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).

Agmatine - a Magic Bullet in Clinical Neuroscience?

Today’s post is about Agmatine, a naturally occurring metabolite of the amino acid arginine, which is referred to in recent studies as both a “magic bullet” and a “magic shotgun”.

Normally when things sound too good to be true, you do need to be rather suspicious, but our reader Tyler has already been trialing Agmatine over the summer months and he continues to be a big believer.

As we will see in this post Agmatine has multiple different effects and while this is often the case with drugs and gives them both good and bad effects, in the case of Agmatine this ability to affect multiple targets is put forward as an advantage.

NAC, the antioxidant now widely used in autism, also has numerous beneficial effects and can even reverse propionic acid induced autism. I think we can call NAC a silver bullet.

You will recall that amino acids are the building blocks of proteins. Nine amino acids are called essential for humans because they cannot be produced by the human body and so must be taken in as food. Arginine is classified as a conditionally essential amino acid, depending on the developmental stage and health status of the individual. Preterm infants are unable to synthesize or create arginine internally, making the amino acid nutritionally essential for them.

Agmatine

Agmatine was discovered in 1910.  It is a chemical substance which is naturally created from the chemical arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism.

Many of agmatine’s effects are potentially relevant to neurological conditions like autism. My initial thought was that with so many different effects, how likely would it be that the overall effect would be positive?

• Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
• Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca²⁺ channels, and acid-sensing ion channels (ASICs).
• Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system.
• Nitric oxide (NO) synthesis modulation. Differential inhibition by agmatine of all isoforms of NO synthase (NOS) is reported.
• Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.
• Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.
• Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.
• Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.
• NADPH oxidase. Activation of the enzyme leading to H₂O₂ production.

Different effects are likely to predominate at different doses, as with many drugs.

Of the above effects many are implicated in autism.

Nicotinic, NMDA, and serotonin receptors are all deeply implicated in autism.

All the above ion channels including ASICs, which have not yet been covered in this blog, are implicated in autism. Acid Sensing Ion Channels (ASICs) are implicated in autism via the genetic research and surprisingly brain pH is disturbed in many neurological conditions. 

“Maintaining the physiological pH of interstitial fluid is crucial for normal cellular functions. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acid-sensing ion channels (ASICs), which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms (i.e., pain, stroke, and psychiatric conditions). Thus, it has become increasingly clear that ASICs are critical in the progression of neurologic diseases.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449961/

Nitric oxide is relevant to autism and any vasodilatory effect might be helpful to those with reduced cerebral blood flow. This benefit potentially goes beyond those with vascular dementia and may enhance memory and cognition in some.

It the effect on nitric oxide which body builders think gives them a benefit from taking Agmatine.

Polyamines and spermidine in particular are involved in autophagy, which is the intra-cellular garbage disposal service. When autophagy is impaired, as in many neurological conditions, this accumulating garbage gets in the way of cellular function. We already know that improving autophagy is one method of combating cognitive decline. We know that autophagy is impaired in autism.

NADPH oxidase and nNOS (Neuronal nitric oxide synthase) redox signaling cascades interact in the brain to affect both cognitive function and social behavior. I am not sure whether Agmatine will have a good or bad effect.                                                                  

The Research

I would be the first to point out that the Agmatine research is not like the high powered research we see from the scientists on this blog’s Dean’s List, but that does not mean the Agmatine may not be highly beneficial.  It is more like the copious research on antioxidants.

Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? 

Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α₂-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague. The purification and biochemical characterization of natural mammalian arginine decarboxylase and agmatinase still are open issues. Nevertheless, the agmatinergic system is currently one of the most promising candidates in order to pharmacologically interfere with some major diseases of the central nervous system, which are summarized in the present review. Particularly with respect to major depression, agmatine, its derivatives, and metabolizing enzymes show great promise for the development of an improved treatment of this common disease.                                                                                                                         

Agmatine: Clinical applications after 100 years in translation

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.

“Agmatine is now considered to be capable of exerting modulatory actions simultaneously at multiple target sites, thus fitting the therapeutic profile of a ‘magic shotgun’ for complex disorders”

  

Mitochondrial protection 

Agmatine has been shown to exert direct protective effects on mitochondria at nanomolar concentrations. It has also been shown

to alleviate oxidative stress-induced mitochondrial swelling, possibly by acting as a free radical scavenger, and prevent Ca2+-dependent induction of mitochondrial permeability transition (MPT) by modulating itochondrial membrane potential and NF-kappaB activation and references therein). Importantly, these effects are implicated in apoptotic cell death. Therefore, mitochondrial protection is considered essential in contributing to the general cytoprotective effects of agmatine in various bodily systems and, thus, to its beneficial effects in a spectrum of disease models. Of special interest is a potential for agmatine utility in neurodegenerativediseases where mitochondrial malfunctions have been implicated (e.g., Parkinson’s disease).  

Drug development: therapeutic potential outweighing risks 

There remain constraints on progress towards practical development of agmatine as a drug. First, the lower level of protection against commercial competition afforded by ‘usage’ patents for new indications of known compounds, such as agmatine with its long known methods of chemical synthesis, is viewed as being much less lucrative by drug developers than that provided by ‘composition of matter’ patents for new chemical entities. Second, although research of new compounds to modulate endogenous agmatine metabolism holds promise, it is rudimentary and remains speculative. Third, even though agmatine, as a naturally occurring substance, has been developed and introduced to the dietary supplement and nutraceutical market, nutraceutical products in the USA fall under the ‘Dietary Supplement Health and Education Act (DSHEA)’, which forbids promotion of nutraceuticals for the treatment, cure, or prevention of any disease. Similar regulatory restrictions exist worldwide and severely limit the advertising of nutraceuticals to the medical market. 

Despite these constraints, compelling evidence indicates the therapeutic potential of agmatine for a spectrum of diseases. A summary of the advances made and the gaps still remaining for future research are indicated in Table 2. Although comparative efficacy studies with presently available drugs are still required, the broad safety profile of agmatine has been established with no serious adverse effects, either as a stand-alone or as an add-on treatment. This should be a paramount advantage when compared with most existing drugs and certainly to combination therapy.

Moreover, its general cytoprotective actions suggest that agmatine should be considered not only as a curative, but also as a preventive therapeutic.

Tyler’s Comments

Tyler’s comments in this blog regarding the use of Agmatine suggest that at different doses, the effect does indeed vary. At lower doses there can be negative effects like anxiety and aggression, but at 1.2 g (in a 50kg boy) the main affect is enhanced cognition.

https://epiphanyasd.blogspot.com/2017/06/modulating-wnt-signaling-in-autism-and.html?showComment=1498387748575#c1577296526823968689

https://epiphanyasd.blogspot.com/2017/08/music-for-autism-acquired-taste.html?showComment=1503773056629#c1943101059018652346

In treating strictly defined autism, cognitive function is often the most important target, unlike in milder forms of autism.

Tyler’s main purpose for trialing Agmatine was that it is thought to normalize the opioid system in the brain, via its action on adrenoreceptors.  Then came a mouse study in the valproic acid model of autism.

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD. 

in addition to a study in OCD:-

AGMATINE AMELIORATES SOCIAL ISOLATION INDUCED OBSESSIVE-COMPULSIVEBEHAVIOR IN MICE

Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. Obsessive-compulsive disorder is classified as an anxiety disorder under DSM-IV-TR guidelines. In OCD, the levels of serotonin and nitric oxide decreased; whereas levels of dopamine and glutamate increased in brain. Environmental conditions such as isolation from social surroundings lead to anxiety and increased level of aggression. The present study was designed to examine the effect of agmatine in social isolation induced obsessive-compulsive behavior on marble burying behavior and locomotor activity. Agmatine (20, 40 and 80 mg/kg, i.p.) was administered in different groups of mice; activity was observed 30 min after dosing. Acute treatment of agmatine (40 and 80 mg/kg, i.p.) significantly reduced marble burying behavior. Moreover, hyperlocomotion was observed in socially isolated animals and agmatine was found to attenuate the same without affecting basal locomotions. In conclusion, agmatine effectively decreases social isolation induced obsessive-compulsive behavior in mice

I think it is fair to say that we do not know which mode(s) of action are in effect at this dosage. Clearly dosage is very important.

Given the importance of maximizing cognitive function in those with some cognitive dysfunction, Agmatine is clearly well worthy of further investigation.

Conclusion

Agmatine does indeed seem to have to potential to benefit some people with neurological disorders.  Is it a magic bullet for everyone? I doubt it, but that is an unrealistic expectation for any drug.

If it can improve cognition, even in a minority of autism, that would be a significant finding. Hopefully other readers of this blog will have the same positive experience as Tyler.  It will be interesting to find out how the effective dose varies. Depending on which brand you use, 1 teaspoon (5ml) of agmatine powder contains between 2.2 and 3.5 grams, which looks odd.  Probably best to weigh it to be sure.

Agmatine sulphate/sulfate is widely available in North America as a body builder’s supplement, but is banned in Europe. It was not banned for safety reasons, rather some odd EU rule that since it was not sold before 1997, it now needs to go through an approval process, that someone would have to pay for, before it can continue to be sold. Agmatine is not such an effective body building supplement to warrant anyone investing much in it. Hopefully the FDA will not ban it in the US.

Music for Autism? – an acquired taste, apparently

Today’s post is about music and music therapy.

A new study reports that music therapy does not improve autism symptoms.

In an earlier post we saw that singing reduces the level of your stress hormone cortisol; this was based on testing adults in a choir, so not music novices.

Music has actually been shown to do much more than just reduce your level of stress, it can actually affect the expression of your genes, but only in those who are “musically experienced”; in people with little experience of music it does nothing. 

The effect of listening to music on human transcriptome

Although brain imaging studies have demonstrated that listening to music alters human brain structure and function, the molecular mechanisms mediating those effects remain unknown. With the advent of genomics and bioinformatics approaches, these effects of music can now be studied in a more detailed fashion. To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n = 48), and after a control study without music exposure (n = 15). As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls. Comparisons were made based on two subphenotypes of musical experience: musical aptitude and music education. In musically experienced participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons (rank product non-parametric statistics, pfp 0.05, >1.2-fold change over time across conditions). Gene ontological overrepresentation analysis (hypergeometric test, FDR < 0.05) revealed that the up-regulated genes are primarily known to be involved in the secretion and transport of dopamine, neuron projection, protein sumoylation, long-term potentiation and dephosphorylation. Down-regulated genes are known to be involved in ATP synthase-coupled proton transport, cytolysis, and positive regulation of caspase, peptidase and endopeptidase activities. One of the most up-regulated genes, alpha-synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude. Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species. We observed no significant findings in musically inexperienced participants.

  

Apparently there are about 7,000 music therapists in the United States and about 6,000 in Europe.  One of the target groups for these therapists is children with autism.

So should parents pay out their cash for music therapy classes?  Well a very recent large study carried out in nine countries by a team from Norway suggests you might not want to open your wallet.

I must say that I hold a different view and that this simplistic kind of research is rather unhelpful. 

From the research in this blog we know that people who develop a love of music express a measurable biological effect, which does indeed look beneficial.

How do you develop a love of music, or indeed dance? Well you have to be exposed to it and engage in it.

Music therapy is all about engaging in music.

Monty, now aged 14 with ASD, has been dancing almost since he was walking, in great part because his then assistant loved music.  Later on you can start to make your own simple music, later you can sing and eventually play an instrument.  This process takes years.  

Music therapy is just a start, years later you can be trampolining to Abba, lying in bed listing to classical music, or just playing the piano.  But it is a long road.

In the recent research they gave 5 months of music therapy to 364 children aged 4 to 7 and then tested their social skills using the Autism Diagnostic Observation Schedule (ADOS).  Their social skill score did not improve. I am not sure why they picked this variable to measure.

This is yet more flawed research, which will then be quoted as fact by others.

You could make a study on teaching judo to kids with autism. I think you would find after 5 months it did not improve their social skills, but those who continue for 5 years might benefit considerably, versus those sat on the sofa watching videos on their iPads.

Clearly not everyone likes music, or indeed judo. Many kids with more severe autism have little interest in anything and so they need a lot more encouragement than typical kids.

The only way to find out if children can develop an interest in music, sport or anything else is to expose them to it at a young age. This is all music therapy is supposed to be, it is not meant to be a cure for anything. 

Music therapy may not lead to big benefits for kids with autism

Researchers found that children with ASD in nine countries scored similarly on a test of their social skills whether or not they had received the music therapy.

"Music therapy - like many other interventions that have been suggested - does not improve autism symptoms," said senior author Christian Gold, of the Grieg Academy Music Therapy Research Center and Uni Research Health in Bergen, Norway.

ASDs are developmental disorders that can lead to social, communication and behavioral challenges. The U.S. Centers for Disease Control and Prevention estimates that one in 68 children in the U.S. has been diagnosed with an ASD.

The anecdotal link between music and ASD goes back many years, Gold and colleagues write in JAMA. During music therapy, a person helps a child spontaneously make music through singing, playing and movement.

There are about 7,000 music therapists in the United States and about 6,000 in Europe, the researchers write.

For the new study, the researchers recruited 364 children ages 4 to 7 years from 10 treatment centers between 2011 and 2015. The centers were in Australia, Austria, Brazil, Israel, Italy, Korea, Norway, the UK and the U.S.

All of the children received the usual care a child with ASD would receive in their region, but half of the children were randomly assigned to also get music therapy.

Usual care could range from early intensive behavioral interventions, to speech and language therapy, to sensory-motor therapies and medications, Gold told Reuters Health by email.

"Music therapy is also among the interventions that have been recommended when it is available," he said. "Some parents who are frustrated with behavioral interventions may experience it as bringing back the joy of being with their child in a natural way."

After five months of therapy, the researchers did not find a difference between the two groups of children on a measure of social skills.

Gold said parents should continue to pursue music therapy if they feel it's a good match for their children, but don't expect it to be a so-called treatment.

The article below is quite a good one:

 Study casts doubt on music therapy for kids with autism

The study itself:

Music Therapy for Children with Autism Spectrum Disorder

In this issue of JAMA, Bieleninik and colleagues¹ present the results of a large, well-designed, multicenter randomized clinical trial (RCT) of improvisational music therapy for young children with autism spectrum disorder (ASD). Music therapy is “a systematic process of intervention wherein the therapist helps the client to promote health, using musical experiences and the relationships that develop through them.”² Among 364 children aged 4 to 7 years, over 5 months, the mean scores on the Autism Diagnostic Observation Schedule (ADOS), social affect domain, decreased from 14.08 to 13.23 among children randomized to improvisational music therapy and from 13.49 to 12.58 among those randomized to enhanced standard care, a mean difference in change scores of 0.06 (95% CI, −0.70 to 0.81), with no significant differences between groups.

  

How Much Music?

I think you need music lessons twice a week to have a meaningful impact and, as with all therapies, you need more practice at home.  Most kindergartens have music and dance as part of their activities. Taken together it is not so hard to get quite a lot of exposure to music at a young age. Then, if the child really likes music, you just keep going.  

Conclusion

Is music therapy a quick fix for autism? Definitely not.

Is music therapy a fun way to engage many young children with autism? The recent research does not say so, but it is clear that many people, with all levels of autism severity, can enjoy music and participate in it.

I think we should put music alongside sport, as a useful activity that young children should be encouraged to engage in.   It can be a struggle to get some people with autism to engage in anything, which is where a music therapist comes in.

Is it worth the investment in time and money? That all depends on the child and the therapist. Buying a piano, 7 years ago, was certainly one of my better investments; but you do also need a lot of lessons.  The end result is someone with a genuine love of many kinds of music and I expect he is now in the cortisol lowering, gene expression modifying category of the musically experienced.

Five months of unspecified music therapy may not be enough to see results and quite possible those results are not increased sociability anyway.