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Showing posts with label Roflumilast. Show all posts
Showing posts with label Roflumilast. Show all posts

Tuesday, 15 January 2019

More Myelin? Or just Better Myelination - Intelligence, PDE4 and Clemastine again




Myelination in the Central Nervous System (CNS)                  Oligodendrocyte myelinating multiple axons

The previous post on myelin was this one.


In that post we saw that you can activate P2X7 receptors with an antihistamine called Clemastine and you can block P2X7 with another cheap antihistamine called Oxatomide. The P2X7 receptor plays a role in both inflammation and myelination and this receptor appears to be linked to neurological disorders including schizophrenia and even depression.
In that post I also compared experimental MS therapies with experimental autism therapies.




The yellow box means, we know it works, at least for some people, based on trial results.

The widely available PDE4 inhibitor, Roflumilast, has been patented as a cognitive enhancer, but even at that lower dose it can make people vomit.  Ibudilast seems to have fewer side effects and is under investigation in the US to treat MS, but is currently only approved in Japan and as an asthma therapy.
The logical next step is to investigate the two P2X7 modifying antihistamines, which should have opposing effects.
Oxatomide is widely used in Italy. Clemastine is OTC in the US and the UK.
I did some more investigation of Clemastine and came across some encouraging reports of off-label use in psychiatry at modest doses. Off label use to treat MS at high doses was associated with quite negative reports, due to the sedating effect, which is inevitable with antihistamines that can cross the blood brain barrier.
Today’s post goes into more detail about myelination and concludes with the open question of who might actually benefit from a half dose of clemastine, (Dayhist in the US, Tavegil in the UK); clearly some people do already benefit. 
At least one US child psychiatrist is a fan and the research suggests many conditions might benefit, ranging from severe to more trivial.  At 15-20 times higher dosage, clemastine is proposed as a therapy for Multiple Sclerosis (MS), but at that dosage clemastine is highly sedating. High dose clemastine might be a potential immediate response to the onset of regression in autism and CDD (Childhood Disintegrative Disorder).
Clemastine and Ibudilast have different modes of action. Clemastine works by activating P2X7 receptors in oligodendrocytes (in the CNS) and schwann cells (in the PNS) to make more myelin.
PDE4 inhibitors cause enhanced differentiation of OPCs (oligodendrocyte progenitor cells). OPC are precursors to oligodendrocytes.
So Roflumilast and Ibudilast should make more oligodendrocytes, while clemastine just kicks the ones you already have to work harder.  So in any one person the effect of these two types of drug may very well differ. 
Also, note that myelin needs to be constantly repaired in a process naturally called remyelination. So really we are just trying to benefit from improving this already existing repair service.

Some relevant background information:



“Myelination is only prevalent in a few brain regions at birth and continues into adulthood. The entire process is not complete until about 25–30 years of age. Myelination is an important component of intelligence. Neuroscientist Vincent J. Schmithorst proposes that there is a correlation with white matter and intelligence. People with greater white matter had higher IQs. A study done with rats by Janice M. Juraska showed that rats that were raised in an enriched environment had more myelination in their corpus callosum. 
In cerebral palsy, spinal cord injury, stroke and possibly multiple sclerosis, oligodendrocytes are thought to be damaged by excessive release of the neurotransmitter, glutamate. Damage has also been shown to be mediated by N-methyl-D-aspartate receptors. Oligodendrocyte dysfunction may also be implicated in the pathophysiology of schizophrenia and bipolar disorder.”

The role of myelin
Myelin has been compared to the insulation on electrical cables.  If only it was that simple, there would not be so many genes involved in the process.

Nodes of Ranvier do matter
If you look at the above graphic of a neuron you will see gaps in the myelin, that are called Nodes of Ranvier.
The electrical signal does not pass along the axon like a piece of copper wire, rather it jumps from one Node of Ranvier to the next, in a process called saltatory conduction.
Also each subsequent piece of myelin along the length of an axon is connected to a different oligodendrocyte. Otherwise there would be no electrical conduction possible; there has to be a “potential difference” for a current to flow.
Each oligodendrocyte can be connected to 50 different pieces of myelin, many on different axons. Just imagine what that looks like; forget the spaghetti of cables connected to your TV, this is something really jumbled up.
If the electrical signal jumps to an adjacent axon rather than jumping along the same axon, there will be a problem.
If there is too much myelin produced you might squeeze out the node of Ranvier and then the signal cannot pass along to the next neuron.



Myelination Defects in Autism
We have already seen in previous posts that myelination is often found to be abnormal in autism.
A very thorough recent study looked at myelination in a number of single gene autisms. The conclusion was that in these very different types of autism there was a common theme of defective myelination.
This adds further weight to the idea of considering impaired myelination a key feature of much autism.
Loss of myelination has been suggested to be a core feature of regressive autism and I propose a very likely driver of Childhood Disintegrative Disorder (CDD).
“Improving myelination” rather than simply “more myelination” might well be very helpful to many types of severe autism. It seems that even in much milder neurological conditions improving myelination can be therapeutic.
The usual target of experimental myelination therapies is Multiple Sclerosis (MS), it may also be the hardest to treat.
Some researchers and clinicians are repurposing MS therapies for other neurological disorders, either in mouse models or in humans.  This seems like a very good idea to me. 

One Sentence Summary: RNA sequencing of seven syndromic autism mouse models identify myelination genes disrupted in human ASD.

Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Ptenm3m4/m3m4, Mecp2KO). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.

To address these questions, we performed integrative transcriptomic analyses of seven independent mouse models of three syndromic forms of ASD generated across five laboratories, and assessed dysregulated genes and their pathways in human postmortem brain from patients with ASD and unaffected controls. These cross-species analyses converged on shared disruptions in myelination and axon development across both syndromic and idiopathic ASD, highlighting both the face validity of mouse models for these disorders and identifying novel convergent molecular phenotypes amendable to rescue with therapeutics. 

Shared myelination gene regulation between mouse models of syndromic ASD. Venn diagram of DEGs (differentially expressed genes) in each mouse model of ASD




Top GO (Gene ontology) terms of the CAGs (convergent ASD genes) enrich for myelination processes



P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.

The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina. The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death, regulation of receptor trafficking, mast cell degranulation, and inflammation.


Our findings point to P2X7R as a potential therapeutic target in schizophrenia.


The P2X7 purinergic receptor: An emerging therapeutic target in cardiovascular diseases

The P2X7 purinergic receptor, a calcium permeable cationic channel, is activated by extracellular ATP. Most studies show that P2X7 receptor plays an important role in the nervous system diseases, immune response, osteoporosis and cancer. Mounting evidence indicates that P2X7 receptor is also associated with cardiovascular disease. For example, the P2X7 receptor activated by ATP can attenuate myocardial ischemia-reperfusion injury. By contrast, inhibition of P2X7 receptor decreases arrhythmia after myocardial infarction, prolongs cardiac survival after a long term heart transplant, alleviates the dilated cardiomyopathy and the autoimmune myocarditis process. The P2X7 receptor also mitigates vascular diseases including atherosclerosis, hypertension, thrombosis and diabetic retinopathy. This review focuses on the latest research on the role and therapeutic potential of P2X7 receptor in cardiovascular diseases.

Clemastine is an extracellularly binding allosteric P2X7 receptor modulator.
Clemastine can potentiate the sensitivity of P2X7 to lower ATP concentrations. Additionally, clemastine increases the release of IL-1β from macrophages. Thus, clemastine may be a potential P2X7 activator.

Brain ischemia leading to stroke is a major cause of disability in developed countries. Therapeutic strategies have most commonly focused on protecting neurons from ischemic damage. However, ischemic damage to white matter causes oligodendrocyte death, myelin disruption, and axon dysfunction, and it is partially mediated by glutamate excitotoxicity. We have previously demonstrated that oligodendrocytes express ionotropic purinergic receptors. The objective of this study was to investigate the role of purinergic signaling in white matter ischemia. We show that, in addition to glutamate, enhanced ATP signaling during ischemia is also deleterious to oligodendrocytes and myelin, and impairs white matter function. Thus, ischemic oligodendrocytes in culture display an inward current and cytosolic Ca(2+) overload, which is partially mediated by P2X7 receptors. Indeed, oligodendrocytes release ATP after oxygen and glucose deprivation through the opening of pannexin hemichannels. Consistently, ischemia-induced mitochondrial depolarization as well as oxidative stress culminating in cell death are partially reversed by P2X7 receptor antagonists, by the ATP degrading enzyme apyrase and by blockers of pannexin hemichannels. In turn, ischemic damage in isolated optic nerves, which share the properties of brain white matter, is greatly attenuated by all these drugs. Ultrastructural analysis and electrophysiological recordings demonstrated that P2X7 antagonists prevent ischemic damage to oligodendrocytes and myelin, and improved action potential recovery after ischemia. These data indicate that ATP released during ischemia and the subsequent activation of P2X7 receptor is critical to white matter demise during stroke and point to this receptor type as a therapeutic target to limit tissue damage in cerebrovascular diseases.

Clemastine as a practical intervention
I came across a discussion among MS sufferers and a specific comment from a US child psychiatrist that drew my attention.


Daniel Kerlinsky says:   september 1 1, 2018 at 123 AM

Clemastine is a highly effective medication for re-myelination of white matter fiber bundles that connect neurons everywhere in the brain.
High doses aren't needed. One quarter of a 2.68 mg tablet is enough to start recruiting new oligodendrocytes to start making and applying myelin.
It does not have to be taken every day; it can be taken twice a week and still have a positive effect by recruiting the worker cells that repair the brain.
Remember normal myelination starts at the top of the brain and works downward during childhood development. At first the baby can't hold its head up, then it can sit up, then crawl, then stand.
Many MS lesions are located further down inside the brain and spinal cord so it takes time to get there.
The anti-inflammatory Minocycline taken once or twice a week is needed to stop the inflammatory part of the disease.                                                                            
And it takes cranio-sacral therapy to take full advantage of the new myelin which plumps the brain and even lubricates stiff joints like the sphenoid-occipital junction.
Don't give up on clemastine.

Its first and most obvious effect is improved emotional self regulation. Because myelination increases the speed of information processing ten-fold you will notice that thinking better comes next.
I can't tell you how long it will take to notice a difference. But the MS patient who told me about Clemastine got up out of her electric wheel chair and walked down the hall and back without a walker or her canes for the first time in two years.
It works great for kids with tantrums and developmental problems in about a month. It helps people with chronic depression and PTSD in about three months.
Back your dose down to 1.34 mg or 0.67 mg and give it two years. It takes a toddler that long.„



Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior.

SIGNIFICANCE STATEMENT Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under demyelinating conditions, successfully reversed social avoidance behavior in adult socially isolated mice. This was associated with enhanced myelination and oligodendrocyte differentiation in the prefrontal cortex through epigenetic regulation. Thus, enhancing myelination may be a potential means of reversing depressive-like social behavior.



BACKGROUND:

Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis.

METHODS:


We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298.

FINDINGS:


Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.

INTERPRETATION:


To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage.



Drug: Clemastine

12mg (4mg 3x/day) clemastine for 7 days followed by 8mg clemastine (4mg 2x/day) until 3 months. Patients will be off treatment from 3-9 months and will be reevaluated at 9 months.



Conclusion
Hopefully this post takes us one step closer to finding safe, side effect free, inexpensive ways to improve myelination in those with impaired myelination.

In the case of treating Multiple Sclerosis (MS), side effects clearly remain an issue. The suggestion of the psychiatrist in today’s post is to just lower the clemastine dosage and give it some time (2 years).  That sounds like smart advice to me.
Fortunately, it appears that in less severe cases of impaired myelination you may not need to wait 2 years.

Who exactly is going to benefit remains an open question, but for people already using H1 antihistamines to treat allergy, or other mast cell activation, switching to a different OTC antihistamine drug does not look like such a big step to take.
People with schizophrenia and allergy also might want to consider switching their antihistamine.

Undoubtedly some people will have the opposite issue with P2X7 receptors and for them there is another old antihistamine drug called Oxatomide.




Thursday, 1 February 2018

Myelin and Skill Acquisition, Treating MS, plus Tuning P2X7



Today’s post was prompted by a recent visit from Monty’s assistant from when he was 3 to 9 years old. She was asking about how to improve fine motor skills in one of her class. In the background Monty, now aged 14 with ASD, was playing the piano and I said just look at those fingers move, no sign of a fine motor skill disorder any more.

Source: http://docjana.com/saltatory-conduction/
Slow going without Myelin

So how do you improve both fine and gross motor skills and why are deficits so common in autism?
It does look like practice makes perfect, but there is actually some science behind this and it might help explain in part why young people with autism are very slow to acquire skills.  I should point out that there are multiple contributing factors, not least any kind of excitatory-inhibitory imbalance, but today’s post is about myelin.
Normally developing babies gradually start to develop fine and gross motor skills, become toilet trained and learn to talk.
The process by which you learn all these skills is at least partially understood. Myelin’s role particularly in acquiring motor skills has been the subject of a great deal of research in recent years.
We now know that without myelin you cannot acquire new skills.
When you acquire a new skill a network has to be created linking neurons together.
Neurons, when myelinated, look something like this:- 








The detail of inside the body of the neuron contains some of things we have looked at like Mitochondria and Endoplasmic reticulum.










Dendritic spines are those small protrusions from the dendrite which are like docking stations where one neuron connects with another. An axon terminal (far right on the first illustration) of one neuron connects with dendritic spine of a neighboring neuron.
A skill (like an app on your smart phone) is just a network of these connections between neurons. To make this network efficient and hopefully permanent, myelin is deposited along this pathway. This speeds up the rate at which the electrical signals can pass along the network. Myelin is white in colour and these myelinated pathways become the brain’s white matter. 
Here is the animation from the beginning of this post, showing that it is slow going, on the left, without myelin.





Source: http://docjana.com/saltatory-conduction/

The Synapse
Just for completeness, the synapse is the place where the axon end of one neuron connects with the dendrite end of another neuron. The synapse is where lots of clever things are happening and sometimes things go wrong. Drugs often target the synapse.

Multiple Sclerosis (MS)
Most people have heard about MS, this is a condition caused by the loss of myelin or the inability to constantly maintain the myelin layer, via remyelination.
MS mainly affects females but has some similarities with autism; there is oxidative stress and chronic inflammation. By treating oxidative stress (with ALA) it has been shown that there is a benefit in MS, just as there is in autism. 
MS may be a family of conditions, because many different things are implicated, bacteria, virus etc.
MS is usually a cyclical disorder with regressions, improvements and remissions.
The inflammatory response in MS leads to damage of the myelin protective insulation in networks in the brain that have been created for specific skills. 
There are experimental finding in MS that might help promote myelination in other disorders. Some MS therapies are immunomodulatory, for example using gut bacteria, while other seek directly to promote (re)myelination and some clever ones do both. Not surprisingly there is some overlap with autism therapies.

Myelination in Autism
The research does show that myelination in autism is different to that found in most people. It does not look like that found in MS. 

There is less myelin in the brains of people with autism than in those of controls, according to a study published 11 August in Psychological Medicine1. Researchers applied a method that measures myelin in living brains with autism for the first time.
Magnetic resonance imaging (MRI) has previously shown abnormally structured white matter in people with autism. White matter is composed of axons, the long, myelin-coated projections that transmit electrical signals between neurons. 
The researchers looked at myelin content in the brains of 14 young men with autism with a mean age of 24 years and 14 controls with a mean age of 28 years, none of whom have intellectual disabilities. They found that those with autism have less myelin in some brain regions than do controls. In the autism group, those with the most severe social interaction difficulties have the lowest myelin levels.
The researchers speculate that low myelin explains the weak connectivity observed in the brains of people with autism. Without proper insulation, electrical signals travel slowly along the axons, making it difficult for regions of the brain to coordinate their activity. 
Full study:- 

  

Myelin and Learning
Logically you would then look at the role of myelin in both skill acquisition in childhood and then in older age look at a role for myelin in the loss of those very skills.

·        Myelination and skill acquisition

·        Demyelination and loss of skills 

In the case of regressive autism you might consider the role of demyelination in the loss of key skills. This would also apply to the old diagnosis of Childhood Disintegrative Disorders (CDD); perhaps CDD is an extreme case of demyelination.
In middle to older age in typical people we also have brain shrinkage, about 5% per decade.

Myelin, Motor Skills and Broader Cognitive Function
Another issue is whether learning motor skills in particular leads to more myelination as opposed to acquiring non-physical or cognitive skills.  To what extent is there a broader benefit to the brain from all this extra myelination? 
First let’s deal with brain shrinkage. I imagine that in aging there is an element of “use it or lose it”.  

Brain Shrinkage and the Mediterranean Diet 
I am interested in the Mediterranean Diet and the Okinawan Diet, both of which may reveal useful information regarding cognitive function. There will soon be a post on the Okinawan Diet.
The study below is supposed to show how eating the Mediterranean diet can stop your brain shrinking, but it was based on research in Scotland, which is notorious for bad diet and reduced life expectancy particularly in urban areas. There is even something called the Glasgow Effect, trying to explain poor health and shorter lifespan.

Mediterranean diet. 


Data from the Scottish Collaborative Group 168-item Food Frequency Questionnaire, version 7,12,13 were used to construct the MeDi score. Exclusions were made for incomplete data (39 had >10 missing items) and for individuals with extreme energy intakes (<2 .5th="" or="">97.5th centile, n = 46) to obtain the most reliable food frequency data.12 For scoring of the MeDi, we closely followed accepted procedure.14 Briefly, individuals were given a value of 1 for each beneficial food component (fruit, vegetables, legumes, cereal, and fish) and a value of 0 for each detrimental component (meat, dairy). The ratio of daily consumption (in grams) of monounsaturated fatty acids to saturated fatty acids was a further beneficial component. Caloric-adjusted sex-specific medians were used as the boundary defining low and high consumption for each of the components. For beneficial components, scores at or above the median were assigned a value of 1, whereas for detrimental components, scores at or above the median were given a value of 0. Moderate alcohol consumption was another positively scored component. It was defined for men as between 10 and 50 g alcohol per day and for women between 5 and 25 g per day. The MeDi score (range 0–9) was calculated by summing the scores for each of the components, with higher scores indicating higher MeDi adherence. 
There is so much more to the Mediterranean diet, to learn about it you need to go to southern Italy or Greece and see how (rural) people eat; not a deep-fried Mars bar in sight, rather a very wide range of vegetables, fruits, herbs etc that actually taste good.

Objective: To assess the association between Mediterranean-type diet (MeDi) and change in brain MRI volumetric measures and mean cortical thickness across a 3-year period in older age (73–76 years).
Conclusions: Lower adherence to the MeDi in an older Scottish cohort is predictive of total brain atrophy over a 3-year interval. Fish and meat consumption does not drive this change, suggesting that other components of the MeDi or, possibly, all of its components in combination are responsible for the association.

From the LA Times:-

This study likely just compared people with a moderate consumption of fruit and vegetables to the group that ate virtually none at all.

One key part of the Mediterranean diet is the large quantity and variety of herbs that are consumed. This is rarely replicated by foreigners. 

Brain Shrinkage in MS
Brain shrinkage, not surprisingly, is another feature of MS. Here one of the drugs that this blog seems to plug, Ibudilast, seems to be highly beneficial


“In 2016, the drug received Fast Track designation from the US Food and Drug Administration (FDA) to help speed its development as an MS treatment.”

Significantly, the presentation included news that a Phase 2 clinical trial shows the drug slows brain shrinkage and the loss of the protective myelin coating around nerve cells in people with MS.

The Phase 2 SPRINT-MS trial (NCT01982942) tested ibudilast’s safety and effectiveness in progressive MS patients, and their ability to tolerate it.

Ibudilast met the trial’s primary objective of reducing brain shrinkage. “Compared to placebo, ibudilast treatment was associated with a 48% slowing in the rate of atrophy (shrinkage) progression,” 


Acquiring Motor Skills 

The following study suggests that “slow and steady” skill acquisition is likely the best for the brain and that motor skills are the key. 

Experience-dependent structural changes are widely evident in gray matter. Using diffusion weighted imaging (DWI), the neuroplastic effect of motor training on white matter in the brain has been demonstrated. However, in humans it is not known whether specific features of white matter relate to motor skill acquisition or if these structural changes are associated to functional network connectivity. Myelin can be objectively quantified in vivo and used to index specific experience-dependent change. In the current study, seventeen healthy young adults completed ten sessions of visuomotor skill training (10,000 total movements) using the right arm. Multicomponent relaxation imaging was performed before and after training. Significant increases in myelin water fraction, a quantitative measure of myelin, were observed in task dependent brain regions (left intraparietal sulcus [IPS] and left parieto-occipital sulcus). In addition, the rate of motor skill acquisition and overall change in myelin water fraction in the left IPS were negatively related, suggesting that a slower rate of learning resulted in greater neuroplastic change. This study provides the first evidence for experience-dependent changes in myelin that are associated with changes in skilled movements in healthy young adults.  
Our results suggest that myelin is modifiable by experience in humans. Increases in myelin may be aided by oligodendrogenesis associated with behavioral changes, as has been demonstrated in a mouse model using optogenetic stimulation [9]. Even modest increases in myelination may

result in large increases in signal propagation speed resulting in more rapid information transfer between gray matter processing centers and improved synchrony between distant cortical regions [7].These results provide insights into tissue specific experience-dependent changes in white matter. Our findings may have important clinical implications and future investigations should evaluate the effect of intensive motor practice on myelin plasticity in individuals with neurologic conditions (e.g., stroke or those with demyelinating diseases such as multiple sclerosis) in order to assess the efficacy of behavioural training on myelin plasticity in the diseased brain.  


New evidence of myelin’s essential role in learning and retaining new practical skills, such as playing a musical instrument, has been uncovered by UCL research. Myelin is a fatty substance that insulates the brain's wiring and is a major constituent of ‘white matter’. It is produced by the brain and spinal cord into early adulthood as it is needed for many developmental processes, and although earlier studies of human white matter hinted at its involvement in skill learning, this is the first time it has been confirmed experimentally.
For a child to learn to walk or an adult to master a new skill such as juggling, new brain circuit activity is needed and new connections are made across large distances and at high speeds between different parts of the brain and spinal cord. For this, electrical signals fire between neurons connected by “axons” – thread-like extensions of their outer surfaces which can be viewed as the ‘wire’ in the electric circuit. When new signals fire repeatedly along axons, the connections between the neurons strengthen, making them easier to fire in the same pattern in future. Neighbouring myelin-producing cells called oligodendrocytes (OLs) recognise the repeating signal and wrap myelin around the active circuit wiring. It is this activity-driven insulation that the team identified as essential for learning.    

Novel Treatments for Multiple Sclerosis  (MS)
In a recent phase II clinical trial, an over-the-counter allergy drug was shown to improve nervous system function in patients with multiple sclerosis.
See the section further below on P2X7, for the reason why an antihistamine can help myelination.

Of the three strains of bacteria, one known as Prevotella histicola effectively suppressed MS in the mice. Specifically, P. histicola produced a drop in two cell types that encourage inflammation, which are known as pro-inflammatory cytokines.Conversely, it increased the level of certain cell types that fight disease, including dendritic cells, T cells, and a type of macrophage. Overall, inflammation and demyelination were reduced, about which the researchers are excited but cautious.
The current findings knit together with other recent studies in a similar vein - for instance, studies looking at MS patients' microbiomes have found lower levels of bacteria in the Prevotella genus. Similarly, levels of Prevotella have been shown to increase when MS patients take drugs that combat the condition.
Another neat dovetail is that Western diets promote an abundance of Bacteroides, whereas a high-fiber agrarian, or cereal-based, diet seems to encourage increased levels of Prevotella, marking another trail of clues to follow.
Although the study has concentrated on MS, the scope of these findings is much broader. First study author Ashutosh Mangalam, Ph.D. - from the University of Iowa Carver College of Medicine in Iowa City - says, "[...] it's not just for MS, because this may have a similar modulating effect on other nervous system and autoimmune diseases."  

Dr. Spain and colleagues suggest that lipoic acid - a naturally occurring antioxidant that is available as an over-the-counter supplement - could be an effective treatment for SPMS (secondary progressive multiple sclerosis), after finding that it helped to reduce the rate of whole brain atrophy among patients with the condition.
Compared with participants who took the placebo, the researchers found that those who took lipoic acid showed a 68 percent reduction in the rate of whole brain atrophy.


Purinergic signaling in Inflammation 
Purinergic signaling is complex and only partially understood. There are three types of purinergic receptor:- 
·        P1 receptors which are activated by adenosine

·        P2Y receptors which are activated by nucleotides, primarily ATP

·        P2X receptors which are activated by ATP

Purinergic signaling is involved in just about every process in humans, to the extent that the purinergic signalling complex of a cell is referred to as the “purinome”.
In this very superficial review we are just looking at inflammation.
Purinergic signaling is an important mechanism in a wide range of inflammatory diseases. There are many instances in which signaling events initiated by adenosine P1 receptors and those initiated by nucleotide P2 receptors have opposing effects in biologic systems, and shifting the balance between purinergic P1 and P2 signaling is an emerging therapeutic concept in efforts to dampen pathologic inflammation and promote healing.
Pharmacologic P2-receptor antagonists inhibit inflammation such as that which occurs in inflammatory bowel disease (IBD), lung inflammation, and ischemia. 
In pathologic conditions such as asthma and vascular inflammation, P2-receptor knockout mice are protected from inflammatory diseases.
Examples of nucleotide ­receptor signaling in inflammatory conditions include P2Y6­ or P2X7­receptor signaling, which mediates vascular inflammation P2Y1­, P2X1­, and P2Y12 ­receptor signaling, which mediates platelet activation. Activation of P2 receptors of the P2Y2 and P2X7 family that are expressed on dendritic cells is thought to play a role in promoting lung inflammation in chronic lung diseases such as asthma. 
P2X7 receptors are known to play a key role in mast cell degranulation and hence allergies.


The results indicate that P2X7 receptors may play a significant role in contributing to the unwanted activation of mast cells in chronic inflammatory conditions where extracellular ATP levels are elevated.

 Note that at times of inflammation the level of extracellular ATP is elevated.  

Not so simple - P2X7 in MS
As mentioned earlier purinergic signaling is complex and only partially understood. In an inflammatory condition like MS, P2X7 appears very likely to be involved, but is it having a good or bad effect? The answer is both, as you can see in the paper below.

The right question to ask becomes is the net effect of P2X7 signaling good or bad?  

Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2'(3')-O-(4 Benzoylbenzoyl)adenosine 5'-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro. P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS.  

A recent trial has shown that the common H1 antihistamine Clemastine is therapeutic in MS.
Clemastine is seen as a positive allosteric modulator of P2X7, meaning that it increases P2X7 signaling. In our superficial view of the science increasing P2X7 signaling looks like a crazy idea to treat an inflammatory condition.
As you can see in the paper below increasing P2X7 signaling has a pro-inflammatory effect and an anti-inflammatory effect.
What matters is the net effect and that will vary depending on the exact type and location of the inflammatory activity.
In the case of MS, the net effect of increasing P2Y7 is highly beneficial.  

Because clinical data do not hint to severe or obvious clemastine-induced adverse drug responses that may involve P2X7 potentiation, augmentation of P2X7 activity in the presence of therapeutic concentrations of the antihistamine possibly exert more subtle changes that require a more thorough and focused evaluation. In addition, although we demonstrated release of the proinflammatory cytokine IL-1β from hMDM, P2X7 activation also gives rise to production and secretion of IL-1 receptor antagonist (IL-1Ra), which is in turn expected to exert anti-inflammatory activity (52,,54). Hence, the pro- or anti-inflammatory net effect of a clemastine-induced P2X7 potentiation may additionally depend on the targeted cell type, local availability of ATP, and pathophysiological background. An accumulating body of evidence points to a beneficial role of P2X7 activation in monocytes and macrophages to contribute to elimination of intracellularly located parasites and mycobacteria (55, 56). Even more strikingly, P2X7 activation in dendritic cells chiefly contributes to the orchestration of the adaptive antitumor immunity by triggering the caspase-1-dependent inflammasome activation in dendritic cells followed by IL-1β secretion and priming of interferon γ-producing CD8+ T cells (57). Therefore, selective P2X7 activators or positive allosteric modulators are intensely sought. In addition, the use of P2X7 activators, by triggering apoptotic cell death, has been put forward as a concept to treat several malignancies (Ref. 58 and references therein). Thus, the approved drug clemastine may serve as an interesting and immediately available starting point to explore these mechanisms in clinical settings.  

Full results from a randomized controlled trial (RCT) suggest that the over-the-counter (OTC) antihistamine clemastine fumarate is safe and effective for treating chronic demyelinating injury in multiple sclerosis (MS)֫ — even in patients who have had symptoms of myelin degeneration for years.

Although preliminary results were presented at the annual American Academy of Neurology meeting last year, full data from the ReBUILD trial were published online October 10 in the Lancet. 


Why P2X7 as the mode of action in MS? 
You may be asking why has Peter assumed that P2X7 is the helpful mode of action of Clemastine in treating MS, nobody else seems to highlight this.
Clemastine is an H1 antihistamine and as such does also have so-called cholinergic effects, meaning it act like the hormone acetylcholine. 
There is a whole class of drugs that increase the amount of  acetylcholine, by inhibiting cholinerases which normally act to degrade acetylcholine.
So if acetylcholine was magical for MS, then you would expect an acetylcholinerase inhibitor like Donepezil to work wonders for MS.  It has been trialed at least twice.


“A small study followed 69 people with MS taking either donepezil or a placebo for 24 weeks. It found that twice as many people in the treatment group reported memory improvement (65.7%) than those on placebo (32.4%). Health professionals also reported that more people in the treatment group showed improved cognitive symptoms. However, a larger study involving 120 people with MS showed no difference in improving memory between donepezil and placebo


Of course there is some existing research showing the role of P2X7 in MS:- 


How about P2X7 more broadly in Neurological Conditions? 


Highlights 


·         P2X7 receptor channels allow the passage of both small and large molecular weight cations.
·         P2X7Rs are expressed on all different cell types of the CNS but their expression is highly dependent on external stimuli.
·         P2X7Rs contribute to various neurodegenerative diseases.
·         P2X7Rs may participate in the pathophysiology of psychiatric disorders.
The ATP-sensitive homomeric P2X7 receptor (P2X7R) has received particular attention as a potential drug target because of its widespread involvement in inflammatory diseases as a key regulatory element of the inflammasome complex. However, it has only recently become evident that P2X7Rs also play a pivotal role in central nervous system (CNS) pathology. There is an explosion of data indicating that genetic deletion and pharmacological blockade of P2X7Rs alter responsiveness in animal models of neurological disorders, such as stroke, neurotrauma, epilepsy, neuropathic pain, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and Huntington's disease. Moreover, recent studies suggest that P2X7Rs regulate the pathophysiology of psychiatric disorders, including mood disorders, implicating P2X7Rs as drug targets in a variety of CNS pathology.


P2X7 in Schizophrenia:-

P2X7 receptors (P2X7Rs) are ligand-gated ion channels sensitive to extracellular ATP. Here we examined for the first time the role of P2X7R in an animal model of schizophrenia. Using the PCP induced schizophrenia model we show that both genetic deletion and pharmacological inhibition of P2X7Rs alleviate schizophrenia-like behavioral alterations. In P2rx7+/+ mice, PCP induced hyperlocomotion, stereotype behavior, ataxia and social withdrawal. In P2X7 receptor deficient mice (P2rx7−/−), the social interactions were increased, whereas the PCP induced hyperlocomotion and stereotype behavior were alleviated. The selective P2X7 receptor antagonist JNJ-47965567 partly replicated the effect of gene deficiency on PCP-induced behavioral changes and counteracted PCP-induced social withdrawal. We also show that PCP treatment upregulates and increases the functional responsiveness of P2X7Rs in the prefrontal cortex of young adult animals. The amplitude of NMDA evoked currents recorded from layer V pyramidal neurons of cortical slices were slightly decreased by both genetic deletion of P2rx7 and by JNJ-47965567. PCP induced alterations in mRNA expression encoding schizophrenia-related genes, such as NR2A, NR2B, neuregulin 1, NR1 and GABA α1 subunit were absent in the PFC of young adult P2rx7−/− animals. Our findings point to P2X7R as a potential therapeutic target in schizophrenia.

More on Clemastine for MS in plain English:-


Modulating P2X7 with H1 antihistamines
Using 2 existing antihistamine drugs you can either increase or decrease the response from P2X7 receptors.
The complication is that pro or anti-inflammatory effect of P2X7 varies depending on which cell types are involved. So it is not so obvious whether a particular condition wants more or less P2X7 activity.  
In the case of MS a positive allosteric modulator of P2X7 (Clemastine) helps. In some other condition it may need the opposite, a P2X7 antagonist (Oxatomide).
Both Clemastine and Oxatomide are well understood inexpensive antihistamines, in many countries Clemastine is OTC. Oxatomide (Tinset) seems very popular in Italy. 

Because clinical data do not hint to severe or obvious clemastine-induced adverse drug responses that may involve P2X7 potentiation, augmentation of P2X7 activity in the presence of therapeutic concentrations of the antihistamine possibly exert more subtle changes that require a more thorough and focused evaluation. In addition, although we demonstrated release of the proinflammatory cytokine IL-1β from hMDM, P2X7 activation also gives rise to production and secretion of IL-1 receptor antagonist (IL-1Ra), which is in turn expected to exert anti-inflammatory activity (52,,54). Hence, the pro- or anti-inflammatory net effect of a clemastine-induced P2X7 potentiation may additionally depend on the targeted cell type, local availability of ATP, and pathophysiological background. An accumulating body of evidence points to a beneficial role of P2X7 activation in monocytes and macrophages to contribute to elimination of intracellularly located parasites and mycobacteria (55, 56). Even more strikingly, P2X7 activation in dendritic cells chiefly contributes to the orchestration of the adaptive antitumor immunity by triggering the caspase-1-dependent inflammasome activation in dendritic cells followed by IL-1β secretion and priming of interferon γ-producing CD8+ T cells (57). Therefore, selective P2X7 activators or positive allosteric modulators are intensely sought. In addition, the use of P2X7 activators, by triggering apoptotic cell death, has been put forward as a concept to treat several malignancies (Ref. 58 and references therein). Thus, the approved drug clemastine may serve as an interesting and immediately available starting point to explore these mechanisms in clinical settings.

P2X7 receptor antagonist activityof the anti-allergic agent oxatomide. 

Abstract


Activation of the P2X7 receptor by extracellular ATP is associated with various immune responses including allergic inflammation. Anti-allergic agents, such as H1-antihistamines, are known to inhibit the effects of different chemical mediators such as acetylcholine and platelet-activating factor. Therefore, we hypothesized that some anti-allergic agents might affect P2X7 receptor function. Using N18TG2 and J774 cells, which express functional P2X7 receptors, the effects of several anti-allergic agents on P2X7 receptor function were investigated by monitoring the ATP-induced increase in intracellular Ca(2+) concentrations ([Ca(2+)]i). Among the various agents tested, oxatomide significantly inhibited P2X7 receptor-mediated [Ca(2+)]i elevation in a concentration-dependent manner without affecting the P2Y2 receptor-mediated response in both N18TG2 and J774 cells. Consistently, oxatomide inhibited P2X7 receptor-mediated membrane current and downstream responses such as mitogen-activated protein kinase activation, inflammation-related gene induction, and cell death. In addition, oxatomide inhibited P2X7 receptor-mediated degranulation in mouse bone marrow-derived mast cells. Whole cell patch clamp analyses in HEK293 cells expressing human, mouse, and rat P2X7 receptors revealed that the inhibitory effect of oxatomide on ATP-induced current was most prominent for the human P2X7 receptor and almost non-existent for the rat P2X7 receptor. The potent inhibitory effects of oxatomide on human P2X7 receptor-mediated function were confirmed in RPMI8226 human B cell-like myeloma cells, which endogenously express the P2X7 receptor. Our results demonstrated that the antihistamine oxatomide also acts as a P2X7 receptor antagonist. Future studies should thus evaluate whether P2X7 receptor antagonism contributes to the anti-allergic effects of oxatomide. 

Other ideas for MS? 
How about immunomodulation by antibiotic to treat MS? We have seen how macrolide antibiotics have immunomodulatory properties, but so do both (fluoro)quinolones and tetracyclines. In MS it is the tetracycline antibiotic minocycline that has the desired immunomodulatory effect. This is another  cheap way to treat MS. Minocycline is a common antibiotic often used to treat acne. In my earlier post we looked at Azithromycin and the idea of modifying such a drug to stop being an antibiotic but retain the immune-modulating property.
There will be a post on (fluoro)quinolones and tetracyclines in the near future.

My earlier post.

Conclusion
If you have MS a PDE4 inhibitor like Ibudilast looks a good idea. Ibudilast is currently only licensed in Japan, where it has long been used for asthma. In the West a different PDE4 inhibitor called Daxas/Roflumilast is approved to treat COPD and we saw in an earlier post that at one fifth of the regular dose it seems to treat sensory gating impairments and also improve cognition in some.
Clemastine, an OTC antihistamine in many countries, shows improved myelination in MS. I suspect the mode of action relates to P2X7.
The cheap tetracycline antibiotic Minocycline is likely another good choice. 
In people with mitochondrial disease, who lose skills, it appears that remyelination may be disturbed and they may be the most likely subgroup of autism that might benefit from the therapies that increase myelination.
Some of the MS therapies are “just” anti-inflammatory and by blunting the immune response, they remove a barrier to remyelination.
A PDE4 inhibitor is anti-inflammatory but it also increases something we have come across called PKA (protein kinase A). If you want myelin you want to activate PKA.
How about autism (and big brother, schizophrenia)? I think much of what helps MS may help at least some autism and vice versa.
For autism the Prevotella histicola bacteria looks interesting and quite possibly more or less P2X7R activity is going to help some autism/schizophrenia.



The yellow box means, we know it works, at least for some people, based on trial results.  

Regarding aging we know that learning new activities, physical activity and avoiding a terrible diet are all good ways to slow your brain shrinking.
Learning a new language, at any age is good for you, but if you are lucky enough to do this from birth you have less chance of dementia later on.
Very recent research shows the benefit of being bilingual if you happen to be autistic. Having strictly defined autism means you will not appear fluent in either language, but you have learnt that there at least two ways of doing the same thing. Some people with autism are extremely inflexible, but if you are bilingual there are two ways to ask for everything and you learnt this as soon as you started to speak.
In the first study of its kind, scientists show that bilingual children with autism spectrum disorders can switch mental gears more easily than those who can only speak one language.
A focus on developing/improving motor skills from a very early age in those even suspected of having autism may well have much broader cognitive benefits.
It is best not to accept sloppy handwriting and lack of coordination when playing ball; gradually improving these skills will pay broader dividends.
Going back to the start of this post and what Monty’s old assistant might do with her new young learner with poor fine motor skills, my advice was to ignore the psychologist and spend half an hour a day practicing fine motor skills with a photocopiable workbook like this one, that years ago she used with Monty:-


I have to make sure to ask for it back !