Epiphany: Glutamate

Showing posts with label Glutamate. Show all posts

Tuesday, 14 January 2025

Out with the old and in with the new? Maybe for iPhones but not for Autism therapies

It is important to move with the times, but it is equally important to realize that some old ideas remain better than some new ideas.

I was both pleased and surprised that my new car came with a full sized spare wheel in the boot/trunk. Where we live you can expect at least one puncture a year. In theory you do not need a spare wheel because cars rarely have punctures and you can carry an aerosol spray that will temporarily inflate the tire and fill a small hole. Some cars have skinny space-saver spare wheels. Neither of these is actually a good alternative.

Old vs new autism therapies

People definitely are interested in new and “cutting edge” therapies for autism.

I was recently contacted again by a reader of this blog who has been struggling to control self injurious behaviors in her child for years. I have provided many ideas that have each worked a sub-group of those with SIB. One idea I had not yet suggested was Memantine/Namenda.

Memantine is a cheap, old, and not very effective Alzheimer’s drug.

It blocks NMDA receptors in the brain to prevent excessive stimulation by glutamate. It does actually have many other modes of action.

It has weak inhibitory effects on L-type calcium channels that add to its neuroprotective profile. This secondary mechanism helps regulate calcium influx, protect neurons from excitotoxicity, and mitigate oxidative stress, making it beneficial for managing various neurodegenerative and excitotoxic conditions.

Memantine has mild inhibitory effects on AMPA receptors, reducing overall excitotoxicity.

Memantine may block certain sodium ion channels, which can reduce neuronal excitability and help prevent excitotoxicity.

Memantine has been found to interact with serotonin (5-HT3) receptors, modulating their activity, which might contribute to cognitive and mood improvements.

Memantine reduces microglial activation, which is associated with neuroinflammation. This anti-inflammatory action can protect against secondary neuronal damage in neurodegenerative conditions.

By preventing excessive calcium influx through NMDA receptors, memantine reduces the production of reactive oxygen species (ROS), protecting neurons from oxidative damage.

Memantine's ability to stabilize calcium homeostasis helps maintain mitochondrial function, reducing energy deficits and apoptosis (programmed cell death).

Memantine may enhance synaptic plasticity by reducing pathological over activation of glutamate receptors. This improves synaptic connectivity and cognitive function.

Some studies suggest that memantine may partially activate or modulate nicotinic acetylcholine receptors, which are important for attention and memory.

Memantine may increase brain-derived neurotrophic factor (BDNF) levels, promoting neuronal survival and plasticity.

Memantine as a treatment for SIB in some, but a cause of it in others

It is clear from the above summary of Memantine’s modes of action that it should indeed be effective for some people’s SIB (self injurious behavior). Unfortunately, all these changes in the excitatory-inhibitory balance can cause problems in some other people where Memantine actually causes SIB.

Too much glutamate can be very damaging

Glutamate excitotoxicity refers to the pathological process in which excessive activation of glutamate receptors, particularly NMDA and AMPA receptors, leads to over-excitation of neurons. This over-excitation can result in cellular dysfunction, oxidative stress, and ultimately neuron death. It is a common mechanism underlying many neurological and neurodegenerative conditions.

NMDA and AMPA receptors, over activated by the high levels of glutamate, trigger a massive influx of calcium (Ca²⁺) ions into neurons.

High intracellular Ca²⁺ levels disrupt cellular homeostasis. It activates enzymes that damage cellular structures it causes oxidative stress, mitochondrial dysfunction and eventually cell death.

Elevated intracellular Ca²⁺ from allergy causing elevated glutamate and SIB

As we know from this blog, some SIB is triggered by allergy. You can halt it via treating the allergy, blocking the L-type calcium channels or targeting other inflammatory pathways.

In this allergy-driven self injurious behavior (SIB), glutamate is likely a significant downstream effector. Allergic reactions and inflammation can disrupt calcium homeostasis and activate pathways that increase glutamate signaling, leading to heightened excitotoxicity and contributing to behaviors such as SIB.

Allergic reactions significantly impact calcium homeostasis, primarily through the activation of immune cells, release of inflammatory mediators, and systemic effects on calcium metabolism. These disruptions contribute to the symptoms and complications of allergic diseases and highlight potential therapeutic targets to restore calcium balance.

When allergens bind to IgE on mast cells or basophils, they activate receptors that trigger intracellular calcium release from the endoplasmic reticulum (via IP3 signaling). Recall Prof Gargus proposed IP3 signaling as a nexus point in autism.

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

This calcium influx promotes the degranulation of histamine, serotonin, and other inflammatory mediators.

Abnormal calcium levels may trigger unregulated, spontaneous release of glutamate, even in the absence of an action potential.

Elevated calcium levels can impair the function of glutamate transporters (e.g., EAATs), responsible for clearing excess glutamate from the synaptic cleft.

Dysfunctional transporters exacerbate extracellular glutamate accumulation, amplifying excitotoxicity.

Memantine in broader autism

Memantine was extensively studied in a large clinical trial in autism that concluded that it was no better than a placebo.

You might well conclude that the matter should end there.

Memantine for Aspies

While looking for information about Memantine for SIB I came across some very positive reviews from Aspies.

If you believed social media you would think that people with level 1 autism are all anti-treatment and see autism as their superpower. In fact the majority of people contacting me about treating autism are actually those with level 1 autism and their parents.

I am really much more familiar with treatments for level 3 autism.

The symptoms may be slightly different, but the potential therapies are exactly the same.

https://www.drugs.com/comments/memantine/for-autism.html

"A life saver. I have autism. It is pretty bad autism. I saw help on day one. But it isn't a fix-it-all for me. Being able to understand nonverbal communication and verbal communication is huge improvements. This helps me with social interaction. This helps me with anxiety. Helps my expressive myself and respond better. Less meltdowns. Helps my cognitive functions. Helps me think. Helps my thought issue due to my autism and auditory processing disorder. Helps me slow down my mind to pay attention more and can respond to changes and sensory problems. Not a full fix for me but huge help. I am more polite. I can talk about others' interests not just my needs or wants or questions that I had trouble asking. Better behavior."

"I was first prescribed this for Asperger's syndrome at the age of 24. I've been on numerous types of medications since I was a teenager, but this is the first one that I've been on that has significantly helped. My quality of life is much better. I don't have as many ruminating, obsessive thoughts that make me miserable."

"I take 20 mg of memantine for my slight autism! And this has been a miracle drug! It helps me in social interactions, I can recognize social cues and skills that I couldn't before! It also helps with my obsessive and aggressive problems! Thank you to whoever made this drug."

"I take 10 mg twice daily for autism spectrum disorder. It stops the intrusive thoughts, rumination, and repetitive thinking, which is a godsend. It also reduces repetitive behavior/stereotypes. I haven't noticed any side effects, maybe a little brain fog, but that has disappeared with continued use."

"Memantine has helped my social anxiety greatly, not through direct anxiolysis, but indirectly through dissociation from reality, albeit mild. It works perfectly for sensory overload as the autistic brain does not filter out unnecessary external stimuli due to NMDAR current blockade, similar to endogenous magnesium. Amazing, wonderful."

Conclusion

Don’t ignore all the therapies from the last 50 years and jump to the latest expensive therapy that is trending. You may after all find one of the oldies like Propranol, Pentoxifylline, Zoloft, Baclofen or Memantine is your Gamechanger. They each worked for some people.

Even though it failed in its phase 3 clinical trial, Memantine continues to have its believers. It is a cheap safe drug that clearly does provide a benefit to a sub group of autism that includes all levels of severity. It clearly does not work for all Aspies, but it certainly is worth trialing.

I think understanding glutamate excitotoxicity is very useful if you are trying to figure out a case of self injurious behavior.

In individuals where the GABA developmental switch has not occurred, oral GABA supplementation could potentially exacerbate glutamate excitotoxicity and trigger/worsen self injurious behavior. These are the people who react badly to benzodiazepine drugs and should respond very well to bumetanide.

Friday, 21 April 2017

The Excitatory/Inhibitory Imbalance – GABAA stabilization via IP3R

This blog aims to synthesize the relevant parts of the research and make connections that point towards some potential therapeutic avenues. Most researchers work in splendid isolation and concentrate on one extremely narrow area of interest.

The GABA_A reset, not functional in some autism

On the one hand things are very simple, if the GABA_A receptors function correctly and are inhibitory and the glutamate receptors (particularly NMDA and mGluRx) function correctly, there is harmony and a perfect excitatory/inhibitory balance.

Unfortunately numerous different things can go wrong and you could write a book about each one.

As you dig deeper you see that the sub-unit make-up of GABA_A receptors is not only critical but changes. The plus side is that you can influence this.

Today we see that the receptors themselves are physically movable and sometimes get stuck in the “wrong place”. When the receptors cluster close together they produce a strong inhibitory effect, but continual activation of NMDA receptors by the neurotransmitter glutamate - as occurs naturally during learning and memory, or in epilepsy - leads to an excess of incoming calcium, which ultimately causes the receptors to become more spread out, reducing how much the neuron can be inhibited by GABA. There needs to be a mechanism to move the GABA_Areceptorsback into their original clusters.

Very clever Japanese researchers have figured out the mechanism and to my surprise it involves one of those hubs, where strange things in autism seem to connect to, this time IP₃R.

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

I guess the Japanese answer to my question above is simple. YES,

A very recent science-light article by Gargus on IP3:-

Mighty element plays major part in autism

Now to the Japanese.

I wonder if Gargus has read the Japanese research, because both the cause and cure for the GABA_A receptors dispersing and clustering is an increase in calcium and both mediated by glutamate.

The excitatory neurotransmitter glutamate binds to the mGluR receptor and activates IP₃ receptor-dependent calcium release and protein kinase C to promote clustering of GABA_A receptors at the postsynaptic membrane - the place on a neuron that receives incoming neurotransmitters from connecting neurons.

If Professor Gargus is correct, and IPR3 does not work properly in autism, the GABA_A receptors are likely not sitting there in nice neat clusters. As a result their inhibitory effect is reduced and neurons fire when they should not.

Gargus has found that in the types of autism he has investigated IP₃ receptor open as they should, but close too fast and so do not release enough calcium from the cell’s internal calcium store (the endoplasmic reticulum).

In particular the Japanese researchers found that:-

“Stabilization of GABA synapses by mGluR-dependent Ca²⁺ release from IP₃R via PKC”

If the IP₃ receptor does not stay open as long as it should, not enough Ca²⁺will be released and GABA synapses will not be stabilized. Then GABA_A receptors will be diffused rather than being in neat clusters.

The science-light version of the Japanese study:-

How excitatory/inhibitory balance is maintained in the brain

Just as a thermostat is used to maintain a balanced temperature in a home, different biological processes maintain the balance of almost everything in our bodies, from temperature and oxygen to hormone and blood sugar levels. In our brains, maintaining the balance -- or homeostasis -- between excitation and inhibition within neural circuits is important throughout our lives, and now, researchers at the RIKEN Brain Science Institute and Nagoya University in Japan, and École Normale Supérieure in France have discovered how disturbed inhibitory connections are restored. Published in Cell Reports, the work shows how inhibitory synapses are stabilized when the neurotransmitter glutamate triggers stored calcium to be released from the endoplasmic reticulum in neurons.

"Imbalances in excitation and inhibition in the brain has been linked to several disorders," explains lead author Hiroko Bannai. "In particular, forms of epilepsy and even autism appear to be related to dysfunction in inhibitory connections."

One of the key molecules that regulates excitation/inhibition balance in the brain is the inhibitory neurotransmitter GABA. When GABA binds to GABAA receptors on the outside of a neuron, it prevents that neuron from sending signals to other neurons. The strength of the inhibition can change depending on how these receptors are spaced in the neuron's membrane.

While GABAA receptors are normally clustered together, continual neural activation of NMDA receptors by the neurotransmitter glutamate -- as occurs naturally during learning and memory, or in epilepsy -- leads to an excess of incoming calcium, which ultimately causes the receptors to become more spread out, reducing how much the neuron can be inhibited by GABA.

To combat this effect, the receptors are somehow continually re-clustered, which maintains the proper excitatory/inhibitory balance in the brain. To understand how this is accomplished, the team focused on another signaling pathway that also begins with glutamate, and is known to be important for brain development and the control of neuronal growth.

In this pathway glutamate binds to the mGluR receptor and leads to the release of calcium from internal storage into the neuron's internal environment. Using quantum dot-single particle tracking, the team was able to show that after release, this calcium interacts with protein kinase C to promote clustering of GABAA receptors at the postsynaptic membrane--the place on a neuron that receives incoming neurotransmitters from connecting neurons.

These findings show that glutamate activates distinct receptors and patterns of calcium signaling for opposing control of inhibitory GABA synapses.

Notes Bannai, "it was surprising that the same neurotransmitter that triggers GABAA receptor dispersion from the synapse, also plays a completely opposite role in stabilizing GABAA receptors, and that the processes use different calcium signaling pathways. This shows how complex our bodies are, achieving multiple functions by maximizing a limited number of biological molecules.

Pre-activation of the cluster-forming pathway completely prevented the dispersion of GABAA receptors that normally results from massive excitatory input, as occurs in status epilepticus -- a condition in which epileptic seizures follow one another without recover of consciousness. Bannai explains, "further study of the molecular mechanisms underlying the process we have uncovered could help develop treatments or preventative medication for pathological excitation-inhibition imbalances in the brain.

"The next step in understanding how balance is maintained in the brain is to investigate what controls which pathway is activated by glutamate. Most types of cells use calcium signals to achieve biological functions. On a more basic level, we believe that decoding these signals will help us understand a fundamental biological question: why and how are calcium signals involved in such a variety of biological phenomena?"

The full Japanese study:-

Bidirectional Control of Synaptic GABA_AR Clustering by Glutamate and Calcium

· Bidirectional synaptic control system by glutamate and Ca²⁺ signaling

· Stabilization of GABA synapses by mGluR-dependent Ca²⁺ release from IP₃R via PKC

· Synaptic GABA_AR clusters stabilized through regulation of GABA_AR lateral diffusion

· Competition with an NMDAR-dependent Ca²⁺ pathway driving synaptic destabilization

GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABA_A receptor (GABA_AR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP₃ receptor-dependent calcium release and protein kinase C to promote GABA_AR clustering and GABAergic transmission. This GABA_AR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses.

In this study, we demonstrate that the mGluR/IICR/PKC pathway stabilizes GABAergic synapses by constraining lateral diffusion and increasing clustering of GABA_ARs, without affecting the total number of GABA_AR on the cell surface. This pathway defines a unique form of homeostatic regulation of GABAergic transmission under conditions of basal synaptic activity and during recovery from E/I imbalances. The study also highlights the ability of neurons to convert a single neurotransmitter (glutamate) into an asymmetric control system for synaptic efficacy using different calcium-signaling pathways.

The most striking conceptual finding in this study is that two distinct intracellular signaling pathways, NMDAR-driven Ca²⁺ influx and mGluR-driven Ca²⁺ release from the ER, effectively driven by the same neurotransmitter, glutamate, have an opposing impact on the stability and function of GABAergic synapses. Sustained Ca²⁺ influx through ionotropic glutamate receptor-dependent calcium signaling increases GABA_AR lateral diffusion, thereby causing the dispersal of synaptic GABA_AR, while tonic mGluR-mediated IICR restrains the diffusion of GABA_AR, thus increasing its synaptic density. How can Ca²⁺ influx and IICR exert opposing effects on GABA synaptic structure? Our research indicates that each Ca²⁺ source activates a different Ca²⁺-dependent phosphatase/kinase: NMDAR-dependent Ca²⁺ influx activates calcineurin, while ER Ca²⁺ release activates PKC.

Taken together, these results lead us to propose the following model for bidirectional competitive regulation of GABAergic synapses by glutamate signaling. Phasic Ca²⁺ influx through NMDARs following sustained neuronal excitation or injury leads to the activation of calcineurin, overcoming PKC activity and relieving GABA_AR diffusion constraints. In contrast, during the maintenance of GABAergic synaptic structures or the recovery from GABA_AR dispersal, the ambient tonic mGluR/IICR pathway constrains GABA_AR diffusion by PKC activity, overcoming basal calcineurin activity. One possible mechanism of dual regulation of GABA_AR by Ca²⁺ is that each Ca²⁺-dependent enzyme has a unique sensitivity to the frequency and number of external glutamate release events and can act to decode neuronal inputs (Fujii et al., 2013x , Li et al., 2012x , Stefan et al., 2008x ) in inhibitory synapses.

Tight control of E/I balance, the loss of which results in epilepsy and other brain and nervous system diseases/disorders, is dependent on GABAergic synaptic transmission (Mann and Paulsen, 2007x ). A recent study showed that the excitation-induced acceleration of GABA_AR diffusion and subsequent dispersal of GABA_ARs from synapses is the cause of generalized epilepsy febrile seizure plus (GEFS+) syndrome (Bouthour et al., 2012x ). Our results indicate that pre-activation of the mGluR/IICR pathway by DHPG could completely prevent the dispersion of synaptic GABA_ARs induced by massive excitatory input similar to status epilepticus. Thus, further study of the molecular mechanisms underlying the mGluR/IICR-dependent stabilization of GABAergic synapses via regulation of GABA_AR lateral diffusion and synaptic transmission could be helpful in the prevention or treatment of pathological E/I imbalances, for example, in the recovery of GABAergic synapses from epileptic states

DHPG = group I mGluR agonist dihydroxyphenylglycine.

On a practical level you want to inhibit GABA_A dispersion and promote GABA_Astabilization. How you might do this would depend on exactly what was the underlying problem.

If the problem is IP₃R not releasing enough calcium, you might activate PKC in a different way or just increase the signal from Group 1 mGluR. If the problem is too much calcium influx through NMDA receptors due to excess glutamate, you could increase the re-uptake of glutamate, via GLT-1, using Riluzole. You could block the flow of Ca²⁺through NMDA receptors using an antagonist.

The Japanese used dihydroxyphenylglycine (DHPG) as their Group 1 mGluR agonist. DHPG is an agonist of mGluR1 and mGluR5. We have come across mGluR5 many times before in this blog. Mavoglurant is an experimental drug candidate for the treatment of fragile X syndrome. It is an antagonist of mGluR5.

We have seen many times before that there is both hypo and hyper function possible and indeed that fragile X is not necessarily a good model for autism.

The selective mGluR5 agonist CHPG protects against traumatic brain injury, which would indeed make sense. Although, that research suggests an entirely different mechanism.

The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway

The calcium released by IP₃ works in complex way together with DAG (diacylglycerol ) to activate PKC (protein kinase C).

Ideally you would have enough calcium released from IP3, but you could also increase DAG. It depends which part of the process is rate-limiting.

Diacylglycerol (DAG) has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat. Diglycerides, generally in a mix with monoglycerides are common food additives largely used as emulsifiers. In Europe, when used in food the mix is called E471.

Conclusion

On the one hand things are getting very complicated, but on the other we keep coming back to the same variables (IP3R, mGlur5, GABA_A etc.).

It is pretty clear that some very personalized therapy will be needed. Is it an mGlur5 agonist or antagonist? Or quite possibly neither, because in different parts of the brain it will have a good/bad effect.

It does look like Riluzole should work well in some people.

A safe IP3R agonist looks a possibility. As shown in the diagram earlier in this post,IP3 is usually made in situ, but agonists exist.

In effect autism could be the opposite of Huntington’s disease. In Huntington’s, type 1 IP₃ receptors are more sensitive to IP₃, which leads to the release of too much Ca²⁺ from the ER. The release of Ca²⁺ from the ER causes an increase in concentrations of Ca²⁺inside cells and in mitochondria.

According to Gargus we should have reduced concentrations of Ca²⁺inside cells in autism.

I suspect it is much more complicated in reality, because it is not just the absolute level of Ca²⁺but rather the flow of Ca²⁺; so it matters where it is coming from. I think we likely have impaired calcium channel activity of multiple types in autism and the actual level of intracellular calcium will not tell you much at all.

As the Japanese commented, it is surprising that glutamate is the neurotransmitter that controls the clustering, or not, of GABA_A receptors. This suggests that you cannot ignore glutamate and just “fix” GABA.

Monday, 3 April 2017

Different Types of Excitatory/Inhibitory Imbalance in Autism, Fragile-X & Schizophrenia

There is much written in the complex scientific literature about the Excitatory/Inhibitory (E/I) imbalance between neurotransmitters in autism.

Many clinical trials have already been carried out, particularly in Fragile-X. These trials were generally ruled as failures, in spite of a significant minority who responded quite well in some of these trials.

As we saw in the recent post on the stage II trial of bumetanide in severe autism, there is so much “background noise” in the results from these trials and it is easy to ignore a small group who are responders. I think if you have less than 40%, or so, of positive responders they likely will get lost in the data.

You inevitably get a significant minority who appear to respond to the placebo, because people with autism usually have good and bad days and testing is very subjective.

There are numerous positive anecdotes from people who participated in these “failed” trials. If you have a child who only ever speaks single words, but while on the trial drug starts speaking full sentences and then reverts to single words after the trial, you do have to take note. I doubt this is a coincidence.

Here are some of the trialed drugs, just in Fragile-X, that were supposed to target the E/I imbalance:-

Metabotropic glutamate receptor 5 (mGluR5) antagonist

· Mavoglurant

· Lithium

mGluR5 negative allosteric modulator

· Fenobam

N-methyl-D-aspartic acid (NMDA) antagonist

· Memantine

Glutamate re-uptake promoter

· Riluzole

Suggested to have effects on NMDA & mGluR5 & GABA_A

· Acamprosate

GABA_B agonist

· Arbaclofen

Positive allosteric modulator (PAM) of GABA_A receptor

· Ganaxolone

Best not to be too clever

Some things you might use to modify the E/I imbalance can appear to have the opposite effect, as was highlighted in the comments in the post below:-

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

So whilst it is always a good idea to try and figure things out, you may end up getting things the wrong way around, mixing up hypo and hyper.

The MIT people who work on Fragile-X are really clever and they have not figured it all out.

Fragile-X and Idiopathic Autism

Fragile-X gets a great deal of attention, because its biological basis is understood. It results in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development.

We saw in the recent post about eIF4E, that this could lead to an E/I imbalance and then autism.

eIF4E inhibitors for Autism – Why not Ribavirin?

Our reader AJ started looking at elF4E and moved on to EIF4E- binding protein number 1.

In the green and orange boxes below you can find elF4E and elF4E-BP2.

This has likely sent some readers to sleep, but for those whose child has Fragile-X, I suggest they read on, because it is exactly here that the lack of fragile X mental retardation protein (FMRP) causes a big problem. The interaction between FMRP on the binding proteins of elF4E, cause the problem with neuroligins (NLGNs), which causes the E/I imbalance. Look at the red oval shape labeled FMRP and green egg-shaped NLGNs.

In which case, while AJ might naturally think Ribavirin is a bit risky for idiopathic autism, it might indeed be very effective in some Fragile-X. You would hope some researcher would investigate this.

Can you have more than one type of E/I imbalance?

Readers whose child responds well to bumetanide probably wonder if they have solved their E/I imbalance.

I think they have most likely improved just one dysfunction that fits under the umbrella term E/I imbalance. There are likely other dysfunctions that if treated could further improve cognition and behavior.

On the side of GABA, it looks like turning up the volume on α3 sub-unit and turning down the volume on α5 may help. We await the (expensive) Down syndrome drug Basmisanil for the latter, given that the cheap 80 year old drug Cardiazol is no longer widely available. Turning up the volume on α3 sub-unit can be achieved extremely cheaply, and safely, using a tiny dose of Clonazepam.

It does appear that targeting glutamate is going to be rewarding for at least some of those who respond to bumetanide.

One agonist of NMDA receptors is aspartic acid. Our reader Tyler is a fan of L-Aspartic Acid, that is sold as a supplement that may boost athletic performance.

Others include D-Cycloserine, already used in autism trials; also D-Serine and L-Serine.

D-Serine is synthesized in the brain from L-serine, its enantiomer, it serves as a neuromodulator by co-activating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site of NMDA receptors. For the receptor to open, glutamate and either glycine or D-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Pb2+).

D-Serine is being studied as a potential treatment for schizophrenia and L-serine is in FDA-approved human clinical trials as a possible treatment for ALS/Motor neuron disease.

You may be thinking, my kid has autism, what has this got to do with ALS/Motor neuron disease (from the ice bucket challenge)? Well one of the Fragile-X trial drugs at the beginning of this post is Riluzole, a drug developed for specially for ALS. Although it does not help that much in ALS, it does something potentially very useful for some autism, ADHD and schizophrenia; it clears away excess glutamate.

Fragile-X is likely quite different to many other types of autism

I suspect that within Fragile-X there are many variations in the downstream biological dysfunctions and so that even within this definable group, there may be no universal therapies. So for some people an mGluR5 antagonist may be appropriate, but not for others.

Even within this discrete group, we come back to the need for personalized medicine.

I do not think Fragile-X is a good model for broader autism.

Glutamate Therapies

There are not so many glutamate therapies, so while the guys at MIT might disapprove, it would not be hard to apply some thoughtful trial and error.

You have:

mGluR5

· mGluR5 agonists (only research compounds)

· mGluR5 positive allosteric modulators (only research compounds)

· mGluR5 antagonists (Mavoglurant, Lithium)

· mGluR5 negative allosteric modulators (Fenobam, Pu-erh tea decreases mGluR5 expression )

Today you can only really treat too much mGluR5 activity. It there is too little activity, the required drugs are not yet available. I wonder how many people with Fragile-X are drinking Pu-erh tea, it is widely available.

NMDA agonists

D-Cycloserine an antibiotic with similar structure to D-Alanine (D-Cycloserine was trialed in autism and schizophrenia)

ɑ-amino acids:

· Aspartic acid (trialed and used by Tyler, suggested for schizophrenia)

· D-Serine (trialed in schizophrenia)

L-Serine

D-Alanine (trialed in schizophrenia)

L-Alanine

NMDA antagonists

· Memantine (widely used off-label in autism, but failed in clinical trials)

· Ketamine (trialed intra-nasal in autism)

Glutamate re-uptake promoters via GLT-1

· Riluzole

· Bromocriptine

· Beta-lactam antibiotics

Friday, 31 March 2017

The Glutamate Side of Things

Some readers have suggested that since we have discovered so many ways to treat the GABA_A dysfunctions common in autism, it is time to look at the glutamate side of things. Glutamate is the main excitatory neurotransmitter and has to be in balance with the opposing influence of GABA.

The chart below is really a summary of what has already been covered in this blog. To newcomers it will look complicated, to regular readers it is just bringing together everything we have already covered, even those tauopathies appear. Tau protein tangles appear in Alzheimer’s and some autism.

Glutamate excitoxicity is what happens when things go really wrong, for example in a severe autistic regression. I doubt you could be in a permanent state like this.

I am beginning to wonder is my son’s summer time raging, though triggered by allergy, develops to a so-called glutamatergic storm. It fades to nothing by using a Cav1.2 channel blocker, which does indeed stop those allergy mast cells de-granulating, but it stops the calcium influx in the above chart. Existing dysfunction in Cav1.2 and Cav1.4 puts you at risk of excitotoxicity.

The oxidative damage to mitochondria causes lipid peroxidation and in particular the 4-HNE produced will cause tau protein, from a recent post and Alzheimer’s, to produce tau tangles, a damaging feature of so-called tauopathies.

The nitrosative stress in particular damages the production of the Complex 1 enzyme leading to mitochondrial disease/dysfunction. The damaging peroxynitrates can be quenched using high doses of calcium folinate. Oxidative stress and the reduced level of GSH can be treated with antioxidants like NAC and ALA.

Reduced reuptake of glutamate, known to be caused by elevated TNF-α and immune dysfunction, is treatable via upregulating the GLT-1 transporter (beta-lactam antibiotics, riluzole and bromocriptine).

Elevated BDNF is a biomarker of autism and unfortunately this increases the chances of glutamate excitotoxicity.

An inactivated GABA switch that leaves neurons immature, will result in GABA acting excitatory rather than inhibitory, this itself can trigger of glutamate excitotoxicity. Use bumetanide.

Some types of autism feature NMDA hyper-function, this is treatable. A deviation of NMDA function in either direction (hypo or hyper) leads to autism, but you need to know which way it is, to treat it.

It is also possible to have over/under expression of NMDA receptors.

Epiphany

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