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Showing posts with label BDNF. Show all posts
Showing posts with label BDNF. Show all posts

Thursday, 15 March 2018

PolyPill Updated with Agmatine




After several months of testing Agmatine, including stopping and then re-starting, it is time to add it to my PolyPill.
The idea to trial Agmatine came from our reader Tyler. It ticks all the boxes, it really does have a benefit; that benefit continues for at least several months. When you stop taking it, the benefit stops and when you restart you see the same benefit return. It is safe, inexpensive and widely available if you live anywhere outside the EU. Since it is relatively recent to the market as a supplement, it can no longer be sold in the EU until someone applies for it to be approved; long established supplements bypass this recent legislation.
There were earlier posts evaluating why it might help some types of autism and now there even is one study on an animal model of autism. 





I think the positive effect very likely comes from the vasodilatory effect produced by the increased eNOS, there is also increased BDNF.  This I believe is why it also effective in two models of dementia. Agmatine is also an NMDAR antagonist, like Memantine and this is the mode of action proposed by autism researchers in the animal model above.  My opinion is that at this "bodybuilder's" dose the mode of action is not NMDAR antagonism.




The effect of Agmatine?



The energetic bunny on the left is the one taking 0.7g a day of Agmatine.
In the case of Monty, aged 14 with ASD, Agmatine gives him boundless energy, which in his case is beneficial.
I think the effect will manifest itself slightly differently in different people. In animal models it improves cognitive function.  
If you have autism + ADHD, then it might not be helpful. When I tried it on myself it made me feel slightly nauseous. In Monty's big brother it made him feel "different", but not better or worse and certainly not more energetic.


Other People’s PolyPills
Other readers of this blog have developed their own science-based “Polypill” therapies, for their specific type of autism. What works for my son may not help your child, but other  things discussed in this blog just might help.
High doses of the immuno-modulating Biogaia Gastrus probiotic bacteria clearly help some people greatly; but others get a negative reaction.
Immunomodulation by antibiotic is used successfully by some, but has some drawbacks. 
PAK1 inhibition ticks the science boxes and if you can obtain a potent PAK1 inhibitor it helps some people.

Butyric acid (from sodium butyrate, Miyairi 588 bacteria, more fiber or even rancid butter) is an HDAC inhibitor and is also required for gut wall integrity and likely BBB integrity. It is widely used in animal feed and some humans respond well to it, but the effect is dose dependent. HDAC inhibition can work epigenetically to change the expression of hundreds of "autism" genes, as highlighted in recent research using a potent cancer drug HDAC inhibitor.
Numerous individual amino acids (glutamine, taurine, methionine, aspartic acid etc) seem to help in some people. These tend to be OTC bulk powders like Agmatine.

In a sub-group of people with autism it is clear that digestive issues, unusual gut bacteria or food sensitivity is a major problem that is treatable relatively easily.

People with regressive autism may have (had) mitochondrial disease and this has a very specific therapy to protect from further regression and to allow for remyelination and mitochondrial biogenesis in the short term and hope for neurogenesis in the long term.




Thursday, 27 July 2017

Targeting Dendritic Spines to Improve Cognitive Function and Behavior in Autism; plus Hair Loss/Graying



I have written several posts about dendritic spines and their varying shapes (morphology).  This sounds like a rather obscure subject, but it looks like it may be a key area where both behavior and cognition can be modified, even later in life.



Homer Simson after using a Wnt Activator 

Dendritic spines

In a typical neuron (brain cell) you have dendrites at one end and so-called axon terminals at the other. When neurons connect with each other, an axon terminal connects with a dendritic spine from another close by neuron.  Axons transmit electrochemical signals from one neuron to the dendrites of other neurons.  The junction formed between a dendritic spine and an axon terminal is called a synapse.







One neuron can have as many as 15,000 spines, some of which are picking up signals from axon terminals of other neurons.
The number and shape of these spines is constantly changing and not surprisingly defects in this process affect both cognition and behavior.
The other end of the neuron, with the axon terminals is much less studied.  The myelin sheath deserves a mention. This protective coating is constantly being repaired in a process called remyelination. MS (Multiple Sclerosis) is caused by damage to the myelin coating that does not self repair. A newly identified feature of autism is an abnormally thin layer of myelin. A lack of insulation along the axon will affect the flow of electrical signals.
Many factors are involved in dendritic spine morphology and plasticity. Many of the same factors are known to be disturbed in autism and other related dysfunctions (schizophrenia, bipolar, ADHD etc).
Recall that within autism there are two broad groups; the larger group has “too many” dendritic spines and the smaller group has “too few”. I am writing about the larger group. My post is a simplification of a complex subject.
Factors that influence dendritic spine morphology and plasticity include:- 

·        BDNF  (want less)

·        Estrogen  (want more)

·        Reelin (want more)

·        BCL2 (want more)

·        PAK1 (want less)

·        GSK3 beta (want more)

·        PTEN (want more)

All the above seem to work via

·        Wnt signaling (want less) 

BDNF is a growth factor within the brain, which tends to be elevated in most autism.
The female hormone estrogen seems to be reduced in male autism and this will have many effects via something called ROR alpha. There is also reduced expression of estrogen receptor beta.
Reelin is a protein that is critical in brain development and maintenance. Reelin is implicated in most brain diseases, including autism. It stimulates dendritic spine development. Reelin is found to be reduced in autism.
BCl2 is a very well-known cancer gene/protein. BCL2 is part of a broader family of genes/proteins that control cell growth/death. BCL2 is anti-apoptotic, meaning it encourages growth rather than cell death. You will find elevated BCL2 in cancers.  BCL2 is implicated in both schizophrenia and autism.
Bax is another key member of the BCL2 family. The BCL2 protein duels with Bax, its counteracting twin. When Bax is in excess, cells execute a death command. When BCL2 dominates, the program is inhibited and cells survive. In cancer you want more Bax.
Modulating BCL2/Bax has been proposed as an autism therapy in Japan.
BCL2 is found to be reduced in autism.
The Japanese proposed the use of Navitoclax, a drug responsible for inhibiting BCL2 production for the treatment of cancer. I think they want to activate BCL2 production. 
I covered PAK1 in some lengthy posts. This was what the Japanese Nobel Laureate at MIT was working on. In summary, a PAK1 inhibitor should be helpful in autism, schizophrenia and some cancer.  Some people with a condition called neurofibromatosis, where non-cancerous tumors grow, use a special kind of bee propolis that contains a substance called CAPE (caffeic acid phenethyl ester), that is a mild PAK1 inhibitor.


GSK3 beta plays a role in several key signaling pathways. Abnormal expression of GSK3 beta is associated with Bipolar disorder. One role played by GSK3 beta is in Wnt signaling, which then affects dendritic spines. A GSK3 beta inhibitor, like lithium, is a Wnt activator which will increase the number of dendritic spines.
PTEN is a tumor suppressor gene/protein that is also an autism gene.
PTEN deficiency results in abnormal arborization and myelination in humans. PTEN-deficient neurons in brains of animal models have increased synaptic spine density.
People with autism and PTEN mutations have large heads because they lacked enough PTEN to reign in cell growth (and head growth).  You would expect them to have increased synaptic spine density.
Note than in both autism/cancer genes (BCL2 and PTEN) the balance is shifted towards growth, which fits in with the broad concept of autism as a growth dysfunction.
Wnt signaling is a complex and only partially understood subject, that has been previously discussed in this blog.  The short version is that most people with autism and particularly the ones with large heads will likely have too much Wnt signaling as the result of their various metabolic “disturbances”. The best way to inhibit their Wnt signaling might be to counter their particular metabolic disturbances, so if you are one of the 2% of autism with a PTEN mutation, then increase your PTEN levels.  If this is not possible than any other way to inhibit Wnt might be effective.
In Bipolar, where GSK3 beta is a known risk gene, you want more dendritic spines and so you want a GSK3 beta inhibitor like lithium. 
I think lithium will have a negative effect on most autism. Within children diagnosed with autism, a minority may well better fit a diagnosis of bipolar.

OBJECTIVE:


Children with autism spectrum disorder (ASD) have higher rates of comorbid psychiatric disorders, including mood disorders, than the general child population. Although children with ASD may experience irritability (aggression, self-injury, and tantrums), a portion also experience symptoms that are typical of a mood disorder, such as euphoria/elevated mood, mania, hypersexuality, paranoia, or decreased need for sleep. Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, lithium has been rarely studied in children with ASD.

METHODS:


We performed a retrospective chart review of 30 children and adolescents diagnosed with ASD by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria who were prescribed lithium in order to assess target symptoms, safety, and tolerability. Clinical Global Impressions - Improvement (CGI-I) ratings were performed by two board-certified child psychiatrists with expertise in ASD. CGI-I scores were dichotomized into "improved" (CGI-I score of 1 or 2) or "not improved" (CGI-I score ≥3).

RESULTS:


Forty-three percent of patients who received lithium were rated as "improved" on the CGI-I. Seventy-one percent of patients who had two or more pretreatment mood disorder symptoms were rated as "improved." The presence of mania (p=0.033) or euphoria/elevated mood (p=0.041) were the pretreatment symptoms significantly associated with an "improved" rating. The mean lithium blood level was 0.70 mEq/L (SD=0.26), and the average length of lithium treatment was 29.7 days (SD=23.9). Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%).

CONCLUSIONS:


This preliminary assessment of lithium in children and adolescents with ASD suggests that lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood. A relatively high side effect rate merits caution, and these results are limited by the retrospective, uncontrolled study design. Future study of lithium in a prospective trial with treatment-sensitive outcome measures may be indicated.


Hair Growth and Graying 
One surprising observation is the apparent connection between dendritic spine modification and modifying growth/color of human hair.
The same pathway is involved in signaling growth and coloring in the hair on your head and growing the dendritic spines on the neurons inside your head. I have mentioned this once before in a previous post. It is relevant because if a substance is potent enough to affect your dendritic spines you would expect it also to have a visible effect on the hair, of at least some people.
For example one reader of this blog uses a PAK1 inhibitor to treat her case of autism and she found that it has a hair graying effect.

EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

Pigmented hair regeneration requires epithelial stem cells (EpSCs) and melanocyte stem cells (McSCs) in the hair follicle.

Thus far, only a handful of signals that regulate McSCs have been identified, including extrinsic signals, such as transforming growth factor beta (TGFB) and Wnts, which are provided by the epithelial niche. Wnt signaling induces activation of EpSCs to drive epithelial regeneration while coordinately inducing McSCs to proliferate and differentiate to pigment regenerating hair follicle


One known but uncommon side effect of my current favourite Wnt inhibitor, Mebendazole, is hair loss. Hair follicles require Wnt signaling and if there is too little Wnt signaling you will lose some hair.
BCL2 is a very important cancer gene/protein but it also plays a role in autism and in dendritic spine morphology.  Low levels of the protein BCl2 leads to premature graying.

The team then looked at what would happen if they 'knocked out' a gene in mice that is known to be important for cell survival.
Mice lacking this Bcl2 gene went grey shortly after birth.

The scientists believe the same principle might apply in humans, which would explain why some people - such as TV presenter Philip Schofield - go grey in their 20s, while others keep their dark locks into retirement.
  

BCL2 is known to be reduced in the reduced in the brains of people with autism, as is another substance called Reelin.  Both Reelin and Bcl-2 are needed for dendritic spines to develop correctly.  

Autism is a severe neurodevelopmental disorder with potential genetic and environmental causes. Cerebellar pathology including Purkinje cell atrophy has been demonstrated previously. We hypothesized that cell migration and apoptotic mechanisms may account for observed Purkinje cell abnormalities. Reelin is an important secretory glycoprotein responsible for normal layering of the brain. Bcl-2 is a regulatory protein responsible for control of programmed cell death in the brain. Autistic and normal control cerebellar corteces matched for age, sex, and post-mortem interval (PMI) were prepared for SDS-gel electrophoresis and Western blotting using specific anti-Reelin and anti-Bcl-2 antibodies. Quantification of Reelin bands showed 43%, 44%, and 44% reductions in autistic cerebellum (mean optical density +/- SD per 30 microg protein 4.05 +/- 4.0, 1.98 +/- 2.0, 13.88 +/- 11.9 for 410 kDa, 330 kDa, and 180 kDa bands, respectively; N = 5) compared with controls (mean optical density +/- SD per 30 microg protein, 7.1 +/- 1.6, 3.5 +/- 1.0, 24.7 +/- 5.0; N = 8, p < 0.0402 for 180 kDa band). Quantification of Bcl-2 levels showed a 34% to 51% reduction in autistic cerebellum (M +/- SD per 75 microg protein 0.29 +/- 0.08; N = 5) compared with controls (M +/- SD per 75 microg protein 0.59 +/- 0.31; N = 8, p < 0.0451). Measurement of beta-actin (M +/- SD for controls 7.3 +/- 2.9; for autistics 6.77 +/- 0.66) in the same homogenates did not differ significantly between groups. These results demonstrate for the first time that dysregulation of Reelin and Bcl-2 may be responsible for some of the brain structural and behavioral abnormalities observed in autism.  

Abstract

The development of distinct cellular layers and precise synaptic circuits is essential for the formation of well-functioning cortical structures in the mammalian brain. The extracellular protein Reelin through the activation of a core signaling pathway including the ApoER2 and VLDLR receptors and the adapter protein Dab1, controls the positioning of radially migrating principal neurons, promotes the extension of dendritic processes in immature forebrain neurons, and affects synaptic transmission. Here we report for the first time that the Reelin signaling pathway promotes the development of postsynaptic structures such as dendritic spines in hippocampal pyramidal neurons. Our data underscore the importance of Reelin as a factor that promotes the maturation of target neuronal populations and the development of excitatory circuits in the postnatal hippocampus. These findings may have implications for understanding the origin of cognitive disorders associated with Reelin deficiency.

While not everything relating to dendritic spines is variable, and hence potentially can be modified, much seems to be.
Rather like in this blog it took a few years to get a comprehensive view of the factors involved in neuronal chloride and extend the list of potential therapies, getting to the bottom of fine tuning dendritic spin morphology for improved behavior and cognition will be a complex task.
Much is already known.
Our reader AJ is busy looking at GSK3 beta inhibitors.
GSK3 beta is best known as a bipolar gene/protein, but it is becoming seen as an autism gene.


GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated β-catenin phosphorylation is known to be the key event in Wnt-β-catenin signaling, the mechanisms which underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-β-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations.
Recent advances indicate that GSK3 also plays a positive role in Wnt signal transduction by phosphorylating the Wnt receptors low density lipoprotein receptor-related protein (LRP5/6) and provide new mechanisms for the suppression of GSK3 activity by Wnt in β-catenin stabilization. Furthermore, GSK3 mediates crosstalk between signaling pathways and β-catenin-independent downstream signaling from Wnt.


it is known that glycogen synthase kinase 3β (GSK-3β) regulates both synaptic plasticity and memory. 
GSK-3β overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased.


Over the past 2 decades, neuroscientists have built a body of evidence that links not only bipolar disease, but other psychiatric disorders including autism and schizophrenia to abnormal brain development. In particular, they have found abnormalities in the numbers of synapses and in the shape of neurons at the points where they form synapses. Their studies have often implicated abnormal signaling in a brain pathway called Wnt, which is involved both in early brain development and later, more complex, refining of brain connections. The role of Wnt could help explain why lithium is effective: It blocks an enzyme called GSK-3 β, which is an inhibitor on the Wnt pathway. By boosting Wnt signaling, lithium could produce a therapeutic effect in psychiatric diseases in which the Wnt pathway is underpowered.

They then treated the mutant mice with lithium. Although the researchers acknowledge that rodents are an imperfect proxy for human mood disorders, they did observe that the animals’ symptoms markedly improved; studies of their brains also revealed normal numbers of spines. “That’s the key finding,” Cheyette says. “It suggests that lithium could have its well-known therapeutic effect on patients with bipolar disorder by changing the stability of spines in the brain.”







GSK3 has numerous effects.

Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. However, this serine/threonine kinase is now known to regulate numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, malfunction of this kinase is also known to be involved in the pathogenesis of human diseases, such as nervous system disorders, diabetes, bone formation, inflammation, cancer and heart failure. Therefore, GSK-3 is recognized as an attractive target for the development of new drugs. The present review summarizes the roles of GSK-3 in the insulin, Wnt/β-catenin and hedgehog signaling pathways including the regulation of their activities. The roles of GSK-3 in the development of human diseases within the context of its participation in various signaling pathways are also summarized. Finally, the possibility of new drug development targeting this kinase is discussed with recent information about inhibitors and activators of GSK-3.  

Estradiol


The present study demonstrates that estradiol may trigger formation of new dendritic spines by activation of a cAMPregulated CREB phosphorylation. Induction of the CREB response requires activation of NMDA receptors, increased intracellularcalciumconcentrationsandcAMP-activatedPKA.These systems together then contribute to the CREB response, which in turn leads to the morphological changes seen with estradiol—i.e., spine formation. The biochemical and cellular routes leading from activated CREB to the morphological change in dendritic spine density are still uncharted.

Dendritic spines of the medial amygdala: plasticity, density, shape, and subcellular modulation by sex steroids.

The medial nucleus of the amygdala (MeA) is a complex component of the "extended amygdala" in rats. Its posterodorsal subnucleus (MePD) has a remarkable expression of gonadal hormone receptors, is sexually dimorphic or affected by sex steroids, and modulates various social behaviors. Dendritic spines show remarkable changes relevant for synaptic strength and plasticity. Adult males have more spines than females, the density of dendritic spines changes in the course of hours to a few days and is lower in proestrous and estrous phases of the ovarian cycle, or is affected by both sex steroid withdrawal and hormonal replacement therapy in the MePD. Males also have more thin spines than mushroom-like or stubby/wide ones. The presence of dendritic fillopodia and axonal protrusions in the MePD neuropil of adult animals reinforces the evidence for local plasticity. Estrogen affects synaptic and cellular growth and neuroprotection in the MeA by regulating the activity of the cyclic AMP response element-binding protein (CREB)-related gene products, brain-derived neurotrophic factor (BDNF), the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and the activity-regulated cytoskeleton-related protein (Arc). These effects on signal transduction cascades can also lead to local protein synthesis and/or rearrangement of the cytoskeleton and subsequent numerical/morphological alterations in dendritic spines. Various working hypotheses are raised from these experimental data and reveal the MePD as a relevant region to study the effects of sex steroids in the rat brain.

PTEN 


CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3β. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.  


Mutations in phosphatase and tensin homolog deleted on chromosome ten (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology using fluorescent dye confocal imaging. Contrary to previous studies in dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory post-synaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors. 


Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.

BDNF
A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p = 0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

Dendritic spines are major sites of excitatory synaptic transmission and changes in their numbers and morphology have been associated with neurodevelopmental and neurodegenerative disorders. Brain-derived Neurotrophic Factor (BDNF) is a secreted growth factor that influences hippocampal, striatal and neocortical pyramidal neuron dendritic spine density. However, the mechanisms by which BDNF regulates dendritic spines and how BDNF interacts with other regulators of spines remain unclear. We propose that one mechanism by which BDNF promotes dendritic spine formation is through an interaction with Wnt signaling. Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.


Other Wnt inhibitors

Yet another anti-parasite drug, Niclosamide,  turns out to be a Wnt inhibitor. 


Not surprisingly, Niclosamide is now a candidate drug to treat several different types of cancer.  It is also thought to have great potential in suppressing the metastatic process of prostate cancer. Another extremely cheap drug, not available in the US.
Even the flavonoid quercetin can inhibit Wnt. 

Therapeutic Avenues

There certainly are many potential ways to fine tune dendritic spine morphology.
Some readers of this blog are already doing just that, perhaps not all realizing it. 
·        BDNF  (want less - TrkB inhibitor)

·        Estrogen 

·        Reelin (want more – statin via RAS activation)

·        BCL2 (want more – statin)

·        PAK1 (want less – PAK inhibitor, BIO30)

·        GSK3 beta (want more – GSK3 activator)

·        PTEN (want more – statin)

All the above seem to work via

·        Wnt signaling (want less – Mebendazole/Niclosamide etc)

If you inhibit GSK3 beta you activate Wnt. You need get things the right way around. 
Statins promote RAS signaling which appears to increase Reelin expression. 


Conclusion

Fine tuning dendritic spine morphology seems like a good target for those with MR/ID and also those with any kind of neurological disorder.
There appear to be many ways to achieve this.
It seems a plausible idea and in many ways seems more credible than the idea of a diuretic (bumetanide) raising some people’s IQ.
The big issue is which substances have sufficient potency, once they have crossed the blood brain barrier, to do anything at all.  This is an issue with all therapies targeting the brain, including bumetanide.
At least substances that can affect hair growth and color are making it through to the bloodstream, which is a start.
Does this mean that tuning your dendritic spines will inevitably make your hair turn grey or begin to thin?  I don’t think so. I think this will happen in people who have low to normal Wnt signaling to start with.
Do some people with naturally premature graying, or thinning, hair have low levels of Wnt signaling? Quite possibly. Are they more likely to have traits of bipolar/creativity? Look for actors with gray or thinning hair.
Do people with autism tend to have full heads of thicker hair, as well as bigger heads?
Do the minority of people with autism and small heads have thinning hair?
Some readers of this blog are already using statins to treat autism. As has been pointed out in earlier posts, other than lowing cholesterol, statins have potent anti-inflammatory effects and they also affect expression of RAS, PTEN and BCL2, all of which are implicated in autism and all affect dendritic spines. It seems plausible that these readers are already modifying dendritic spine morphology.




Wednesday, 15 June 2016

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?



In this composite image, a human nerve cell derived from a patient with Rett syndrome shows significantly decreased levels of KCC2 compared to a control cell.  This will be equally true of about 50% people with classic autism, people with Down syndrome, many with TBI and many with epilepsy


In a recent post I highlighted an idea from the epilepsy research to treat a common phenomenon also found in much classic autism.  Neurons are in an immature state with too much intracellular chloride, the transporter that brings it in, called NKCC1, is over-expressed and the one that takes it out, KCC2, is under-expressed.  The net result is high levels of intracellular chloride and this leaves the brain in an over-excited state (GABA working in reverse) reducing cognitive function and with a reduced threshold to seizures.

The epilepsy research noted that increased BDNF is one factor that down regulates KCC2, which would have taken chloride out of the cells.  So it was suggested to block BDNF, or something closely related called trkB.

Unfortunately there is no easy way to this.  But I did some more digging and found various other ways to upregulate KCC2.

There is indeed a clever safe way that may achieve this and it is a therapy that I have already suggested for other reasons, intranasal insulin.

BDNF is a neurotrophin and other neurothrophins also have the ability to regulate KCC2. IGF-1 is another such neurotrophin and we even have very recent experimental data showing its effect on KCC2.

Regular readers will know that several trials with IGF-1, or analogs thereof, are underway.

I actually am rather biased against IGF-1 as a therapy, since in my son’s case the level of IGF-1 in blood is already high.  So I do not want to inject him with IGF-1 or even give him an oral analog.

However by using intranasal insulin the effect would be just within the CNS and insulin binds at the same receptors as IGF-1. So if IGF-1 upregulates KCC2 so will insulin.

We know from extensive existing trial data and direct feedback from one researcher that intranasal insulin is well tolerated and has no effect outside the CNS.

So rather to my surprise there seems to be a safe, cheap way to treat KCC2 down-regulation and this would also be applicable in epilepsy, traumatic brain injury (TBI) and any other condition involving immature neurons or neuronal trauma. 


The Science

There is a very thorough recent review paper that looks at all the ways that KCC2 expression is regulated.




The epilepsy researchers consider trkB, top left in the figure below.  But just next to it is IGFR which can be activated by both insulin and IGF-1.

In Rett syndrome they are already using IGF-1 to modulate KCC2.  The research is done at Penn State.

As you can see in the figure the mechanism for IGF-1 and insulin is not the same as BNDF/trkb, but Penn State have already shown that IGF-1 works in vitro.

We saw in early posts regarding intranasal insulin that this was a safe way to deliver insulin to the brain without effects in the rest of the body.

So we know it is safe and in theory it should achieve the same thing that the Penn State researchers are trying to achieve.








Signaling pathways controlling KCC2 function. The regulation of KCC2 activity is mediated by many proteins including kinases and phosphatases. It affects either the steady state protein expression at the plasma membrane or the KCC2 protein recycling. All the different pathways are explained and discussed in the main text. The schematic drawings of KCC2 as well as other membrane molecules do not reflect their oligomeric structure. GRFα2, GDNF family receptor α2; BDNF, Brain-derived neurotrophic factor; TrKB, Tropomyosin receptor kinase B; Insulin, Insulin-like growth factor 1 (IGF-1); IGFR, Insulin-like growth factor 1 receptor; mGluR1, Group I metabotropic glutamate receptor; 5-HT-2A, 5-hydroxytryptamine (5-HT) type 2A receptor; mAChR, Muscarinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; mZnR, Metabotropic zinc-sensing receptor (mZnR); GPR39, G-protein-coupled receptor (GPR39); ERK-1,2, Extracellular signal-regulated kinases 1, 2; PKC, Protein kinase C; Src-TK, cytosolic Scr tyrosine kinase; WNKs1–4, with-no-lysine [K] kinase 1–4; SPAK, Ste20p-related proline/alanine-rich kinase; OSR1, oxidative stress-responsive kinase -1; Tph, Tyrosine phosphatase; PP1, protein phosphatase 1; Egr4, Early growth response transcription factor 4; USF 1/2, Upstream stimulating factor 1, 2.




The Penn State research on using IGF-1 to increase KCC2 in Rett Syndrome



The researchers also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 is a molecule that has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the disease in humans.
"The finding that IGF1 can rescue the impaired KCC2 level in Rett neurons is important not only because it provides an explanation for the action of IGF1," said Xin Tang, a graduate student in Chen's Lab and the first-listed author of the paper, "but also because it opens the possibility of finding more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders."





More Melatonin?

As Agnieszka pointed out in the previous post it appears that extremely high doses of melatonin can increase KCC2 in traumatic brain injury (TBI). In this example BDNF was increased by the therapy, so I think TBI may be a specific case.  In most autism BDNF starts out elevated and in epilepsy, seizures are known to increase BDNF and that process is seen as down regulating KCC2 expression.  So in much autism and epilepsy you want less BDNF.

Melatonin attenuates neuronal apoptosis through up-regulation of K+ -Cl- cotransporter KCC2 expression following traumatic brain injury in rats



Compared with the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.



More Science

There is plenty more science on this subject.

It is suggested that in addition to IGF-1/insulin it may be necessary to involve Protein tyrosine kinase (PTK).




Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes, including proliferation, growth, and differentiation, and has also been implicated in synaptogenesis. Protein tyrosine kinases are subdivided into the cytosolic nonreceptor family and the transmembrane growth factor receptor family, which includes receptors for insulin and insulin-like growth factor (IGF-1). The maturation of postsynaptic inhibition may require both a cytoplasmic PTK, which increases GABAA receptor-mediated currents, and insulin, which was shown to induce a rapid translocation of GABAA receptors from intracellular compartments to the plasma membrane. KCC2 is also known to have a C-terminal PTK consensus site. Therefore, the maturation of postsynaptic inhibition may, in addition to other mechanisms, also involve the effects of PTK and insulin acting on KCC2.








Conclusion

I would infer from all this science that intranasal insulin is likely to increase KCC2 expression in the brain, certainly worthy of investigation.

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes.  This might be a limiting factor on the effectiveness of insulin in raising KCC2.  This would then add yet more complexity.

Protein kinases are enzymes that add a phosphate(PO4) group to a protein, and can modulate its function.  A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases.

Abnormal protein tyrosine kinases (PTKs) cause many human leukaemias, so there is research into PTK inhibitors (PTK-Is).

As we know from Abha Chauhan’s mammoth book, oxidative stress controls the activities of PTK.