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Wednesday, 3 February 2021

Vasopressin, Oxytocin, the Lateral Septum, Aggression and Social Bonding, Autism gene NLGN3 and MNK inhibitors for reversing Fragile-X and likely more Autism

 

The Lateral Septum, in green, turns the volume

 up or down in aggression


Today’s post started by me checking for anything new in the research about the hormone Vasopressin and autism. I was surprised by just how much research continues to be published on the subject – no smoke without fire, perhaps.

We also get another insight into how aggressive raging develops in the brain; we even have a photo.

A novel therapy for Fragile-X is also thrown into the mix, due to a link to oxytocin.

So, what is cooking in the research?

The first thing to note is that you really do have to look at both Oxytocin and Vasopressin, because these two hormones are very closely related.

We have previously looked at the autism gene NLGN3, this gene encodes the cute sounding neuroligin-3.

 

https://epiphanyasd.blogspot.com/search/label/neuroglin

 

The reason people with Fragile-X have autism is because they lack the protein FMRP (Fragile X mental retardation protein).

In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

When you look at the interactions of the FMRP protein you can find ways to compensate for this deficiency.  This is nicely illustrated in the graphic below. You just need to find another way to influence elF4E and elF4G.

Some people have told me they find these charts a bit overwhelming, but they precisely show what is going on.  You just have to look up all the terms, you do not know.  In the chart below there is NF1 autism, there is PTEN autism, problems with Ras are called RASopathies and cause MR/ID plus autism. We have at least one reader with TSC (Tuberous sclerosis) type autism. We have readers whose kids lack FMRP, because they have Fragile-X syndrome. 

Today we see that an inhibitor of MnK (in yellow in the chart below) is another via option to treat Fragile-X.

Beyond Fragile-X, we can see that numerous other upstream dysfunctions in the chart can result in miss-expression of neuroligins (NLGNs) in the chart below and then result in autism.

 


 One of the papers below goes further and suggests

“This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses”

“We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis”

“Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome to a non-syndromic model of ASD”

 

Regarding Fragile X 

“Collectively, this work establishes eFT508 (an MNK inhibitor) as a potential means to reverse deficits associated with FXS.”

 

What is the connection to Oxytocin?

A problem with your neuroligins causes an impairment in oxytocin signalling.

 

The role of the Lateral Septum (LS) in both aggression and desirable social behavior 

If you scan through the research on vasopressin and oxytocin you will eventually come across references to the LS.  The LS is a part of your brain called the Lateral Septum.

In the picture below you see a mouse brain and the green part is the Lateral Septum (LS).

 

Source: https://neurosciencenews.com/rage-lateral-septum-3637/ 

“Our research provides what we believe is the first evidence that the lateral septum directly ‘turns the volume up or down’ in aggression in male mice, and it establishes the first ties between this region and the other key brain regions involved in violent behavior”


Both social bonding and offensive aggression involve vasopressin receptors in a part of the brain called the Lateral Septum (LS).  Activity in the Lateral Septum (LS) is regulated by inhibitory GABA, and excitatory glutamate.

There is a notable difference between males and females, at least in rats.  No sex differences were found in extracellular GABA concentrations during social playing; however, glutamate plays a major role in female social playing. When glutamate receptors are blocked in the LS pharmacologically, there is a significant decrease in female social playing, while males had no decrease in playing. This suggests that in the lateral septum, GABA neurotransmission is involved in social play behavior regulation in both sexes, while glutamate neurotransmission is sex-specific, involved in regulation of social play only in females.

 

Aggressive behavior in females 

Neural mechanisms of female aggression: Implications on the oxytocin and vasopressin systems

These models allowed me to investigate the role of the brain oxytocin (OXT) and vasopressin (AVP) systems on aggressive behavior. Both neuropeptides are known to regulate social including aggressive behaviors in males and lactating females.

Taken together this part of my thesis shows that the balance between OXT and AVP release within the LS regulates female aggression in a receptor and region-specific manner via modulating GABAergic neurotransmission.

Overall, this thesis shows that females are able to develop escalated as well as abnormal aggression just like males. In addition, the OXT and the AVP system seem to be main players in regulating aggressive behavior in female Wistar rats, especially, regarding their role in controlling aggression by acting on the LS.

 

The effect of Vasopressin as a therapy

 

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model 

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.

 

In humans, intranasal administration of AVP increased activity in the LS and reciprocated social collaboration (47). Intranasal OXT administration enhances the suppression of oscillatory activity (8–25 Hz) during execution and observation of social actions (48). Altogether, OXT- and AVP-dependent modulation of neural activity in response to social stimuli directly affect EEG activity, which may have a predictive value for the impact of such treatment in ASD-associated disorders. Furthermore, an imbalance between inhibition and excitation is associated with ASD, and AVP treatment could reset the balance by altering the functions of SST neurons (49).

  

Predicting Autism measuring Neonatal CSF vasopressin concentration 

We have yet another predictor of future autism.


Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder


The Russian paper below is very thorough. At least in the case of autism, I do not agree with the therapeutic implications.  The paper suggests Oxytocin agonists (like oxytocin itself) and Vasopressin antagonists.

I propose Oxytocin agonists and Vasopressin agonists, as a practical solution today.  It is not a perfect solution, but totally doable today.

  

The role of oxytocin and vasopressin dysfunction in cognitive impairment and mental disorders 

Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally homologous peptide hormones synthesized in the hypothalamus. Nowadays, the role of OXT and AVP in the regulation of social behaviour and emotions is generally known. However, recent researches indicate that peptides also participate in cognitive functioning. This review presents the evidence that the OXT/AVP systems are involved in the formation of social, working, spatial and episodic memory, mediated by such brain structures as the hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have demonstrated that the OXT receptor's polymorphisms are associated with impaired memory in humans, and OXT knockout in mice is connected with memory deficit. Additionally, OXT and AVP are involved in mental disorders' progression. Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of various mental disorders, including depression, schizophrenia, and autism. At the same time, cognitive deficits are observed in stress and mental disorders, and perhaps peptide hormones play a part in this. The final part of the review describes possible therapeutic strategies for the use of OXT and AVP for treatment of various mental disorders.

 

4.4. Autism

Autism spectrum disorder (ASD) is a group of disorders that are characterized by early disturbances of social communication and limited, repetitive behaviour. Individuals with autism have impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. Additionally, they exhibit atypical neural development at the systems level . Autism is characterized by a disturbance of social interaction first of all, but it is also characterized by cognitive dysfunctions, including working memory impairment. The OXT/AVP system plays a role in such deficits. In male mice with a mutation in the Magel2 gene, social behaviour and cognitive functions are disrupted in adulthood, which makes this model similar to ASD. The lack of Magel2 causes a change in the OXT system. Subcutaneous administration of OXT to mice with this mutation during the first week of life suffices to restore normal social behaviour and learning abilities in adult mice. Exogenous OXT stimulates the release of endogenous OXT and inhibits the accumulation of intermediate forms of OXT (this is observed in OXT neurons in mice with the Magel2 mutation). This was revealed by neuroimaging methods. Human ASD is associated with altered face processing and decreased activity in brain areas involved in this process. OXT enhances the importance of social stimulus in ASD, and probably can stimulate face processing and eye contact in people with ASD. Genetic polymorphisms of the OXT and AVP receptor genes are associated with ASD. Additionally, this review revealed a link between social cognition disorders in autism and some SNPs in the OXTR and V1a receptor genes. The most significant associations between SNPs in OXTR and social cognition were found for rs2254298, rs53576 and rs7632287. SNP rs2254298 has been associated with a diagnosis of ASD. SNP in the V1a receptor gene, rs7294536, is closely associated with a deficit in social interactions. In addition, OXTR rs237887 polymorphism affects facial recognition memory in families with autistic children.

 




 

 

 

Fig 1. The role of oxytocin and vasopressin systems in the pathogenesis of mental disorders. Stress activates the HPA axis and rises in plasma glucocorticoid levels, which leads to social through the cortisol release. HPA axis activation increases the risk of development of psychopathologies. OXT and AVP regulate emotional behaviours, multiple aspects of social behaviour and cognitive functions. Negative environment, including stress factor, causes an imbalance of the OXT/AVP system, which also leads to psychopathological behaviour: aggression, social impairment, anxiety, emotional and cognitive disorders. At the same time, the OXT/AVP system forms a reaction to stress oppositely. OXT inhibits the HPA axis stress induced activity (anxiolytic effect). AVP activates the HPA axis (anxiogenic effect). OXT and AVP can be used as the treatment of mental diseases associated with social and cognitive dysfunctions. OXT – oxytocin; AVP – arginine-vasopressin; iOXT – intranasal oxytocin; iAVP – intranasal arginine-vasopressin; ACTH - adrenocorticotropic hormone; CRH – corticotropin releasing hormone; HPA axis - hypothalamic-pituitary-adrenal axis.

 

 

5. OXT and AVP systems in mental disorder treatments in recent years, interest in the usage of OXT as the treatment of various psychiatric diseases is growing. OXT and AVP systems that exist in balance produce the contrary effect on emotional behaviour. Positive social stimuli and/or psychopharmacotherapy can shift this balance towards OXT and can help to stimulate emotional behaviour and restore mental health through this shifting. OXT produces an effect on several neurobiological systems, including the HPA axis, limbic system, neurotransmitters, and immune processes related to stress disorders. The exact effects of iOXT still remain unclear; nevertheless, it is known that iOXT action depends on individual sensitivity. Data from functional magnetic resonance imaging demonstrated that iOXT induces temporary activation of some cortex areas and prolonged activation of hippocampus and forebrain areas. These structures are characterized by a high density of OXT receptors. At the same time, iAVP causes stable deactivation in the parietal cortex, thalamus, and mesolimbic pathway. Importantly, the intravenous administration of OXT and AVP does not repeat activation patterns caused by intranasal administration of OXT and AVP. Nevertheless, it is possible that a small amount of OXT which crosses the blood-brain barrier may lead to an additional central OXT release since OXT is able to bind to brain OXT ergic neurons and cause its own release. Generally, OXT doses administered in studies vary from 15 IU to more than 7000 IU. As the table indicates, the results of these studies are very different. The most frequently used dose is 24 IU. Many studies are focused on the capability of OXT in the treatment of depressive disorders. It was demonstrated that iOXT reduces the time of concentration on aggressive facial expressions and increases the time of concentration on happy faces in men and women with chronic depression. Therefore, iOXT regulates emotion recognition in depression. iOXT can be used in combination with antidepressants, enhancing antidepressant efficiency. iOXT administration positively affects mother-child relationship in mothers with postpartum depression (PPD). iOXT activates the protective behaviour of mothers with PPD towards their children. Similar results were found in animal experiments. In rats, iOXT reduced the depressive-like behaviour in adult animals subjected to early maternal separation. Moreover, the research of specific neurogenesis markers Ki67 and BrdU demonstrated that iOXT promotes hippocampal neurogenesis, which is impaired in depressed rats. Many studies investigate the therapeutic properties of iOXT and iAVP for the treatment of schizophrenia and autism. It is known that schizophrenia disturbs social behaviour; and cognitive function. iOXT has the potential for usage as a therapeutic tool to restore impaired functions during schizophrenia. Some data suggest that iOXT reduces the negative symptoms of schizophrenia, improves working memory, verbal memory and cognitive function, and also improves social function in patients with schizophrenia and schizoaffective disorder. Although many studies indicate a positive effect of iOXT on cognitive function in people with schizophrenia, the neuropeptide has a very selective action on behaviour. The exact mechanism of iOXT action is also indefinite; therefore, its therapeutic potential requires further research. Eventually, iOXT can be used as an additional therapeutic agent in traditional schizophrenia treatment. iOXT can also be applied to ASD treatment. It was found that iOXT improves social abilities in children and emotionality in adult men with ASD. Moreover, the improvement of emotional state was observed in adults after an 8 IU dose, but not after 24 IU. The study of iOXT's therapeutic properties was also carried out using a mouse valproate autism model. iOXT improved social behaviour in that model, and reduced anxiety, depressive-like behaviour, and repetitive behaviour. iOXT has some positive effects in the ASD treatment. Despite this, studies of the potential therapeutic usage of iOXT are still at an early stage, and doctors have insufficient data to prescribe iOXT to patients. A few data indicate the therapeutic possibilities of AVP compared to OXT. It is known that iAVP was used in the treatment of the first episode of schizophrenia, in addition to the traditional benzodiazepine treatment. Cognitive functions (namely the memorization process, long-term and short-term memory) improved in patients. iAVP treatment ameliorated social ability in children with ASD. Additionally, iAVP treatment reduced anxiety and repetitive behaviors in these children. These data indicate the necessity of further investigation of AVP's treatment potential.

 

 

Rescue of oxytocin response and social behaviour in a mouse model of autism

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1-3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4-6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions. 

Social recognition and communication are crucial elements in the establishment and maintenance of social relationships. Oxytocin and vasopressin are two evolutionarily conserved neuropeptides with important functions in the control of social behaviours, in particular pair-bonding and social recognition7,8 . In humans, genetic variation of the oxytocin receptor (OXTR) gene is linked to individual differences in social behaviour9 . Consequently, signalling modulators and biomarkers for the oxytocin or vasopressin system are being explored for conditions with altered social interactions such as autism spectrum disorders (ASDs)5,6 . In mice, mutation of the genes encoding oxytocin or its receptor results in a loss of social recognition and social reward signalling10–14. Mutation of Cntnap2, a gene linked to ASD in humans, resulted in reduced levels of oxytocin in mice, and the addition of oxytocin improved social behaviour in this model15. However, the vast majority of genetic risk factors for autism have no known links to oxytocinergic signalling. 

Thus, modification of translation homeostasis in Nlgn3KO mice by MNK inhibition restores oxytocin responses and social novelty responses. This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses. Although loss of Nlgn3 impairs oxytocin responses in VTA DA neurons, the behavioural phenotype does not fully phenocopy genetic loss of oxytocin. Oxytocin knockout mice exhibit impaired habituation in the social recognition task10, whereas Nlgn3KO mice habituate normally but exhibit a selective deficit in the response to a novel conspecific. This is probably due to differential roles of Nlgn3 and oxytocin across several neural circuits and over development. Moreover, Nlgn3 loss-of-function also affects signalling through additional GPCRs23. We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis. Notably, MNK loss-of-function appears to be overall well tolerated. MNK1/2 double-knockout mice are viable46 and several MNK inhibitors are entering clinical trials for cancer therapy47. Previously available MNK inhibitors were greatly limited by specificity and brain penetrance. Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome41 to a non-syndromic model of ASD. The common disruption in translational machinery and phenotypic rescue in two very different genetic models indicate that genetic heterogeneity of ASD might be reduced to a smaller number of cellular core processes. This raises the possibility that pharmacological interventions targeting such core processes may benefit broader subsets of patient populations.

 

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice 

Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.

  

Conclusion

I think I have written enough about Oxytocin and Vasopressin.

The research is not entirely consistent regarding Vasopressin, but my assumption is that for my kind of autism I want an Oxytocin Agonist and a Vasopressin Agonist, some people might think it would be a Vasopressin Antagonist.

The good news is that there is significant research in humans, reported in previous posts, to support the use of both Oxytocin Agonist and a Vasopressin Agonist

I also think there will be both short-term, or immediate effects, from both treatments but also potentially different long-term effects from continued therapy, that is indeed suggested by the animal research models.  For example, neurite outgrowth is stimulated by oxytocin.  It is suggested that oxytocin may contribute to the regulation of scaffolding proteins expression.


Is it worth using oxytocin as a therapy to generate some extra hugs? You can argue both ways, but the longer-term benefits of correcting low oxytocin levels may be more profound.

The effects of vasopressin and oxytocin are somewhat overlapping. We know that low levels of vasopressin in spinal fluid are a good marker for autism, so putting a little extra vasopressin in the brain does not seem unreasonable.

As usual with the human body, the effects of oxytocin and vasopressin are different within the brain and in the rest of your body.  Also, the levels of these hormones in your blood are not a good predictor of their levels within the brain.  This is a reoccurring problem.  Because taking a spinal fluid sample is an invasive procedure, it is rarely taking place and then endless time and money is wasted on blood tests that may well send the doctor in the wrong direction, or just no direction.

It is highly likely that increasing Oxytocin and Vasopressin in the brain is going to affect aggressive behaviors, via actions in the Lateral Septum (LS).  Due to the role of GABA potentiating activity in the Lateral Septum (LS) you might expect a possible difference in bumetanide-responders and bumetanide non-responders (because GABA is acting as excitatory).

I would consider Oxytocin and Vasopressin as fine-tuning autistic behavior and you would have to personalize the dosage. In some people it might be a case of either or, rather than both.

Using MNK inhibitors to treat human Fragile-X looks a great idea and hopefully a commercialized therapy could then be trialed in broader autism.

 



33 comments:

  1. I am on my way to get both Vaso and Oxyt. I just hate those ‘no exact dosage known’ things...but will try to make them happen. They are both also sensitive products, needing cooling. That makes them a bit hard to source. But I think I will make it happen in the next two months.

    ReplyDelete
    Replies
    1. For oxytocin you can use Biogaia Protectis probiotic drops, which you can buy in your pharmacy. This has the same effect as intranasal oxytocin. I give just 2 drops a day.

      For Vasopressin you either use vasopressin itself in a nasal spray, or use Minirin Nasal spray, when available, this contains the analog of Vasopressin called Desmopressin.

      Delete
    2. Hi Peter, mind clarify which strain boosts oxytoxin via the vagus nerve? I read reports on the PTA 6745 but yet to find one for DSM 17938 in Protectis.
      Besides, you mentioned that oxytoxin may provide different responses on bumetanide responders and non-responders - do you mean that if one responds to bumentanide, you should use agonist, but not antagonist, and vice versa?

      Delete
    3. MH, multiple health benefits are attributed to L.reuteri increasing oxytocin. I think multiple bacteria in this class have this same effect.

      Microbial lysate upregulates host oxytocin
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431580/

      I know Protectis has the “oxytocin effect”, because I have seen it with my own eyes.

      In a significant minority of people PTA 6745 actually has an immediate extreme negative effect, this is not the oxytocin effect. It also has an effect on histamine, which may be causing this problem.

      Since the effect is mediated by oxytocin, GABA and Glutamate, you would expect different responses in different people. My point is do not be surprised when things work differently in different people.

      Delete
  2. My son is excessively affectionate so I am not sure he needs oxytocin as he even goes to strangers for hugs .Maybe vasopressin will help in his case but will be very hard to source here .

    Will look for it and have a trial

    ReplyDelete
  3. The circuit (at least in mice) for aggression from the lateral septum goes to a part of the hypothalamus called the ventrolateral part of the ventromedial hypothalamus. A subset of neurons of this subset of the hypothalamus has an area called the Hypothalamic Attack Area:

    https://pubmed.ncbi.nlm.nih.gov/8058117/

    Interestingly, the lateral septum also has a circuit that ends in almost the same area of the hypothalamus that involves mounting behavior of male mice, though they don't seem to be from the same upstream circuit of the lateral septum:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783202/

    In humans sexuality is more complicated because we have entire parts of the cortex that regulate sexual behavior that mice do not. Nevertheless, with respect to autism, it is interesting how aggression and sexual behavior are intertwined much of the time and how almost all chemical interventions to modulate aggression in violent individuals end up with impotence and lack of desire as a side-effect.

    ReplyDelete
  4. Hello Peter, thank you for another great post.

    I ran into this article:

    A Special Extract of Bacopa monnieri (CDRI-08)-Restored Memory in CoCl2-Hypoxia Mimetic Mice Is Associated with Upregulation of Fmr-1 Gene Expression in Hippocampus

    https://www.hindawi.com/journals/ecam/2015/347978/?fbclid=IwAR2JoXgbc_-90nBIaxSJmyvwN7yx3BYq67TQNVx2d7FMDP1r6yLRB7-vuiw

    ReplyDelete
    Replies
    1. Lisa, Bacopa monnieri extract upregulated expression of Fmr-1, making it yet another interesting potential therapy for people with Fragile-X.

      You do wonder why there is little follow-up on these potential therapies.

      Bacopa is an inexpensive medicinal plant, sold as a powder in bulk.

      Delete
  5. Malarone update: we are still on 2 pills, the treatment dosage for malaria. For the first few days, by mistake, I gave double the dose for treating malaria. It was only 3 days and especially the first 3 days so I can’t swear by it but she seemed to advance better in that dose than the regular malaria treatment dose. I have started to contact experts to help me understand what dose would be still ok. What she is on now is safe for sure.
    The advancements she made are sticking very firmly and every day she is using them more and more. Speech is richer every day, pronounciation has jumped almost to perfect level in both languages. She has most definitely grasped the most basic levels of math. It seems that she is also more prone to trying again after not succeeding. In the game connect 4 she is developing new ideas every time we play and there is 0 opposition to playing, and some enjoyment in winning. If this intervention had come earlier, and if we did not have additionally Pandas with tics, I would say that the only missing piece for her being cured is the social component, so ocytocin/vasopressin.
    She is additionally on antibiotics and antifungals for the pandas and some normal supplenental dose magnesium, b6 and potassium in the mornings and evenings. Middle of next week I will switch to just 1 pill, and see what happens, and update you.

    ReplyDelete
    Replies
    1. Very interesting Tatiana,

      Who was the Dr that suggested Malarone? Are there more people trialing it with similar results?
      I might have some leftover from working in Africa a couple of years back. A couple of my coworkers were getting quite vivid nightmares from it. My only side effect was a bit of a rash however being Africa it could have been anything.

      Delete
    2. If you look back at my comments in previous posts - a mother i met at Synchrony conference had amazing results with it visible in 48h. her son was prescribed this as part of a protocol against Babesia. since the safety profile of the drug was so good I decided to give it a go. From what I heard the nightmares are associated maybe more with Lariam, another antimalarial of totally different effects. a few parents are trialing it now and so far everyone has more or less similar effects to me. but its really a handful of people so not enough to give a good picture.

      Delete
  6. multumim,TATJANA sa ne tii la curent,fiul meu cu autism a inceput de cateva saptamani bune sa arune mancarea din gura dupa canapele si mobila dupa ce o mesteca in gura ,care credeti ca ar fii cauza,sa fie candida sau paraziti in prezent suntem pe verapamil,NAC,happy bioray.

    ReplyDelete
  7. Hi Peter

    I’m looking for a good genetic test I understand I need whole exome sequencing as well as whole genome sequencing along with good interpretation of the result, is there any that you would recommend?

    ReplyDelete
    Replies
    1. Ross, it does rather depend on where you live and what your budget is. If you live in the US and have a big budget, you could ask Dr Boles and he would tell you what to do. If you are in the UK you could see what you can get for free. The UK is supposed to be the world leader on sequencing genomes.

      I think interpretation will generally be weak and some parents have actually identified the causal mutation themselves, by studying the raw data. This is not simple.

      Some people are lucky and there are genetic mutations that clearly relate to autism. Some may be treatable. Most times it is not so clear.

      Delete
  8. Buna Peter,vroiam sa te gandesti la TOXOPLASMOZA GONDI,crezi ca ar putea fii cauza problemelor noastre autiste,poate inflamatia permanenta si probleme cu reglarea dopaminei si serotoninei si multe turburari comportamentale,TOC,sa fie vinovat T.gondi,antiparazitarele intotdeauna au linistit copilul meu,suramin este un antiparazitar,ce zici.....

    ReplyDelete
    Replies
    1. When it comes to autism, parasites can have good effects, bad effects or no effect.

      Many anti-parasite drugs have addition modes of action that do not relate to parasites, this is the reason I think they are helpful, in most cases.

      Delete
  9. PETER,scuze asta este un articol referitor la T.GONDI http://www.ghrnet.org/index.php/ijnr/article/view/2430

    ReplyDelete
  10. Peter, does your son taste the drops?

    ReplyDelete
  11. A mindblowing article spelling doom (hopefully) for the practice of looking at psychiatric issues as ‘mental’ problems: https://www.nytimes.com/2018/09/29/opinion/sunday/schizophrenia-psychiatric-disorders-immune-system.html?smid=url-share&fbclid=IwAR0iX9pjmzQFhcnSrvKJiqwmKAO9b_nBZz6KowehYrkuBBtQTIgFP9amyLQ

    ReplyDelete
  12. TATJANA,ce se mai intampla cu malarone???sa ne tii la curent te rugam frumos,mersi asteptam comentarii....

    ReplyDelete
  13. Thursday we start with the prophylactic dose of Malarone. Gains sticking and new microgains popping up as we go - a result of better receptive language and sensory issues. Example - finally able to wear a chewy sensory toy necklace at school because she doesnt mind the necklace. doesnt even take it off all day even at home. Addition is definitely in her head now. Reading probably more fluent as well. This is especially hard because due to local education systems she actually has to learn both western letters (classic alphabet), which she learned years ago, and cyrillic, learning it this year, and it is visually complex.

    ReplyDelete
  14. Very exciting Tatjana, hopefully this is a beginning of something significant that can help lots of people.
    You mentioned in an earlier post that your also using anti fungal medicine and antibiotics. Do think it’s the combination your daughter is taking that’s producing your results?
    The reason I ask is I recently spoke with a couple of parents that were patients of the somewhat infamous Dr Goldberg who’s protocol commonly includes both Antifungals and Antivirals. One parent told me that the Antifungal was the game changer while the other said it wasn’t until the antiviral was added that she noticed improvements.

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  15. She has been on long term asntibiotics because she has Pans/Pandas. The antifungals are necessary when you take the antibiotics so long. I am not willing to remove this from her plan right now because the consequences can be quite drastic.
    If, however, the Malarone is actually working on some kind of ‘killing stuff’ level for her, and not due to its effect on the cell danger response; then combining it with azithromycin is absolutely helping.
    I have ordered a lot of tests from Armin labs to check whether there is any whiff of known pathogens such as Babesia, Lyme etc. Should have the results in about a month.
    What I really like about the change Malarone has had on her is that so far its super stable.

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  16. Hi Peter

    I was just wondering if the person commenting on https://sciencebasedmedicine.org/ called Peter was you or not. He mentioned he also has a severely autistic son.

    Thanks in advance

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  17. Biogaia releases a new product with 10 billion PTA 6475 per tablet, vs 100 million in the Gastrus. This new product is intended to increase bone density. I recall another reader sharing her positive experience with Gastrus that requires 5 tablets per day (i.e. 500 million PTA 6475) to make an effect. It seems the new product is much more cost efficient, provided that too MUCH PTA 6475 is not harmful. Or at least you can chop it into quarters with 2.5 billion each.

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    1. MH, that is good to know. Some people were growing their own PTA 6475 using milk and the bacteria to make yoghurt.

      You can also use some L.reuteri to improve wound healing. That would be good for older people and diabetics with foot/leg ulcers.

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  18. Hi Peter,I am thinking of increasing the dose of Pentoxifylline from 400mg a day to 800mg,2 tablets.It didn't work dividing one 400mg tablet.What do you think, did you try it?
    Valentina

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    1. Valentina, you could try the higher dose, but if that does not help I would assume your son is not a responder.

      So far I have just tried Pentoxifylline and the 100mcg Roflumilast/Daxas on myself. Taken with food I noted nothing from Pentoxifylline, without food I got GI side effects. The 1/5th dose of Roflumilast/Daxas did have a cognitive effect on me, but did give GI mild side effects. In my elder son it has no side effects at all and I think this will be the case in Monty.

      I had a reader contact me to say her Aspie son did benefit from Roflumilast/Daxas.

      I will try both on Monty, but I have not done so yet. I will try 80 mcg Roflumilast, for my first trial and then 200 mg twice a day of Pentoxifylline for my other trial.

      The mechanism of Pentoxifylline and Roflumilast do overlap, but they are not exactly the same. I think both are worth trying.

      Roflumilast/Daxas is not cheap, but one pack will last 5 months at the suggested adult dose of 100 mcg and even longer if you give a "smaller person dose".

      I am currently trying to get the benefit from Calcium Folinate, without the side effect of occasional aggressive behavior.

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    2. Ok, I will try 2 tablets Pentoxifylline a day.One tablet did have a good effect,but I want to know if 2 tablets improve the benefit. I would like to try Calcium Folinate, as we also have the Mthfr mut, but as you said I am afraid of the agressive response. Good luck with your interventions!
      Valentina

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    3. Valentina, can you describe the good effect that you are seeing from Pentoxifylline? This will be interesting to many readers.

      How long did it take before you saw these effects?

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  19. Ciao vorrei sapere anche io che risultati stai vedendo con pentissifillina.

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