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Showing posts with label aging. Show all posts
Showing posts with label aging. Show all posts

Thursday 7 February 2019

Pterostilbene for Neuromodulation – worth a look?

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Blueberries

A common criticism of this blog is that it is mainly about prescription drugs rather than OTC supplements.
Today’s post is about a supplement that is highly regarded by our reader Ling.
Pterostilbene is like a super potent version of resveratrol.  

Resveratrol is quite well known and has long been put forward as having some potentially highly beneficial health effects, but in practise it is just too poorly absorbed to have much effect in humans.
Pterostilbene is found in blueberries.  Also found in blueberries is Anthocyanin, which is worth a mention in this post, it is what gives blueberries their colour; very often it is the colour in a food that underlies part of its health benefit. This is why eating a mixed colour diet is a wise idea.
Aronia is extremely rich in anthocyanins and Aronia juice is very common where I live. We even have a bottle of the dark coloured juice in the kitchen.
The purple colour in beetroot is betanin, a so-called betacyanin and may well have anti-Alzheimer’s effects, inhibiting plaque formation.
Anthocyanin is put forward as one reason certain Japanese who eat large amounts of purple sweet potato do not suffer much cancer or dementia and live a very long time.


Today we are mainly looking at pterostilbene, but if you want Anthocyanins, to avoid dementia, just eat blue and purple coloured fruit and vegetables on a very regular basis.
Ling has proposed pterostilbene as a PDE4 inhibitor, but as is often the case, it has numerous other effects, so it would be hard to know which is the main reason it might be therapeutic.  


Known biological effects of Pterostilbene                                                                                   
Here is an excellent graphic that highlights many of the effects of Pterostilbene, other than on PDE4.





The regular readers of this blog will note that the great majority of the above signalling molecules are implicated in autism.

The proposed effects on the brain are highlighted in the next graphic





The source paper is here: -  

           

Based on the evidence presented, PTE (Pterostilbene) is more bioavailable and better at evoking molecular and functional events than RES (Resveratrol) in vivo

Although clinical trials are underway to assess the effects of RES in diseases such as dementia and AD, pre-clinical and clinical studies on PTE have yet to be conducted. Furthermore, the biological effects of many of the structural analogues of RES and PTE are unknown, and no studies have identified the metabolites of RES or PTE in brain tissues. There is a need for future studies to identify means of enhancing the efficacy and bioavailability of these compounds and to analyse the metabolites of these compounds in thebrain. Altogether, the evidence from a variety of studies strongly suggests the potential of RES and PTE as promising bioactive agents to improve brain health and prevent neurodegeneration

Most research, but not all, concerns aging and dementia. 


Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.

Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer's disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

Low-dose pterostilbene, but not resveratrol, is apotent neuromodulator in aging and Alzheimer's disease.

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene                                                                                                        


Effect of resveratrol and pterostilbene on aging and longevity.

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms.

One area of autism research concerns targeting mTOR signalling. This is covered in the paper below


and was the subject of this blog post from 2015


Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.


Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.


And finally, PDE4
Inhibiting PDE4 has some very useful anti-inflammatory benefits. It may also improve myelination and indeed cognition.  PDE4 inhibitors are currently used to treat severe asthma and in clinical trials for Multiple Sclerosis (MS) and cognitive enhancement.
There are different sub-types of PDE4.
Inhibiting one of the subtypes has the tendency to make you want to vomit.  This is currently the drawback that limits the use of PDE4 inhibiting drugs.
A selective PDE4 inhibitor is required.
As Ling has found, research does indeed show that pterostilbene is a PDE4 inhibitor.

The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.

The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2',3,5',5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.


Conclusion
Based on Ling’s recommendation, I have ordered some Pterostilbene and I am curious to see its effects. It is another substance that might be helpful for older adults, if not for your case of autism.
It is clear that in most cases resveratrol is a substance whose effect is limited to the test tube rather than humans. As a “super-resveratrol” we should take a closer look at Pterostilbene.
Eating large amounts of fruits, vegetables and berries with anthocyanins and betacyanins is going to do you no harm and does look a way to possibly secure a long healthy future, like those Japanese centenarians in Okinawa.







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 !