rose 19% (all p < or = 0.001). BDI fell at all nine Rx visits (p < or = 0.001), a major reduction in a test of depressive symptoms. The HAS score also fell at all nine visits (p < or = 0.05 - < or = 0.001). Comparing pre-Rx baseline BDI vs BDI at 30 and 54 weeks on Rx, there was a major shift towards absence or amelioration of depressive symptoms (chi 2= 5.9, p = 0.016). On Rx, the greater the percent reduction in TG, the greater the percent fall in BDI (r = 0.47, p < or = 0.05); the greater the percent reduction in TC, the greater the percent fall in HAS (r = 0.41, p < or = 0.05). Improvement in the BDI and HAS accompanied treatment of severe hypertriglyceridemia, possibly by virtue of improved cerebral perfusion and oxygenation. There may be a reversible causal relationship between high TG and symptoms of depression.

Mood symptoms and serum lipids in acute phase of bipolar disorder inTaiwan.

 

Abstract

Serum lipids have been found to play important roles in the pathophysiology of mood disorders. The aim of the present study was therefore to investigate the relationship between symptom dimensions and serum cholesterol and triglyceride levels, and to explore correlates of lipid levels during acute mood episodes of bipolar I disorder in Taiwan. Measurements were taken of the serum cholesterol and triglyceride levels in patients with bipolar I disorder hospitalized for acute mood episodes (68 manic, eight depressive, and six mixed). The relationships between serum lipids levels and various clinical variables were examined. The mean serum levels of cholesterol (4.54 mmol/L) and triglycerides (1.16 mmol/L) of sampled patients were comparable to those of the general population in the same age segment. Severe depressive symptoms and comorbid atopic diseases were associated with higher serum cholesterol levels. A negative association was noted between serum triglyceride levels and overall psychiatric symptoms. Compared with previous studies on Western populations, racial differences may exist in lipids profiles of bipolar disorder patients during acute mood episodes. Increased serum cholesterol levels may have greater relevance to immunomodulatory system and depressive symptoms, in comparison with manic symptoms.

Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in non-diabetic subjects with hypertriglyceridemia.

Abstract

Biotin is a water-soluble vitamin that acts as a prosthetic group of carboxylases. Besides its role as carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism. Several studies have reported a relationship between biotin and blood lipids. In the present work we investigated the effect of biotin administration on the concentration of plasma lipids, as well as glucose and insulin in type 2 diabetic and nondiabetic subjects. Eighteen diabetic and 15 nondiabetic subjects aged 30-65 were randomized into two groups and received either 61.4 micromol/day of biotin or placebo for 28 days. Plasma samples obtained at baseline and after treatment were analyzed for total triglyceride, cholesterol, very low density lipoprotein (VLDL), glucose and insulin. We found that the vitamin significantly reduced (P=0.005) plasma triacylglycerol and VLDL concentrations. Biotin produced the following changes (mean of absolute differences between 0 and 28 day treatment+/-S.E.M.): a) triacylglycerol -0.55+/-0.2 in the diabetic group and -0.92+/-0.36 in the nondiabetic group; b) VLDL: -0.11+/-0.04 in the diabetic group and -0.18+/-0.07 in the nondiabetic group. Biotin treatment had no significant effects on cholesterol, glucose and insulin in either the diabetic or nondiabetic subjects. We conclude that pharmacological doses of biotin decrease hypertriglyceridemia. The triglyceride-lowering effect of biotin suggests that biotin could be used in the treatment of hypertriglyceridemia.

The hypotriglyceridemic effect of biotin supplementation involves increased levels of cGMP and AMPK activation

Abstract

In addition to its role as a carboxylase cofactor, biotin modifies gene expression and has manifold effects on systemic processes. Several studies have shown that biotin supplementation reduces hypertriglyceridemia. We have previously reported that this effect is related to decreased expression of lipogenic genes. In the present work, we analyzed signaling pathways and posttranscriptional mechanisms involved in the hypotriglyceridemic effects of biotin. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg of free biotin/kg diet, respectively for 8 weeks after weaning. The abundance of mature sterol regulatory element-binding protein (SREBP-1c), fatty-acid synthase (FAS), total acetyl-CoA carboxylase-1 (ACC-1) and its phosphorylated form, and AMP-activated protein kinase (AMPK) were evaluated in the liver. We also determined the serum triglyceride concentrations and the hepatic levels of triglycerides and cyclic GMP (cGMP). Compared to the control group, biotin-supplemented mice had lower serum and hepatic triglyceride concentrations. Biotin supplementation increased the levels of cGMP and the phosphorylated forms of AMPK and ACC-1 and decreased the abundance of the mature form of SREBP-1c and FAS. These data provide evidence that the mechanisms by which biotin supplementation reduces lipogenesis involve increased cGMP content and AMPK activation. In turn, these changes lead to augmented ACC-1 phosphorylation and decreased expression of both the mature form of SREBP-1c and FAS. Our results demonstrate for the first time that AMPK is involved in the effects of biotin supplementation and offer new insights into the mechanisms of biotin-mediated hypotriglyceridemic effects.

Triglycerides are also elevated in autism:-

Alterations in lipid profile of autistic boys: a case control study.

Abstract

We hypothesize that autism is associated with alterations in the plasma lipid profile and that some lipid fractions in autistic boys may be significantly different than those of healthy boys. A matched case control study was conducted with 29 autistic boys (mean age, 10.1 +/- 1.3 years) recruited from a school for disabled children and 29 comparable healthy boys from a neighboring elementary school in South Korea. Fasting plasma total cholesterol (T-Chol), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), the LDL/HDL ratio, and 1-day food intakes were measured. Multiple regression analyses were performed to assess the association between autism and various lipid fractions. The mean TG level (102.4 +/- 52.4 vs 70.6 +/- 36.3; P = .01) was significantly higher, whereas the mean HDL-C level (48.8 +/- 11.9 vs 60.5 +/- 10.9 mg/dL; P = .003) was significantly lower in cases as compared to controls. There was no significant difference in T-Chol and LDL-C levels between cases and controls. The LDL/HDL ratio was significantly higher in cases as compared to controls. Multiple regression analyses indicated that autism was significantly associated with plasma TG (beta = 31.7 +/- 11.9; P = .01), HDL (beta = -11.6 +/- 2.1; P = .0003), and the LDL/HDL ratio (beta = 0.40 +/- 0.18; P = .04). There was a significant interaction between autism and TG level in relation to plasma HDL level (P = .02). Fifty-three percent of variation in the plasma HDL was explained by autism, plasma TG, LDL/HDL ratio, and the interaction between autism and plasma TG level. These results indicate the presence of dyslipidemia in boys with autism and suggest a possibility that dyslipidemia might be a marker of association between lipid metabolism and autism.

Omega-3 Oil and Niacin in Schizophrenia

Like Autism, Schizophrenia is another observational diagnosis, with many different underlying genetic and environmental causes.  I keep referring to it as adult-onset autism.  It is also characterized by oxidative stress.

I found it interesting that two very widely used therapies for schizophrenia are omega-3 fish oil and high doses of niacin.  2 g a day of NAC is another common therapy in schizophrenia.

The clinical trials of omega-3 oil in schizophrenia, are just like the ones in autism, far from conclusive.  Yet people with schizophrenia continue to buy the expensive EPA fish oils, just like many parents of children with autism.

Another very popular treatment is Niacin.

Niacin does many things but these include increasing your HDL (good) cholesterol, reduce LDL (bad) cholesterol and, importantly, can reduce triglycerides by up to 50%.

Management of Hypertriglyceridemia

Niacin in Anxiety

Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports

Niacin in autism

People do use high dose niacin and niacinamide in autism, but in general niacin levels are totally normal in people with autism, according to this study:-

Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity

For the vitamins, the only significant difference was a 20% lower biotin (p < 0.001) in the children with autism. There were possibly significant (p < 0.05) lower levels of vitamin B5, vitamin E, and total carotenoids. Vitamin C was possibly slightly higher in the children with autism. Vitamin B6 (measured as the active form, P5P, in the RBC) had an unusually broad distribution in children with autism compared to controls (see Figure ​Figure1),1), with the levels in the children with autism having 3 times the standard deviation of the neurotypical children.

Niacin was very similar in the autism group (7.00 μg/l and the control group (7.07 μg/l)

Other interesting findings highlighted the usual metabolic differences:-

·        ATP, NADH, and NAHPH were significantly different between the autism and neurotypical groups

·        Sulfation, methylation, glutathione, and oxidative stress biomarkers which were significantly different between the autism and neurotypical groups

·        Amino Acids which were significantly different between the autism and neurotypical groups, rescaled to the average neurotypical value

Peter Triglyceride Hypothesis in Autism & Schizophrenia

Elevated triglycerides in autism/schizophrenia may contribute to behavioral/mood problems.  The lipid contribution to the dysfunction may be correlated to elevation of triglycerides.  In other words triglycerides aggravate the existing disorder.

Some CAM treatments currently used in autism/schizophrenia, including high dose niacin, high dose biotin and high dose omega 3 oils may be effective due to their ability to lower triglycerides.

Biotin may be the safest, cheapest and most effective option to reduce triglycerides and improve mood/behavior.

The underlying cause of lipid dysfunction in autism/schizophrenia is the ongoing oxidative stress.

Fish oil is claimed to be good for your heart, but it has been shown not to affect cholesterol levels.  In some studies it did lower triglycerides.  In some countries doctors prescribe omega-3 oil to patients with stubbornly high triglycerides.  Perhaps they should read the research and try biotin?

  

Other functions of biotin

Biotin does have other more complex functions and the triglycerides may, so to speak, be a red herring.

Regulation of gene expression by biotin (review).

Abstract

In mammals, biotin serves as coenzyme for four carboxylases, which play essential roles in the metabolism of glucose, amino acids, and fatty acids. Biotin deficiency causes decreased rates of cell proliferation, impaired immune function, and abnormal fetal development. Evidence is accumulating that biotin also plays an important role in regulating gene expression, mediating some of the effects of biotin in cell biology and fetal development. DNA microarray studies and other gene expression studies have suggested that biotin affects transcription of genes encoding cytokines and their receptors, oncogenes, genes involved in glucose metabolism, and genes that play a role in cellular biotin homeostasis. In addition, evidence has been provided that biotin affects expression of the asialoglycoprotein receptor and propionyl-CoA carboxylase at the post-transcriptional level. Various pathways have been identified by which biotin might affect gene expression: activation of soluble guanylate cyclase by biotinyl-AMP, nuclear translocation of NF-kappaB (in response to biotin deficiency), and remodeling of chromatin by biotinylation of histones. Some biotin metabolites that cannot serve as coenzymes for carboxylases can mimic biotin with regard to its effects on gene expression. This observation suggests that biotin metabolites that have been considered "metabolic waste" in previous studies might have biotin-like activities. These new insights into biotin-dependent gene expression are likely to lead to a better understanding of roles for biotin in cell biology and fetal development.

It does appear that biotin is more important than generally appreciated. 

Conclusion

In earlier posts I highlighted that elevated cholesterol is a bio-marker for inflammation.  In a large sub-group in autism, cholesterol is elevated.

In today’s post we looked at  a different type of lipid, triglycerides, they have a different role to cholesterol.  Not surprisingly the lipid profile is dysfunction, since it is closely linked to oxidative stress, which appears to be at the root of many problems in autism.

It is extremely easy and inexpensive to check your lipid profile (LDL, HDL and triglycerides); if elevated, there are safe established ways to bring things back to “normal”.

Parents seeing a small positive effect with their fish oil supplements might consider saving a lot of money and seeing if an extremely inexpensive biotin (5mg) supplement has an equal or greater effect.  The cost of biotin would be $2 a month.  The cost of fish oil with anything like the concentration used in the more effective trials (0.84g EPA and 0.7g DHA) will cost around $50 a month and may not lower triglycerides by as much as the cheap biotin.

By measuring the lipid profile before and after, you will be able to determine for yourself the relative merits.

Niacin also has been shown to improve mood/anxiety.  It is used by people with autism and schizophrenia.  Niacin is also extremely effective at reducing triglycerides.  High doses of Niacin can be accompanied by side effects and so use is discouraged.

Biotin levels do seem to be slightly low in autism.  Effective methods of accurately diagnosing deficiency are disputed.  Biotin is very effective at reducing triglycerides.

Elevated triglycerides have been associated with mood disorders and depression.

It seems plausible that the benefits from Omega-3 , niacin and biotin stem from their effectiveness in reducing triglycerides.

Biotin would seem to be a very cost effective and safe way to achieve this, without the side effects of niacin.  

Biotin also appears to have other key functions, including transcription of cytokine genes. Over expression of pro-inflammatory cytokines is a common feature of autism.