pH and Neuronal Excitability - Therapy in Autism, Epilepsy, Mitochondrial Disease and ASIC mutations. Plus GPR89A

 

Diamox or Meldonium would make it easier

 

Several times recently the subject of pH (acidity/alkalinity) has come up in my discussions with fellow parents. It is not a subject that gets attention in the autism research, so here is my contribution to the subject.

If your child has a blood gas test a day after a seizure and it shows high pH, this is not the result of the seizure, but a likely cause of it. Treat the elevated pH to avoid another seizure and likely also improve autism symptoms. It may be respiratory alkalosis which is caused by hyperventilation, due to stress, anxiety etc.

The regulation of pH inside and outside brain cells is a delicate balance with far-reaching consequences. Subtle shifts toward acidity (low pH) or alkalinity (high pH) can alter calcium handling, neuronal excitability, and ultimately drive seizures, fatigue, or even inflammation. This interplay becomes especially important in conditions like autism, epilepsy, and mitochondrial disease, where metabolism and excitability are already dysregulated.

You can measure blood pH quite easily, but within cells different parts are maintained at very different levels of pH and this you will not be able to measure. Blood pH is about 7.4 (slightly alkaline) the gogli apparatus is slightly acidic, whereas the lysome is very acidic (pH about 4.7).

 

pH and Calcium Balance

Calcium (Ca²⁺) is central to neuronal excitability. Small pH changes shift the balance between intracellular and extracellular calcium:

• Alkalosis (↑ pH): reduces extracellular calcium availability, destabilizes neuronal membranes, and promotes hyperexcitability and seizures.
• Acidosis (↓ pH): activates acid-sensing ion channels (ASICs), leading to Na⁺ and Ca²⁺ influx and further excitability.

Thus, both too much acidity and too much alkalinity can increase seizure risk, though through different mechanisms.

Your body should tightly regulate its pH. You can only nudge it slightly up or down. Even small changes can be worthwhile in some cases.

When extracellular (ionized) calcium enters neurons through ion channels it can drive inflammation, excitability, and mitochondrial stress. Calcium needs to be in the right place and in autism it often is not, for a wide variety of reasons.

 

 

Mitochondrial Disease and pH

Mitochondria produce ATP through oxidative phosphorylation. Dysfunction can impair this process and lead to accumulation of lactate (acidosis) or, paradoxically, reduced proton flux (relative alkalosis). In autism, mitochondrial dysfunction is reported in a significant minority (10–20%) of cases.

 

Hyperventilation and Alkalosis

Another often-overlooked contributor is hyperventilation. By blowing off CO₂, blood pH rises (respiratory alkalosis), leading to reduced ionized calcium and increased excitability. This is the reason why hyperventilation is used during EEG testing to provoke seizures in susceptible individuals.

 

Therapeutic Approaches - Adjusting pH

Several therapies—old and new—intentionally alter pH balance:

1. Sodium and Potassium Bicarbonate

• Mechanism: Buffers acids, increases systemic pH (alkalinization).
• Applications: Beneficial in some cases of autism and epilepsy, as reported in blogs and small studies.
• Note: Raises extracellular pH, which can reduce ASIC activation but may increase excitability if alkalosis is excessive.
• Beyond buffering, sodium bicarbonate (baking soda) has been shown to trigger anti-inflammatory vagal nerve pathways. This effect may be especially valuable in neuroinflammation seen in autism and epilepsy.

 

2. Acetazolamide (Diamox)

• Mechanism: A carbonic anhydrase inhibitor that causes bicarbonate loss in the urine, lowering blood pH (mild acidosis).
• Neurological Effects: Used as an anti-seizure drug, especially in patients with channelopathies and mitochondrial disorders.
• In Climbers: At altitude, the body tends toward alkalosis due to hyperventilation (blowing off CO₂). Diamox counteracts this by inducing a mild metabolic acidosis, which stimulates ventilation, improves oxygenation, and prevents acute mountain sickness (AMS). This is why mountaineers often describe Diamox as helping them “breathe at night” in the mountains.

3. Zonisamide

• Mechanism: Another carbonic anhydrase inhibitor, with both anti-seizure and mild acidifying effects.
• Benefit: Often used in refractory epilepsy.

 

ASICs: Acid-Sensing Ion Channels

ASICs are neuronal ion channels directly gated by protons (H⁺). Their activity is pH-sensitive:

• Low pH (acidosis): Activates ASICs → Na⁺/Ca²⁺ influx → excitability and seizures.
• High pH (alkalosis): Reduces ASIC activity, but destabilizes calcium balance in other ways.

 

ASIC Mutations

Mutations in ASIC genes can alter how neurons respond to pH shifts. In theory, modest therapeutic modulation of pH (via bicarbonate or acetazolamide) could normalize excitability in patients with ASIC mutations.

 

ASIC2 is seen as a likely autism gene. There is even an ASIC2 loss of function mouse model.

Give that mouse Diamox!

 

Meldonium vs Diamox — Two Paths to Survive Altitude

During the Soviet–Afghan war in the 1980s, Russian troops were supplied with meldonium, while American soldiers and climbers commonly used acetazolamide (Diamox) for altitude adaptation. The Mujahideen and Taliban need neither, because they have already adapted to the low oxygen level.

Meldonium is a Latvian drug made famous by the tennis star Maria Sharapova who was found to be taking it for many years. It is a very plausible therapy to boost the performance of your mitochondria and so might help some autism. I know some people have tried it.

Although both drugs were used to improve performance under hypoxia, they worked in almost opposite ways:

 

At high altitude without Diamox

• You hyperventilate to compensate for low oxygen.
• Hyperventilation ↓ CO₂ in the blood → respiratory alkalosis (↑ pH).
• The alkalosis suppresses breathing (since the brainstem senses “too alkaline, slow down”), which is why people breathe shallowly at night, leading to periodic apnea and low oxygen saturation.

With Diamox

• Diamox blocks carbonic anhydrase in the kidneys → you excrete more bicarbonate (HCO₃⁻).
• This causes a metabolic acidosis (↓ pH).
• The brainstem now senses blood as “acidic,” which stimulates breathing.
• So, you hyperventilate more, but this time it’s sustained, because the metabolic acidosis counterbalances the respiratory alkalosis.

The net effect

• Without Diamox: hyperventilation → alkalosis → suppressed breathing → poor oxygenation.
• With Diamox: hyperventilation + mild metabolic acidosis → balanced pH → sustained ventilation and better oxygen delivery.

 So, the key is that Diamox shifts the body’s set point for breathing, letting climbers breathe harder without shutting down from alkalosis.

The Irony

• Meldonium - indirect alkalinization to reduce stress on cells.
• Diamox - deliberate acidification to stimulate respiration.
• Both approaches improved function under low oxygen, but they pulled physiology in opposite pH directions.

 

Another irony is that not only is Meldonium banned in sport, but so is Diamox. Diamox is banned because it is a diuretic and so can be used to mask the use of other drugs.

Now an example showing the impact of when pH control within the cell is dysfunctional.

 

GPR89A - the Golgi “Post Office” gene that keeps our cells running

When we think about genes involved in neurodevelopment, most people imagine genes that directly control brain signaling or neuron growth. But some genes quietly do their work behind the scenes, keeping our cellular “factories” running smoothly. One such gene is GPR89A, a gene that plays a critical role in regulating Golgi pH — and when it malfunctions, the consequences can ripple all the way to autism and intellectual disability (ID).

 

The Golgi Apparatus: The Cell’s Post Office

To understand GPR89A, it helps to picture the cell as a factory:

• The endoplasmic reticulum (ER) is the protein factory, producing raw products — proteins and lipids.
• The Golgi apparatus is the post office, modifying, sorting, and shipping these products to their proper destinations.

Just like a real post office, the Golgi must maintain precise conditions to function. One key condition is pH, the acidity inside the Golgi.

 

GPR89A: The Golgi’s pH Regulator

Inside the Golgi, acidity is carefully balanced by:

• V-ATPase pumps, which push protons (H⁺) in to acidify the lumen.
• Anion channels like GPR89A, which allow negative ions (Cl⁻, HCO₃⁻) to flow in, neutralizing the electrical charge and keeping the pH just right.

Think of GPR89A as the electrical wiring in the post office: without it, the machinery may be overloaded or misfiring, even if the raw materials (proteins) are fine.

 

When Golgi pH Goes Wrong

If GPR89A is mutated:

1.     The Golgi cannot maintain its normal acidic environment.

2.     Enzymes inside the Golgi — responsible for adding sugar chains to proteins (glycosylation) — cannot work properly.

3.     Proteins may become misfolded, unstable, or misrouted. Some may be sent to the wrong destination, while others are degraded.

This is akin to a post office with wrong sorting labels: packages (proteins) either go to the wrong address or get lost entirely.

 

Consequences for the Brain

Proteins are not just passive molecules; many are receptors, ion channels, adhesion molecules, or signaling factors essential for brain development. Mis-glycosylated proteins can lead to:

• Disrupted cell signaling
• Impaired synapse formation
• Altered neuronal communication

The end result can manifest as intellectual disability, autism spectrum disorders, or other neurodevelopmental conditions, because neurons are particularly sensitive to these trafficking and signaling errors.

 

Could Modulating Blood pH Help?

Since Golgi pH depends partly on cellular bicarbonate and proton balance, I have speculated whether small changes in blood pH could indirectly influence Golgi function:

• Sodium/potassium bicarbonate
• Increases extracellular bicarbonate and buffering capacity.
• Might slightly influence intracellular pH and indirectly affect Golgi pH.
• Acetazolamide (Diamox):
• Inhibits carbonic anhydrase, altering H⁺ and bicarbonate handling in cells.
• Could theoretically shift intracellular pH including Golgi pH

 

Systemic pH changes are heavily buffered by cells, so the impact on Golgi pH is likely to be modest at best.

Neither approach has been validated in human studies for improving glycosylation. Currently, there is no established therapy for GPR89A mutations.

Because there is no treatment, a reasonable option is a brief, carefully monitored trial.

• Try both interventions (bicarbonate then Diamox) for a short period.
• Observe for any measurable benefit in function or clinical outcomes.
• If there is no benefit, stop the trial — nothing is lost.

This approach allows cautious exploration without committing to a long-term therapy that may be ineffective.

 

The Bigger Picture

Even though GPR89A itself is not classified as a major autism or ID gene, its role in Golgi ion balance and glycosylation highlights how basic cellular “infrastructure” genes can profoundly affect brain development.

GPR89A reminds us that neurodevelopment is not only about neurons or synapses but also about the tiny cellular logistics systems that make them function. Maintaining Golgi pH is not glamorous, but without it, the entire cellular supply chain collapses, illustrating a pathway from a single gene mutation → cellular dysfunction → potential autism and ID outcomes.

Manipulating blood pH with bicarbonate or Diamox is an intriguing idea, will it provide a benefit?

 

Conclusion

pH regulation is a critical but underappreciated factor in autism, epilepsy, and mitochondrial disease. Subtle shifts in acidity or alkalinity affect calcium handling, ASIC activation, and neuronal excitability. Therapeutic strategies—from bicarbonates to carbonic anhydrase inhibitors—show that intentionally modulating pH can be both protective and symptomatic. Understanding the individual’s underlying metabolic and genetic context (eg mitochondrial function, ASIC mutations etc) will help determine whether a person might benefit more from raising or lowering pH.

For people with inflammatory conditions like some autism, or even MS, the simple idea of using baking soda to activate the vagus nerve is interesting.

·      Sodium bicarbonate → slight systemic alkalization.

·      Alkalization → reduced acidosis-related inflammatory signals.

·      Sensory neurons detect the pH change → activate vagus nerve.

·      Vagus nerve triggers cholinergic anti-inflammatory pathway → lowers pro-inflammatory cytokines.

We saw this in an old post and the researchers even went as far as severing the vagus nerve to prove it.

Potassium bicarbonate is a better long-term choice than sodium bicarbonate (baking soda) since most people lack potassium and have too much sodium already. It is cheap and OTC.

Diamox, Meldonium and Zonisamide are all used long term.

If you mention any of this to your doctor, expect a blank look coming back! Unless he/she is a mountaineer or perhaps a Latvian sports doctor!

 

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).