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Thursday 23 March 2017

Targeting Angiotensin in Schizophrenia and Some Autism





 A home run? Certainly worth further consideration.

Just when you thought we had run out of hormones to connect to autism and schizophrenia, today we have Angiotensin. 

Angiotensin is a hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs (ACE inhibitors) that lower blood pressure. Angiotensin also stimulates the release of aldosterone, a hormone that promotes sodium retention which also drives blood pressure up.

Angiotensin I has no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II  by the enzyme angiotensin-converting enzyme (ACE).  ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of Angiotensin II production.  

It turns out that Angiotensin has some other properties very relevant to schizophrenia, some autism and quite likely many other inflammatory conditions. 

Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1,Th2 and Th17. 

In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.  

Drugs that reduce Angiotensin are very widely prescribed, so they are cheap and well understood. This means that yet another cheap generic has the potential to be repurposed to treat neurological disorders. 

As one paper puts it “modulation of the RAAS (renin-angiotensin-aldosterone system) with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.” 

No big profits then for big pharma. 


IL-17a 

We learnt all about the inflammatory cytokines IL-17 and IL-17a in a recent post. That post was about autism, but not surprisingly, elevated levels of IL-17a are a feature in big brother schizophrenia. Big brothers do tend to get more research attention.

In schizophrenia there is increased plasmatic Angiotensin Converting Enzyme (ACE) activity in patients compared to healthy controls, which is also associated to poor cognitive functioning. The ACE main product angiotensin II has known pro-inflammatory properties. 

So an ACE inhibitor looks an obvious choice for schizophrenia.  Very slowly research is indeed moving in that direction.

Angiotensin receptor blockers have even been proposed for bipolar disorder, autism’s other elder brother.
  

What about ACE and Autism? 

As we have got used to, kid bother autism has not had the same level of research attention as given to schizophrenia, but we do have this:- 



Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism. 

Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.
   

Here is the supporting research:-  



The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.
  

In an effort to find a marker that predicts psychosis, postdoctoral researcher Lindsay Hayes, Ph.D., learned unexpectedly that mice and people with behavior disorders have abnormally low levels of a hormone system tied to blood pressure regulation and inflammation. In the cerebrospinal fluid of patients with first episode psychosis, she noticed abnormally low levels of the enzyme that makes the hormone angiotensin. To see if these results correlated to animals and could be studied in the lab, Hayes, who works in the laboratory of treated brain cells with angiotensin and inflammation activators in their mouse model for behavior disorders, then measured the output of proteins involved in inflammation. Compared to normal mice, the cells from the mouse with behavioral disorders released more inflammation protein when treated with low levels of angiotensin and less when treated with high levels. Next, she looked at gene expression levels of the angiotensin system components in the brain cells of the behavioral disorder mice. The gene expression levels for the receptor that detects angiotensin were abnormally low in a specific type of brain cell. Hayes says these specific cells in the behavior disorder mice seem to be less susceptible to angiotensin’s immunosuppressive properties, because they have less receptor to detect angiotensin than the same brain cells in normal mice. Hayes and Sawa plan to investigate whether targeting angiotensin could control inflammation and perhaps treat psychosis. 

Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia.

Abstract


Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ. 

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia. 

Abstract


The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0 .001="" span=""> These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process. 



The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.


African Americans have been shown to exhibit lower urinary potassium excretion when compared to Caucasians. Angiotensin II regulates both potassium handling by the kidney and the Na-K-2Cl (NKCC) cotransporter in vitro . However, little is known about the role of the reninangiotensin system (RAS) in human NKCC cotransport regulation in vivo. We hypothesized that regulation of RAS would induce concomitant alterations in NKCC activity in humans. The kidney and erythrocyte express NKCC-1 isoform. Therefore, we measured NKCC-1 activity in freshly isolated ex vivo red cells from 12 healthy blacks and 11 healthy whites in high (200 mmol/d) and low (10 mmol/d) salt balance, followed by a measure 24 h-post candesartan [16 mg] to block angiotensin II type I receptors on low salt diet. Baseline NKCC cotransport activity was significantly lower in Blacks when compared to Whites in balance on a typical high salt diet, and was reduced when the subjects were placed on a low salt diet in whites only. Administration of candesartan reversed the reduction seen with low salt diet in whites, where as in blacks there was no significant effect. These data suggest altered in vivo regulation of NKCC-1 via RAS in Blacks when compared to Whites, and provide a mechanism that may in part explain the altered potassium handling observed among otherwise healthy African Americans.


Conclusion

I think it is likely that some sub-types of autism would likely benefit from an ACE inhibitor. As a secondary benefit, it will also reduce any troubling high levels of leptin.

There are other ways to modulate Th1, Th2 and Th17, but if you have elevated Angiotensin Converting Enzyme (ACE), then an ACE inhibitor would appear the logical choice.

How about a clinical trial in adults with Asperger's?











34 comments:

  1. Peter, very interesting post, my son could be a responder taking all things in consideration, but i wouldn´t know how to try an angiotensin blocker for him, my mother takes them for hypertension, to lower blood presure.Are you going to try it? which dose would be safe for a kid?
    Valentina

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    1. Valentina, enalapril and captopril are apparently often used in children . Enalapril is given as a tablet once a day and captopril is given as a tablet three times a day. There are interactions with other drugs. I think you said you have a doctor relative. I suggest you talk to that doctor. Lots of people are on ACE inhibitors preventatively, like people with type 1 diabetes.

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    2. Enalapril is very very cheap here, my mother´s husband is the doctor´s familiy but he is very conservative,he is practicaly retirated,for his age,is an excellent clinician and helped me a lot with this theme, unfortunatley the neurologist that could have made the difference for my son was a close friend of him,but died when my son was diagnosed. I don´t know if enalapril is sold with prescription,don´t think so.

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  2. Peter,Tyler I don´t know what do you think, I will do a trial of enalapril and start with 2,5 mg,it is safe up to 20 mg a day.What says in the first link for me is very revealing,¨ dopamine synthesis is further induced in inflammatory conditions of the brain, IL6 stimulates HPA and the release of catecholamines such as dopamine, the overproduction of AngII is one of the major causes of HPA axis dysregulation wich has been observed in autism.
    Valentina

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    1. This type of intervention you will probably want to monitor judiciously and get your doctor to do it as well if that is at all practical. While high blood pressure is the leading risk factor for all-around mortality, a severe drop in low blood pressure can cause acute death. Check blood pressure once or twice a day if you don't already do so.

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    2. Valentia

      There is an old post that Tyler referred to concerning the angiotensin II receptor antagonist Candesartan. It is not an ACE inhibitor, but the mode of action is very closely related.

      https://epiphanyasd.blogspot.com/2015/06/primary-and-secondary-dysfunctions-in.html

      In that post I refer to a patent for its use in Autism, the inventor wrote:-

      00051] After obtaining consent from his parents, Candesartan was started. An initial dose of 8 mg resulted in significant attenuation of aggressive behavior. Blood pressure remained stable. After 2 weeks, the dose was raised to 16 mg. Further improvement in aggression was noted with no adverse lowering of blood pressure.

      [00052] The patient has remained on Candesartan with beneficial anti aggression effects being maintained over one year.

      [00053] A preferred dose found by the inventor to treat autism is approximately O.lmg/kg. In children, a liquid form may be used.

      Now compare this to the Usual Pediatric Dose for Hypertension

      1 TO LESS THAN 6 YEARS:
      Initial dose: 0.2 mg/kg/day orally in 1 to 2 divided doses
      Maintenance dose: 0.05 to 0.4 mg/kg/day orally in 1 to 2 divided doses

      6 TO LESS THAN 17 YEARS:
      Less than 50 kg:
      -Initial dose: 4 to 8 mg/day orally in 1 to 2 divided doses
      -Maintenance dose: 2 to 16 mg/day orally in 1 to 2 divided doses
      Greater than 50 kg:
      -Initial dose: 8 to 16 mg/day orally in 1 to 2 divided doses
      -Maintenance dose: 4 to 32 mg/day orally in 1 to 2 divided doses

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    3. Peter, it seems that the initial dose should be more than 2.5 mg, 4 mg would be ok for two weeks.The top maintenance dose is 16 mg.So I think that to be in the safe side 10 mg a day is the best dose for maintenance.I will buy a wrist blood pressure gauge to check the bp each day.
      Valentina

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  3. How does spironolactone act on RASS? It is a diuretic and an anti inflammatory and proved effective in one type of autism. Or the mechanism is entirely different?

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  4. Hi everyone,

    Here is an interesting paper on the role of APP in the GABAergic system, and involvement of NKCC1 and KCC2:

    http://www.nature.com/articles/s41598-017-00325-2

    Have a great evening!

    AJ

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    1. AJ, at least two studies link elevated APP to severe autism.

      High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression.

      https://www.ncbi.nlm.nih.gov/pubmed/16948926

      It has even been proposed as a biomarker.

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    2. Hi Peter,

      Thank you for the additional details! I hadn't had a chance to dive into APP's connections with ASD, and didn't know that the connection was with more severe cases. That would make sense.

      Have a great day Peter!

      AJ

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  5. I posted about Candesartan a while back about its use in Parkinson's disease and you followed up on it more extensively in this post:

    https://epiphanyasd.blogspot.com/2015/06/primary-and-secondary-dysfunctions-in.html

    Have you trialed candesartan since then and since you apparently followed up researching it quite extensively, do you have any idea how well it passes the BBB?

    It sounds like another potential tool in the NKCC1/KCC2 modulation toolbelt. Last but not least, Angiotensin II stimulates vasopressin (ADH) secretion in the hypothalamus which is very interesting in that I have read multiple studies relating to autism that suggest either there is too much vasopressin synthesis, too little vasopressin synthesis, or that agonizing or antagonizing the vasopressin receptors has beneficial or detrimental properties to anxiety and socialization. A lot of this research is on various animals, but at the moment I can't really figure out one way or another what the current scientific consensus happens to be, if there even is one in terms of vasopressin's role in autism.

    It is interesting that bedwetting is a common problem in autism and that vasopressin is released by the suprachiasmatic nucleus as sleep time approaches. The suprachiasmatic nucleus of course also stimulates a pathway that leads to the release of melatonin from the pineal gland as well. The reason this happens is that since vasopressin causes an increase in blood pressure (i.e. more water is stored) and causes animals to become more thirsty if the blood pressure set point is lower than normal (so as to increase blood pressure) and to prevent dehydration during sleep, this natural vasopressin release occurs normally before bedtime.

    Now disturbed circadian rhythms in those with autism is not new news, nor is bedwetting or that melatonin supplementation is one of the most popular interventions for autism, however, it is an interesting idea to modulate vasopressin levels indirectly with ACE inhibitors and it would also be interesting to think about whether circadian timing of their use would be important as well. It is also interesting to think about whether the bedwetting problem is partially the result of blood pressure changes via vasopressin causing the body to dump more water into the bladder, or rather the problem could be excess vasopressin before bedtime causing too much water to be released into the blood and then as vasopressin levels drop, you have too much water being dumped back into bladder which leads to a child peeing the bed before they wake up and go to the bathroom.

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    1. Tyler, I did not try it. Re-reading that old post does suggest the ACE inhibitors could be very useful. They do interact with diuretics, so if you are already on bumetanide, some ACE inhibitors might be more appropriate than others. It would be useful to have some input from doctors already using bumetanide for autism, and familiar with the use of ACE inhibitors with diuretics in older people.

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    2. Regarding the BBB, here they suggest intranasal use of perindopril or captopril in AD.

      Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer’s Disease

      https://link.springer.com/article/10.1007/s11481-016-9703-8

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  6. I also might add that both vasopressin and oxytocin are co-released from the paraventricular nucleus and supraoptic nucleus of the hypothalamus in response to a drop in blood pressure. In light of the known positive effects of Bumetanide, and anecdotal resports of the benefits of other types of BP medication on autism symptoms, it would be very interesting if a study was done with a broad spectrum of blood pressure lowering drugs on autism symptoms to see which ones have the most impact on autism symptoms and most importantly to see if there is anything specific about the manner in which BP is lowered and outcomes on autism symptoms, and if not then how much of a positive effect on autism symptoms is due to the lowering and/or the cyclic variability in blood pressure alone?

    This would probably be a fairly expensive study as it would require a lot of research subjects, but one that would be fairly straightforward and could be done relatively quickly as there would not be a need to recruit ASD subjects with specific syndromal diagnoses.

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    1. Hello Tyler,

      I think I too had raised this issue of mode of action about bumetanide and diuretics in general on autistic individuals in relation to their beneficial effects and had wondered about role of vasopressin, hypertension ....it was not based on a very technical backup but general logic. I am raising this issue again because I trialled oral methylcobalamin, 1000mcg , on my son for a fortnight and it seemed to make him cleverer, both in a negative and positive way. However, I observed an increase in frequency of urination and then yesterday the odd running/pacing forward and backward focussing on the door knob or switchboard. This was the very behaviour which had disturbed me while dosing my son on bumetanide...and which I now think is indeed caused by hypokalemia. So methylcobalamin might be causing porassium deficiency in my son either due to diuresis or as a,result of increased potassium uptake which is a known associated effect of its use.

      Coming back to my point, could it be the diuretic effect of methylcobalamin in my son which seems to make him smarter ...in which case diuresis in itself might be of benefit at least in some autistic individuals, apart from hypothesized removal of chloride ion by bumetanide which is said to turn gaba back to inhibitory.

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    2. Hello Tyler, Peter,

      Could you elaborate on the concept of 'cyclic' variability in blood pressure. I am intrigued because as I have mentioned earlier also in this very blog, my son, in the absence of any external chemical intervention, seemed to have bouts of diuresis, once in every two or three months, since the age of 2.10 or so (or probably removal of diaper made it more apparent from that age). These phases were associated with a clear cognitive jump. A bizarre episode during each of these bouts was a single urination, my son deliberately carried out on the bed or floor while observing the process. I am fascinated..what else to say. As I mentioned, we had the phase again and few hours earlier, he just sat and urinated on the floor, closely focussing on the evacuation. He has undergone a cognitive jump..I will not take further space describing in what way. But if you could throw further light, any stray thought, on what might be going on, it will be really helpful.

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    3. Well what I meant by "cyclic" is that blood pressure as I mentioned before follows circadian rhythms and changes somewhat during the day in response to environmental factors (feeding, sleeping, stress, etc.). My point was maybe not very clear in that if something is causing blood pressure to remain constantly high or low, then secondary systems in the body which are put into motion as a result of a change in blood pressure never get initiated. My example here was oxytocin/vasopressin which has systemic effects as well as effects in the brain and is produced in the paraventricular nucleus and supraoptic nucleus (vasopressin is also produced in the suprachiasmatic nucleus), but its release systemically happens from the pituitary gland after vasopressin/oxytocin travels down the exons to the pituitary gland. Many hormones are synthesized directly in the pituitary gland, but oxytocin/vasopressin are actually synthesized in the hypothalamus and then are delivered to the pituitary gland which is then phasically released automatically (at least that is my understanding).

      The point is that these systems in the body are not linear and so it is not intuitive to think that what matters more is the fluctuation of a particular hormone, protein, or peptide rather than some maintained threshold level. Trying to brute force these kind of problems more or less describes a lot of the fallacies in how psychotropic medication is often prescribed to treat mental disorders like depression these days.

      Generally speaking, something that goes up is supposed to come down and if it is not coming down (or coming down enough), then you can have secondary signaling problems.

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    4. Ok Tyler,

      You were referring to diurnal variations in body paramaters. I was curious/wondering more about other cyclic processes...might be exhisting which we might not know about probably arising out of bodies own physiology/biochemistry and thresholds with feedback mechanism resulting in observed periodicity in body functions and/or patterns of behaviours. Anyway, this us just a vague idea based on what I have observed in my child and does not really help me help him in any way.

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  7. Effect of tangeretin is more power when PEA is added. I use to add tangeretin when the tooth is changing - by your advice, Piter, and it is fascinating - even the look of her face becomes more sharper. Sadly, effect last only couple of days.
    So, I am testing combination of PEA and luteolin (PEApure and BrainGain - can't get Glialin from Italy).

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    1. Maja, that is interesting. I am talking to another doctor parent about PGC-1α activators, this is a logical way improve mitochondrial function. Here again we see PPAR alpha and PPAR gamma.

      One method suggested is to use fibrate type drugs such as Bezafibrate, which is an agonist of PPAR alpha, but also it seems PPAR gamma.

      Your combination of tangeretin plus PEA will be similar to Bezafibrate. The advantage of Bezafibrate is that it is standardized, well studied, likely more potent and cheaper.

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    2. Well, Benzafibrate would be my next choice, thank you...
      Now I would like to try inulin.
      https://www.nemechekconsultativemedicine.com/…/reversing-a…/
      These studies are reason why I believe in Nemechek protocol
      1- MacFabe
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747729/
      2- Gastrointestinal flora and gastrointestinal status in children with autism
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072352/
      Started yesterday with inulin + CLO + krill oil.
      For amplification of anti inflammatory effect, I am still using PEApure+BrainGain (one caps.)
      Added simethicone for possible side effects.

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  8. Article: 5-HT modulation of auditory and visual sensorimotor gating: I. Effects of 5-HT releasers on sound and light prepulse inhibition in Wistar rats.

    Conclusion: These data support a potential role of excessive 5-HT activity as a contributing factor to disrupted sensory gating processes seen in schizophrenia and possibly other neuropsychiatric disorders.

    Sunlight tends to improve our general well-being and make us happier. It does this by causing us to produce more of a "happy hormone" called serotonin.
    Spring Often Makes Symptoms of Mental Illness Worse.

    Article:The antidepressant fluoxetine restores plasticity in the adult visual cortex.

    Article:Specific GABAA circuits for visual cortical plasticity.

    Article:Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex1,2,3

    Abstract: Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile.
    Artice: Spinal cord injury: Fluoxetine shows promise as a neuroprotective therapy following spinal cord injury


    Abstract:Fluoxetine, an antidepressant drug, has shown promise as a therapy in spinal cord injury (SCI), but the mechanism underlying this neuroprotection was unknown. Using a mouse contusion-injury model, Lee et al.

    I am just making a hypothesis for possible mechanism behind sensory overload. Sorry for my copy/paste style. I suppose I have to trial low dose fluoxetine for my adult son. If this doesn't work, I hope at least it lowers testosterone levels.

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  9. Peter, I really don't know if this makes sense in relation to autism research, but what exceptionally impressed me is the fact that improvement seen with fluoxetine reversed with benzodiazepines.
    I thought this is relevant to my son's phenotype as he dramatically worsens even with the slightest dose of benzodiazepines.

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  10. Yes, I tried 5-HT but didn't rescue sensory overload.
    Maybe fluoxetine has a different mechanism of action.
    The way this medicine works is not fully understood. It is thought to positevely affect communication between nerve cells in the central nervous system and/or restore chemical balance in the brain.

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    1. Petra, fluoxetine is better known as Prozac. It is widely used in the US to treat anxiety in people with autism. It is seen as over-prescribed in general.

      Delete
    2. Petra, while it looks like the alpha-7 nicotinic receptor gets the research attention for sensory gating, there is recent research into both H3 and H1 histamine receptors. H1 is east to trial, H3 is not.

      "These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli."

      Meclizine Enhancement of Sensorimotor Gating in Healthy Male Subjects with High Startle Responses and Low Prepulse Inhibition

      http://www.nature.com/npp/journal/v39/n3/abs/npp2013248a.html

      Delete
  11. What about the anti diabetic ppar agonists like actos. I asked my doc about bezafibrate and he suggested actos? Tyler, Peter, everyone, thoughts?

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  12. I guess what I'm wondering ... is should I push for bezafibrate or would actos make as much sense to try ? Thnks!

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    Replies
    1. Actos is a PPAR gamma agonist that also has some effect on PPAR alpha, whereas Bezafibrate is a PPAR alpha agonist that also effects PPAR gamma. So they are very similar, but slightly different. It is more a question of which one is safest for use in a child. I think Actos will be more likely to be effective. There is also Metformin, which I think will help some people, in others it will make things worse.

      So Audrey, it is trial and error, but there is some logic to support both Actos and Bezafibrate.

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  13. Hi Peter Lloyd-Thomas,

    Here's my notes on autism and interleukin-17a and vitamin D.
    I thought you and your reader may be interested.

    # Part 1
    ---
    * Cracking the Fever-Autism Mystery
    https://hms.harvard.edu/news/cracking-fever-autism-mystery
    "Immune influence Choi and Huh previously explored other links between inflammation and autism. In 2016, they showed that mice born to mothers who experience severe infections during pregnancy are much more likely to show behavioral symptoms such as deficits in sociability, repetitive behaviors and abnormal communication. They found these symptoms stem from exposure to maternal IL-17a, which produces defects in a specific brain region of the developing embryo. The brain region, S1DZ, is part of the somatosensory cortex and believed to be responsible for sensing where the body is in space.

    “Immune activation in the mother leads to very particular cortical defects, and those defects are responsible for inducing abnormal behaviors in offspring,” Choi said.

    A link between infection during pregnancy and autism in the offspring has also been documented in humans."
    ---
    * Maternal Immune Activation and Interleukin 17A in the Pathogenesis of Autistic Spectrum Disorder and Why It Matters in the COVID-19 Era
    https://www.frontiersin.org/articles/10.3389/fpsyt.2022.823096/full
    (This article discusses various cytokins in ASD, including IL-17A)
    "A growing body of evidence supports a role in ASD pathogenesis for Th17 cells and their product cytokine, IL-17A (Figure 1) (79, 82). The IL17A gene itself has been identified by a small genome-wide CNV study to have amplified CNVs in ASD affected cohorts (83). Elevated levels of IL-17A have been reported in the blood of ASD affected individuals, and these correlate positively with severity of ASD behavioral symptoms (35, 63, 79). Yet, others have found high concentrations of IL-17A in individuals affected by obesity or high BMI (84), both of which are more likely in ASD groups (85). This is a potential confounder for any retrospective cohort based study designs."
    ---
    * Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase
    https://pubmed.ncbi.nlm.nih.gov/15142659/

    "it is hypothesized that the child may have LCAD (Long chain acyl-CoA dehydrogenase) deficiency. Additional metabolic abnormalities seen in this patient include alterations of TCA energy production, ammonia detoxification, reduced synthesis of omega-3 DHA, and abnormal cholesterol metabolism."
    ---
    https://www.healthline.com/nutrition/coconut-oil-and-skin
    If someone has LCAD, then more MCT oil, and less Long Chain oils may help.
    ---
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292950/
    "the existence of distinct metabolite differences could relate to concurrent vitamin D deficiency that was observed in a large proportion of patients with ASD (62%) in this study. Vitamin D has a pivotal role in neurodevelopment through several mechanisms including gene regulation and anti-inflammation/immunological modulation. Lower Vitamin D levels were consistently reported in subsets of patients with ASD compared to healthy controls"
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    A T cell cause for autism?
    https://www.science.org/doi/10.1126/science.aad0314
    "Therapeutic targeting of interleukin-17a during gestation reduced ASD symptoms in offspring."
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    The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring
    https://www.science.org/doi/10.1126/science.aad0314
    "Maternal IL-17a promotes ASD-like behavioral abnormalities in offspring"
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  14. # Part 2
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    Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation
    https://molecularautism.biomedcentral.com/articles/10.1186/s13229-017-0125-0

    "Experimental work in animals indicates that this link is mediated by maternal immune activation (MIA) involving an interplay between cytokine-associated inflammatory events [7,8,9], oxidative stress [10], and other pathophysiological processes such as hypoferremia [11] and zinc deficiency [12]. The centrality of inflammatory cytokine production to MIA phenotypes is supported by the findings that blocking the actions of pro-inflammatory cytokines such as IL-1β, IL-6, or IL-17a in the pregnant maternal host is capable of preventing the long-term brain and behavioral consequences of prenatal immune activation [7, 9, 13, 14]. Similarly, over-expression of the anti-inflammatory cytokine IL-10 prevents the emergence of multiple behavioral and pharmacological abnormalities typically seen after prenatal immune challenge [8]."

    "Another epidemiologically valid developmental risk factor for later psychiatric disease is developmental vitamin D (DVD) deficiency [22]. Besides its role in schizophrenia etiology, there is a growing body of evidence linking vitamin D deficiency with autism [23]. Birth cohort studies have provided evidence that maternal vitamin D deficiency is associated with a range of later autism-related outcomes including impaired language development [24] and cognitive development in offspring [25]. Most recently, we have shown that low levels of vitamin D at birth are associated with increased incidence of autism in children [26]. Low vitamin D would also appear to be prevalent in children diagnosed with autism [27].

    In addition to its classical role in calcium and bone homeostasis, vitamin D has major immunomodulatory roles associated with inflammation [28]. For instance, vitamin D interferes with pro-inflammatory transcription factors and signaling pathways, regulates the expression of pro-inflammatory enzymes, and modulates cytokine gene expression, protein production, and signaling. More specifically, vitamin D inhibits the production of pro-inflammatory cytokines such as IL-6 or TNF-alpha in monocytes via the inhibition of p38 MAP kinase [29], and it downregulates the expression of IL-6 mRNA [30]. Vitamin D also reduces the release of IL-1β in stimulated peripheral blood mononuclear cells (PBMC) [31]. Developmental vitamin D deficiency has further been shown to induce persistent alterations in immune function, by increasing central immune organ size and inducing a pro-inflammatory lymphocyte phenotype [32].

    Therefore, inflammatory factors produced early in brain development either directly, by inducing MIA, or indirectly, by the maternal absence of a potent anti-inflammatory factor such as vitamin D may, represent a convergent pathway towards developmental brain abnormalities and psychiatric conditions later in life. Initial evidence for this hypothesis stems from previous observations showing prenatal poly(I:C)-induced MIA, and developmental vitamin D deficiency in rodents produce an overlapping spectrum of long-term behavioral abnormalities and early molecular changes in the fetal brains [33,34,35,36,37]."

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  15. # Part 3
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    Paradoxical Effects of a Cytokine and an Anticonvulsant Strengthen the Epigenetic/Enzymatic Avenue for Autism Research
    https://www.frontiersin.org/articles/10.3389/fncel.2020.585395/full
    (This article discusses "valproate and IL-17a", however I'm more interested in Vitamin D and IL-17a.)

    "Maternal exposure to the valproate short-chain fatty acid (SCFA) during pregnancy is known to possibly induce autism spectrum disorders (ASDs) in the offspring. By contrast, case studies have evidenced positive outcomes of this anticonvulsant drug in children with severe autism. Interestingly, the same paradoxical pattern applies to the IL-17a inflammatory cytokine involved in the immune system regulation. Such joint apparent contradictions can be overcome by pointing out that, among their respective signaling pathways, valproate and IL-17a share an enhancement of the “type A monoamine oxidase” (MAOA) enzyme carried by the X chromosome. In the Guided Propagation (GP) model of autism, such enzymatic rise triggers a prenatal epigenetic downregulation, which, without possible X-inactivation, and when coinciding with genetic expression variants of other brain enzymes, results in the delayed onset of autistic symptoms."

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