Autism & Schizophrenia - Histamine degradation via HMT (requiring SAMe) and via DAO

Today’s post is a little complicated because it links together various issues ranging from food allergies to severe headaches, brain inflammation to arthritis.

The common link here is histamine, which has been covered at length on this blog.  You may recall that the H1 histamine receptor is the one associated with hay fever, H2 is expressed in the intestines and is involved in regulating acidity levels, H3 is mainly found in the central nervous system (CNS).

The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis.

Here is the full paper, for those interested in mast cells:-

Histamine H4 Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells 

In addition to all these receptors, histamine causes an increase in the pro-inflammatory cytokine IL-6.  IL-6 is elevated in autism and many other inflammatory conditions ranging from arthritis to traumatic brain injury (TBI). 

One of interesting interventions in this post is SAMe (S-Adenosyl methionine )and its precursor L-methionine.  We will see why a deficit of SAMe causes a problem when the body tries to degrade/deactivate histamine.

We will also see in a later post that the level of SAMe in the body modulates the release anti-inflammatory cytokines like IL-10 and IL-35.  Here is one link, for now.

IL-35 Is a Novel Responsive Anti-inflammatory Cytokine — A New System of Categorizing Anti-inflammatory Cytokines

5. Higher expression of IL-35 could be induced by higher hypomethylation status in tissues

Previous reports showed that epigenetic mechanisms, including methylation and demethylation, control T helper cell differentiation and cytokine generation [41]. As we discussed in our recent review [42], the ratio of cellular methylation donor S-adenosylmethionine (SAM) levels over S-adenosylhomocysteine (SAH) levels is an important metabolic indicator of cellular methylation status [43], [44]. A higher SAM/SAH ratio suggests a higher methylation status than normal (hypermethylation) whereas a lower SAM/SAH ratio indicates a lower methylation status than normal (hypomethylation).  A previous report showed that feeding rats with SAM, a methyl donor, inhibits the expression of TGF-βR1 and TGF-βR2 [45], suggesting that intracellular global methylation status regulates anti-inflammatory cytokine signaling.  … Cont/

Interestingly, I found that for decades SAMe  has been a mainstream drug therapy used in Italy to treat arthritis.

    

Histamine degradation

In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase (HMT) and oxidative deamination via diamine oxidase (DAO).

HMT and uses S-adenosyl-L-methionine (SAMe) as the methyl donor.  If SAMe is lacking HMT cannot degrade histamine.

In the brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation.  It is disputed whether diamine oxidase is found in the central nervous system.  Some sources say it is not, but other studies specifically measure DAO levels in the brain, finding them elevated in schizophrenia.

A common genetic polymorphism affects the activity levels of HMT in red blood cells.  This can be tested for.

People with low levels of DAO will not be able to degrade histamine in their body nor, it appears to me, in the brain.

People with low levels of SAMe will not be able to degrade histamine as they should, that has crossed the BBB (blood brain barrier).  Those same low levels of SAMe will have raised the inflammatory cytokines and reduced the anti-inflammatory cytokines.

Methionine metabolism

I am always very wary when I see charts like the one below.  Often they are used to justify all kinds of strange ideas.  So the following methionine description is just a cut and paste from Wikipedia.

If anything goes wrong in this metabolism, you might indeed expect strange things to happen.  The ratio of SAMe/SAH is measurable  and tends to be markedly low in people with ASD.  This why DAN doctors use vitamin B12 injections, other B vitamins and other exotic sounding “supplements”.

Metabolic biomarkers of increased oxidative stress and impairedmethylation capacity in children with autism

Methionine is an essential amino acid that must be provided by dietary intake of proteins or methyl donors (choline and betaine found in beef, eggs and some vegetables). Assimilated methionine is transformed in S-adenosyl methionine (SAM) which is a key metabolite for polyamine synthesis, e.g. spermidine, and cysteine formation (see the figure on the right). Methionine breakdown products are also recycled back into methionine by homocysteine remethylation and methylthioadenosine (MTA) conversion (see the figure on the right). Vitamins B₆, B₁₂, folic acid and choline are essential cofactors for these reactions. SAM is the substrate for methylation reactions catalyzed by DNA, RNA and protein methyltransferases.

The products of these reactions are methylated DNA, RNA or proteins and S-adenosylhomocysteine (SAH). SAH has a negative feedback on its own production as an inhibitor of methyltransferase enzymes. Therefore SAM:SAH ratio directly regulates cellular methylation, whereas levels of vitamins B₆, B₁₂, folic acid and choline regulates indirectly the methylation state via the methionine metabolism cycle.^[44][45] A near ubiquitous feature of cancer is a maladaption of the methionine metabolic pathway in response to genetic or environmental conditions resulting in depletion of SAM and/or SAM-dependent methylation. Whether it is deficiency in enzymes such as methylthioadenosine phosphorylase, methionine-dependency of cancer cells, high levels of polyamine synthesis in cancer, or induction of cancer through a diet deprived of extrinsic methyl donors or enhanced in methylation inhibitors, tumor formation is strongly correlated with a decrease in levels of SAM in mice, rats and humans.^[46][47]

Low levels of SAMe do seem to cause problems in some people and it is straightforward to increase it.  You can either give extra SAMe, which is expensive, or L-methionine, which is cheap.

Interestingly, L-methionine is used at Johns Hopkins to treat autism and apparently is particularly effective at increasing speech.

If L-methionine was effective it could be for reasons including:-

·        cellular methylation was dysfunction

·        histamine in the brain had been elevated

·        the level of pro/anti-inflammatory cytokines had been out of balance 

Here are some examples of the use of SAMe (methionine)

S-Adenosyl-l-methionine(SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule

In its native form, SAMe is labile and degrades rapidly. However, several patents for stable salts of SAMe have been granted. Among them, toluenedisulfonate and 1,4-butanedisulfonate forms have been chosen for pharmaceutical development, and as a result, preclinical and clinical studies have been performed. Numerous studies over the past 2 decades have shown that SAMe is effective in the treatment of depression (4–6), osteoarthritis (7–8), and liver disease (9–11). Moreover, SAMe has a very favorable side-effect profile, comparable with that of placebos. Thus, SAMe offers considerable advantages as an alternative to standard medications.

Depression

Clinical studies performed as early as 1973 indicated that SAMe had antidepressant effects (38). Over the next 2 decades, the efficacy of SAMe in treating depressive disorders was confirmed in > 40 clinical trials. Several review articles that summarize these studies were published in 1988 (4), 1989 (5), 1994 (6), and 2000 (12). In a meta-analysis, Bressa (6) reviewed 25 controlled trials including a total of 791 patients. The outcome of this analysis showed that SAMe had a significantly greater response rate than did placebo and was comparable to tricyclic antidepressants. Brown et al (12) summarized the literature on the use of SAMe in depressive disorders up to the time of publication in 2000; they reported that SAMe had been studied in 16 open, uncontrolled trials (660 patients); 13 randomized, double-blind, placebo-controlled trials (537 patients); and 19 controlled trials comparing SAMe with other antidepressants (1134 patients). Significant antidepressant effects were observed in all 16 open trials. In 18 controlled trials, SAMe was as effective as was impramine, chlorimipramine, nomifensine, and minaprine. An important observation from these studies is that SAMe had far fewer side effects than did standard medications.

Neurologic disorders

Several studies indicate that a CNS methyl group deficiency may play a role in the etiology of Alzheimer disease (AD). Reduced SAMe concentrations were found in CSF (34) and in several different brain regions (51) of patients with AD. In addition, reduced phosphatidylcholine concentrations were found in postmortem brain tissue from AD patients (52), and significant changes in brain phospholipids that are dependent on SAMe metabolism were detected in vivo with 31p magnetic resonance spectroscopy in the early stages of AD (53). Deficiencies of folate and vitamin B-12 are common in the elderly (39, 40) and can lead to decreased CNS SAMe concentrations. Several studies indicate that elevated blood homocysteine concentrations, considered to be a marker for folate deficiency, vitamin B-12 deficiency, and impaired methylation, may be a risk factor for AD (54–56). It is therefore important to note that preliminary studies using either SAMe (57) or alternative methyl group donors [such as betaine (58) or folate and vitamin B-12 (59, 60)] can improve measures of cognitive function. These treatments may be able to restore methyl group metabolism and normalize blood homocysteine concentrations. Reduced SAMe concentrations in CSF were also reported in patients with subacute combined degeneration of the spinal cord resulting from folate or vitamin B-12 deficiency (39) and in children with inborn errors of the methyl-transfer pathway who had demyelination (61). In these cases, treatment with methyl-group donors such as SAMe, methyltetrahydrofolate, betaine, and methionine was associated with remyelination and a clinical response (61).

Lancet. 1991 Dec 21-28;338(8782-8783):1550-4.

Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway.

We have shown that demyelination is associated with cerebrospinal-fluid S-adenosylmethionine deficiency and that restoration of S-adenosylmethionine is associated with remyelination.

Remyelination is also interesting.  Damage to the critical myelin layer has been suggested to occur with mitochondrial disease.  Most young people with autism show signs of mitochondrial disease (based on post mortem samples) but not old people with autism.

Demyelination is the loss of the myelin sheath insulating the nerves, and is the hallmark of some neurodegenerative autoimmune diseases, including multiple sclerosis.

Liver disease

The potential benefit of SAMe in treating liver disease stems from several important aspects of SAMe metabolism. In mammals, as much as 80% of the methionine in the liver is converted into SAMe (23). Hepatic glutathione, which is dependent on methionine and SAMe metabolism, is one of the principal antioxidants involved in hepatic detoxification. Studies have shown that abnormal SAMe synthesis is associated with chronic liver disease, regardless of its etiology. Early studies indicated that patients with liver disease are unable to metabolize methionine, resulting in elevated blood concentrations (67). Subsequent studies in patients with liver disease showed that the defect resulted from decreased activity of a liver-specific isoenzyme, MAT I/III; this defect effectively blocks the conversion of methionine to SAMe (68). Several well-designed experimental studies indicated that MAT I/III is regulated by cellular concentrations of both nitric oxide and glutathione. Thus, increased nitric oxide concentrations and decreased glutathione concentrations were shown to inhibit MAT I/III via mechanisms involving increased S-nitrosylation and free radical damage to the enzyme protein (69, 70). Experimental studies and clinical trials showed that parenteral and oral SAMe administration can increase glutathione concentrations in red blood cells (71) and in hepatic tissue (72, 73) and can effectively replenish depleted glutathione pools in patients with liver disease. The literature on the clinical potential of SAMe in the treatment of liver disease (including cholestasis, hepatitis, and cirrhosis) has been the subject of several review articles (9–11, 74, 75).

  

Osteoarthritis

The potential benefit of SAMe in treating osteoarthritis was discovered when patients enrolled in clinical trials of SAMe for depression reported marked improvement in their osteoarthritis symptoms (76). Nine clinical trials in Europe (77) and 1 in the United States (7) with a total of > 22 000 participants have confirmed the therapeutic activity of SAMe against osteoarthritis. SAMe has effects similar to those of the nonsteroidal anti-inflammatory drugs, but its tolerability is higher.

  

Back to DAO

I think we have established the one mechanism for histamine degradation has useful pointers for those interested in autism; now it is time to look at the other one.

D-amino acid oxidase (DAAO; also DAO, OXDA, DAMOX) is an enzyme. Its function is to oxidize D-amino acids to the corresponding imino acids, producing ammonia and hydrogen peroxide.

Recently, mammalian D-amino acid oxidase has been connected to the brain D-serine metabolism and to the regulation of the glutamatergic neurotransmission. In a postmortem study, the activity of DAAO was found to be two-fold higher in schizophrenia.
DAAO is a candidate susceptibility gene and may play a role in the glutamatergic mechanisms of schizophrenia.  Risperidone and sodium benzoate are inhibitors of DAAO.

Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia.

Abstract

We review the role of two susceptibility genes; G72 and DAAO in glutamate neurotransmission and the aetiology of schizophrenia. The gene product of G72 is an activator of DAAO (D-amino acid oxidase), which is the only enzyme oxidising D-serine. D-serine is an important co-agonist for the NMDA glutamate receptor and plays a role in neuronal migration and cell death. Studies of D-serine revealed lower serum levels in schizophrenia patients as compared to healthy controls. Furthermore, administration of D-serine as add-on medication reduced the symptoms of schizophrenia. The underlying mechanism of the involvement of G72 and DAAO in schizophrenia is probably based on decreased levels of D-serine and decreased NMDA receptor functioning in patients. The involvement of this gene is therefore indirect support for the glutamate dysfunction hypothesis in schizophrenia.

Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia.

Abstract

D-serine has been shown to be a major endogenous coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptors. Accumulating evidence suggests that NMDA receptor hypofunction contributes to the symptomatic features of schizophrenia. d-serine degradation can be mediated by the enzyme d-amino acid oxidase (DAAO). An involvement of d-serine in the etiology of schizophrenia is suggested by the association of the disease with single nucleotide polymorphisms in the DAAO and its regulator (G72). The present study aims to further elucidate whether the DAAO activity is altered in schizophrenia. Specific DAAO activity was measured in postmortem cortex samples of bipolar disorder, major depression and schizophrenia patients, and normal controls (n=15 per group). The mean DAAO activity was two-fold higher in the schizophrenia patients group compared with the control group. There was no correlation between DAAO activity and age, age of onset, duration of disease, pH of the tissue and tissue storage time and no effect of gender, cause of death and history of alcohol and substance abuse. The group of neuroleptics users (including bipolar disorder patients) showed significantly higher D-amino acid oxidase activity. However, there was no correlation between the cumulative life-time antipsychotic usage and D-amino acid oxidase levels. In mice, either chronic exposure to antipsychotics or acute administration of the NMDA receptor blocker MK-801, did not change d-amino acid oxidase activity. These findings provide indications that D-serine availability in the nervous system may be altered in schizophrenia because of increased D-amino acid degradation by DAAO.

Association of the DAO and DAOA gene polymorphisms with autism spectrum disorders in boys in Korea: a preliminary study.

Abstract

We examined the association of autism spectrum disorders (ASD) with polymorphisms in the DAO and DAOA genes. The sample comprised 57 children with ASD, 47 complete trios, and 83 healthy controls in Korea. Although the transmission disequilibrium test showed no association, a population-based case-control study showed significant associations between the rs3918346 and rs3825251 SNPs of the DAO gene and boys with ASD.

The neurobiology of D-amino acid oxidase (DAO) and its involvement inschizophrenia

DAO as a target for the treatment of schizophrenia

As noted above, both D-serine and D-alanine show some effectiveness as add-on treatment in schizophrenia, in particular for the amelioration of negative and possibly cognitive symptoms. There are also comparable approaches and data regarding glycine augmentation. Since enzymes represent viable drug targets, DAO is receiving attention as a potential alternative therapeutic means to enhance NMDAR function in schizophrenia. The fact that DAO activity appears to be increased in schizophrenia provides another reason to propose that its inhibition might be beneficial. It is also intriguing that the original antipsychotic, chlorpromazine, was shown to be a DAO inhibitor in vitro over fifty years ago,² confirmed recently and also found to apply to risperidone; whether these observations are relevant clinically are unknown, but they do provide a precedent for the potential therapeutic benefits of selective DAO inhibitors.

To date there have been no clinical trials of DAO inhibitors in schizophrenia, but several preclinical studies which, although findings remain preliminary, show that inactivation of DAO, either in ddY/DAO- mice or after pharmacological DAO inhibition in rats and mice, produces behavioural, electrophysiological and neurochemical effects suggestive of a pro-cognitive profile (Table 4). The Table includes the three DAO inhibitors for which functional data have been published thus far: AS057278,¹⁰ CBIO,^201,203 and Compound 8.²⁰² Several other small molecule DAO inhibitors have been patented but their behavioural effects have yet to be reported.^62,204

Conclusions and future directions

DAO, as the enzyme which degrades the NMDAR co-agonist D-serine, has the potential to modulate NMDAR function and to contribute to NMDAR hypofunction in schizophrenia. Both genetic and biochemical data support an involvement of DAO in the disorder, however the processes involved are difficult to interpret. This is due to the many questions left unanswered concerning the neurobiology of DAO and its physiological roles. Notably there is still much that is unclear as to its localization and activity within the brain, and its spatial and functional relationships with its substrates. In addition, D-serine and thus DAO may have roles other than NMDAR modulation, whilst other DAO substrates, especially D-alanine, may also be relevant to any involvement of DAO in schizophrenia. Similarly, although recent preclinical data hint at potential therapeutic benefits of DAO inhibitors, extensive further study is required to establish their efficacy, tolerability, and mechanism.

Many drugs act as DAO inhibitors to a limited degree, even though this is not their intended mode of action.

We have heard about Sodium benzoate and Risperidone, but there are many others.

Evaluation of theinhibitory effect of various drugs / active ingredients on the activity ofhuman diamine oxidase in vitro

           

Results

Chloroquine and clavulanic acid showed greatest inhibition potential on diamine oxidase (> 90%). Cimetidine and verapamil showed inhibition of about 50%.

Moderate influence on DAO was caused by isoniazid and metamizole, acetyl cysteine and amitriptyline

(>20%). Diclofenac, metoclopramide, suxamethonium and thiamine have very low inhibition potential (<20%).  Interestingly cyclophosphamide and ibuprofen displayed no effect on DAO.

Conclusion

Since even levels of about 30% inhibition may be critical, most of the observed substances, can be designated as DAO inhibitors. Other drug components than active ingredients did not affect DAO activity or its interaction with a specific drug.

Note that cimetidine (Tagamet), a histamine H2-receptor antagonist drug used in promoting the healing of active stomach and duodenal ulcers.  Verapamil is in my “Polypill” and is a potent mast cell stabilizer.   Is this link back to histamine a coincidence?  I think not.

Antihistamine May Decrease Schizophrenia Symptoms

Histamine H₂ Receptor Antagonists in Schizophrenia

Histamine and schizophrenia

Conclusion

The experts are yet to conclude much, but it does seem that SAMe levels are low in autism and brain DAO levels are high schizophrenia (adult onset autism).  In Korea, DAO was shown to be dysfunction in autism.

It seems that, by coincidence, Risperidone happens to be an inhibitor of DAO and this indeed accounts for some its side effects.  Risperidone has actions at several 5-HT (serotonin) receptor subtypes, Dopamine receptors, Alpha α1/2 adrenergic receptors and even H1 histamine receptors.  Risperidone seems to be drug of last resort.

There are no selective DAO inhibitors currently in use.

We did see that two old drugs Tagamet and Verapamil are potent DAO inhibitors in vitro.

This suggest to me that while sodium benzoate has been trialed “successfully” in schizophrenia, perhaps it would be worth comparing the effect of Tagamet and Verapamil.

When it comes to autism/schizophrenia, it would seem that in some people one or more of the following might be helpful:-

·        Sodium benzoate, or cinnamon a precursor
·        Tagamet the H2 antihistamine, already used by some people with mastocytosis

 ·        Verapamil, the calcium channel blocker that actually does much more

·        SAMe, or L-methionine a precursor.
 

Cinnamon and DJ-1 as a general Anti-Oxidant and perhaps Much More

I am shortly going to introduce a complicated sounding substance called DAAO (D-amino acid oxidase) to this blog.  DAAO seems to be important in some types of autism, most schizophrenia and bipolar.  This will take us back to Cinnamon and Sodium Benzoate that were discussed in earlier posts.

The connection to UCLA will come at the end of the post.  UCLA is home to the Lovaas Model of Applied Behavior Analysis (ABA), but this post is all about biochemistry.  Before the internet existed,  I used to use one of their libraries for some research.

Prior to DAAO, I just want to make the case again for the medical effects of Cinnamon in typical people.

Accepted medical wisdom is that there is currently no proof of any benefit from Cinnamon.  Cinnamon does have known and quantifiable anti-oxidant properties in vitro, but research has shown that what happens in vivo can be quite different.  The whole idea of the ORAC scale, which measures the relative power of antioxidants, has lost credibility and is no longer used by “serious science”.

In an earlier post we saw a study that showed in both people with type 2 diabetes and the control group, cholesterol and fasting glucose levels were reduced by cinnamon.  This implied an increase in insulin sensitivity (and reduction in insulin resistance).

I also found numerous people posting their before and after cinnamon blood test results, confirming this benefit.

However, there were other studies showing no effect on fasting glucose levels and insulin sensitivity, which looked odd.

Why does this matter?

I am trying to establish that one effect of cinnamon comes from being metabolized to sodium benzoate (“benzoate”).  Benzoate then upregulates production of a protein called DJ-1.  DJ-1 was discovered by researchers looking at Parkinson’s Disease.  DJ-1 is known to have anti-oxidant properties, both directly and in support of a clever substance called Nrf-2.  Nrf-2 is released by the body when it senses an oxidative attack and its job is to switch on the body’s anti-oxidant genes.  But Nrf-2 cannot do this without some help from DJ-1; if DJ-1 is lacking, the key genes stay switched off.

One well established effect of Sulforaphane (from broccoli) is that it activates the production of Nrf-2.  This seems to account for the anti-oxidant and chemo-protective effects.

One reader of this blog confirmed the increase in insulin sensitivity produced by Sulforaphane from broccoli.  For the doctors among you, 2.5ml of broccoli powder had 25% of the effect of 600 mg of Alpha lipoic acid (ALA).  600mg of ALA reduced the insulin requirement by 25%.

In some people they lack DJ-1.  This raises their risk of Parkinson’s Disease, likely also COPD and I suggested possibly Autism and any other condition associated with oxidative stress.

Then I came across a trial of sodium benzoate in schizophrenia:-

Sodium benzoate (Cinnamon) trialed for Schizophrenia (Adult-onset Autism)

We know that a characteristic of anti-oxidants, in varying degrees, is that they also reduce cholesterol and increase insulin sensitivity.

So we should expect that eating cinnamon would quickly cause sodium benzoate to be produced, causing an up-regulation in DJ-1.  The first effect should be a reduction in oxidative stress and then an increase in insulin sensitivity and a reduction in fasting glucose levels. Reduced oxidative stress will affect the lipid metabolism and lower cholesterol.

Some clinical trials last for 12 weeks, some even longer, but many are shorter.  In the following cinnamon trial, blood parameters were measured at week 0, week 6 and week 12.

They happened to test people who were overweight (so at higher risk of developing type 2 diabetes), but I think it would apply to everyone.

Antioxidant Effects of a Cinnamon Extract in People with Impaired Fasting Glucose That Are Overweight or Obese

  

They choose to measure several markers of oxidative stress, as well as fasting glucose and plasma insulin levels.

  

Therefore, this work was designed to investigate in people that are overweight or obese, with impaired fasting glycemia, the effects of a twelve week supplementation of the dried aqueous extract of cinnamon on oxidative stress markers including plasma malondialdehyde (MDA) levels, plasma thiol (SH) group oxidation, FRAP (Ferric Reducing Activity Plasma), antioxidant erythrocyte enzyme activities as superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GPx), and the possible correlation with fasting glucose and plasma insulin levels.

The interesting thing is that while by week 6 the oxidative 3 of the 4 markers of oxidative stress were changing, glucose levels had not.

So if the trial had ended at week 6 we would conclude that cinnamon does not increase insulin sensitivity.

But all changed by the end of week 12, fasting glucose had gone down and fasting insulin had gone up.

This study did not measure cholesterol.  If it had done, we would have expected triglicerides down, LDL (bad) cholesterol down and HDL cholesterol increased.

Since cinnamon is a non standardized natural product, this might explain why in some studies the beneficial effects take longer to become established.

Cinnamon as a DAAO inhibitor

In the next post we will look at D-amino acid oxidase (known as DAAO and also DAO, OXDA, DAMOX).

DAAO is interesting because it is known to be elevated by a factor of two in the brains of people with schizophrenia.  The underlying gene is a probable susceptibility gene for schizophrenia and also bipolar disorder.  DAAO gene polymorphisms were found in boys with autism spectrum disorders in in Korea.

Risperidone and sodium benzoate are the well-known inhibitors of DAAO, but there are others.  Risperidone is an anti-psychotic drug approved for use in schizophrenia, bipolar and autism.  The usually claimed modes of action are that as a dopamine antagonist it possesses anti-serotonergic, anti-adrenergic and anti-histaminergic properties.

This will bring us back to the potential of cinnamon in autism/schizophrenia and whether the mode of action is antioxidant, DAAO inhibitor or both.  If it is just as an antioxidant, does it confer any additional benefit over NAC + Sulforaphane ?  I am interested to find out whether Nrf-2 will be more effective, with the increase in DJ-1; if you were deficient in DJ-1 this should be the case.

DJ-1 produced by cinnamon is one antioxidant, but there clearly are others since no DJ-1 would be produced by cinnamon in vitro.

DAAO inhibitors may produce allergic reactions in people with histamine intolerance.

This might explain one of the warnings for Risperidone:-

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

  

Patent Search

I did a quick patent search to see if anybody else thinks that sodium benzoate might be useful in autism and related conditions.  Here is a small sample of the many patents.  In some cases benzoate is used to increase the effectiveness of other ingredients and others it is the claimed active ingredient.

In the UCLA patent below they combine a D-amino Acid Oxidase Inhibitor (DAAOI), a NMDA enhancer and a Glycine transporter inhibitor.

Modulation of in vivo glutamine and glycine levels in the treatment of autism

Abstract

A method of treating autism in a patient. The method includes administering to the patient an effective amount of a glutamine level reducing agent, a glycine level reducing agent or combinations thereof. Representative glutamine level reducing agents are phenylbutyrate and phenylacetate, and a representative glycine level reducing agent is sodium benzoate. Optionally, an N-methyl-D-aspartate receptor antagonist can also be administered to the patient. A representative N-methyl-D-aspartate receptor antagonist is dextromethorphan.

Combination treatment of nmda(n-methyl-d-aspartate)-enhancer, glycine transporter inhibitor, d-amino acid oxidase inhibitor(daaoi) for neuropsychiatric disorders

Abstract

The invention provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder or as at risk for a neuropsychiatric disorder administering to a D-amino Acid Oxidase Inhibitor (DAAOI); in conjunction with an NMDA enhancer and/or a glycine transporter inhibitor.

An orally administrable mixture comprising donepezil hydrochloride, polyvinylpyrrolidone, sorbitol solution, citric acid and sodium citrate, sodium benzoate and methylparaben, propylene glycol, sodiummetabisulfite; treating Parkinson's disease, cognitive impairments, dementia

Abstract

The invention describes novel methods for treating and preventing dementia caused by vascular diseases; dementia associated with Parkinson's disease; Lewy Body dementia; AIDS dementia; mild cognitive impairments; age-associated memory impairments; cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepsy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders; cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. The invention also describes novel methods for treating and preventing delirium, Tourette's syndrome, myasthenia gravis, attention deficit hyperactivity disorder, autism, dyslexia, mania, depression, apathy, and myopathy associated with diabetes by administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. The invention also describes novel methods for delaying the onset of Alzheimer's disease, for enhancing cognitive functions, for treating and preventing sleep apnea, for alleviating tobacco withdrawal syndrome, and for treating the dysfunctions of Huntington's Disease by administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. A preferred cholinesterase inhibitor for use in the methods of the invention is donepezil hydrochloride or ARICEPT®. The invention also provides orally administrable liquid dosage formulations comprising cholinesterase inhibitor compounds, such as ARICEPT®.

  

Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical 

Applicant

Los Angeles Biomedical Research Institute At Harbor - Ucla Medical Center

  

Abstract

Methods and compositions are provided for treating neuropsychiatric disorders such as schizophrenia, depression, attention deficit disorder, mild cognitive impairment, dementia, and bipolar disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder (e.g., schizophrenia, depression, attention deficit disorder, mild cognitive impairment, dementia bipolar disorder, etc.) or as at risk for a neuropsychiatric disorder a benzoic acid, benzoic acid salt, and/or benzoic acid derivative, and/or a sorbic acid, sorbic acid salt, and/or sorbic acid derivative, in combination with a neuropharmacological agent (e.g., an antipsychotic, an antidepressant, medications for attention deficit and hyperactivity disorder, cognitive impairment, or dementia, etc.) where the benzoic acid, benzoic acid salt, or benzoic acid derivative, and/or a sorbic acid, sorbic acid salt, and/or sorbic acid derivative, is in an amount sufficient to increase the efficacy of the neuropharmacological agent.

[0062] Without being bound to a particular theory, it is believed that the DAAOI enhances the levels of both D-serine and D-alanine which are agonists of NMDA receptor and have been shown by the inventor to be beneficial for patients with schizophrenia and other disorders. It can help a wide variety of patients with cognitive impairment and other mental or behavioral symptoms. The combination therapies boost the NMDA and/or neuropharmaceutical activity and benefit subjects more than single agent treatments (e.g., antipsychotic drug, antidepressant, anxiolytic, mood stabilizer, psychotropic medication for attention deficit and hyperactivity disorder, drug for dementia, and the like).

[0063] Accordingly, in certain preferred embodiments, "combination" therapies are contemplated, where the subjects are administered a benzoic acid, a benzoic acid salt, a benzoic acid ester, or another benzoic acid derivative, and/or a sorbic acid, a sorbic acid salt, sorbic acid ester, or another sorbic acid derivative, in conjunction with a neuropharmaceutical (e.g., a therapeutic agent selected from the group consisting of an antipsychotic, an antidepressant, a phsychostimulant, a mood stabilizer, an anxiolytic, an Alzheimer's disease therapeutic, and/or other psychotropic for the treatment of a neuropsychiatric disorder).

[0072] In certain embodiments the combination formulation for the treatment of schizophrenia, bipolar disorder, and the like comprises a combination of benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and an antipsychotic drug. Suitable antipsychotic drugs include, but are not limited to the antipsychotic drugs described above.

[0073] In certain embodiments the combination formulation for the treatment of schizophrenia, bipolar disorder, and the like comprises a combination of depression, panic disorder, social phobial, GAD, and the like comprises a combination of benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and an antidepressant and/or mood stabilizer. Suitable antidepressants and mood stabilizers include, but are not limited to the antidepressants and mood stabilizers described above. [0074] In certain embodiments the combination formulation for the treatment of

ADD and/or ADHD, and the like comprises a combination of benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and an agent for the treatment of ADD and/or ADHD. Suitable agents for the treatment of ADD and/or ADHD include, but are not limited to the agents for the treatment of ADD and/or ADHD described above.

[0076] Typically, in various embodiments, the benzoic acid, benzoic acid salt, or derivative thereof (e.g., a benzoate), and/or sorbic acid, a sorbic acid salt, or a derivative thereof, is present in an amount sufficient to enhance therapeutic efficacy of the neuropharmaceutical rather than as a preservative, and/or melting point lowering agent, and/or stabilizer, and/or a lubricant, and/or a stabilizer, etc. In effect, the benzoic acid, benzoic acid salt, or derivative thereof, and/or sorbic acid, sorbic acid salt, or a derivative thereof, is an active agent. Thus, in various embodiments the benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative, is not substantially present as an acid addition salt of the neuropharmaceutical (or at least the majority of the benzoic or sorbic acid or derivative thereof) is not present as an acid salt addition salt of the neuropharmaceutical.. Similarly, in certain embodiments the benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative, (or at least the majority of the benzoic or sorbic acid or derivative thereof) is not present as a co-crystal of the neuropharmaceutical.

The various treatment strategies described herein can be applied to most if not all of them including, for example, learning disorder, attention deficit and hyperactivity disorder, schizophrenia, bipolar disorder, depression, Alzheimer's Disease, autism, benign forgetfulness, close head injury, dementia, mild cognitive impairment, ataxia, spinocerebellar degeneration, Parkinson's disease, obsessive compulsive disorder (OCD), phobia, social phobia, generalized anxiety disorder (GAD), panic disorder, substance abuse, and substance dependence. In addition to their benefits for human subjects, the treatments described herein can be used in veterinary applications (e.g., to canines, felines, equines, bovines, porcines, etc.) with treatment of household pets (e.g., canine, feline) being of considerable interest. In addition, the combination treatments described herein can improve cognition in animal models of learning and model of schizophrenia, depression, anxiety, and the like. [0080] In certain embodiments the treatment methods of the invention entail administering to a subject in need thereof (e.g., a patient diagnosed as having or at risk for a neuropsychiatric disorder) one or more a pharmaceutical compositions containing a therapeutically effective amount(s) of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI). Where combinations of two or all three of these agents are utilized they can be administered separately (simultaneously or sequentially), in a single "combination" formulation, or in simultaneously or sequentially a combination formulation comprising two agents and a second formulation comprising a single agent. [0081] The effective doses of the active agent(s) (of an NMDA (N-methyl-D- aspartate) -Enhancer, and/or Glycine Transporter Inhibitor, and/or D-amino Acid Oxidase Inhibitor (DAAOI)) can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. In various embodiments, for human patients, the effective unit dose of typical compounds include: DAAOI (e.g., benzoate, range of 50 mg-150 grams), NMDA enhancers (D-serine, range of 50 mg-50 grams; D-alanine, range 1-150 grams), glycine transporter inhibitor (for example: sarcone, range 50 mg-50 grams); including DAAOI+NMDA enhancer, DAAOI+glycine transporter inhibitor, NMDA enhancers +glycine transporter inhibitor or three classes of compound together. [0082] In various embodiments, then, effective doses of each of the active agent(s) ranges from 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, or 500 mg, 300 g, 20Og, 150 g, 100 g, 50 g, 25 g, 1Og, 5 g, or 1 g depending of factors including, but not limited to 150 g. In certain embodiments the compounds and compositions of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, it is estimated that a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. The amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound(s) employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Conclusion

[0117] In the most accepted animal model of schizophrenia, which tests the sensory gating, we found that combination treatment improve the startle habituation and PPI significantly more than the individual agent alone. . The effect of benzoate was close to combination treatment in habituation.

Conclusion

I have convinced myself of the merits of Cinnamon  (the Cinnamomum verum variety, not the “cassia” variety) for typical people. 

I have been testing it myself for a month and then I will measure the effect.

For people with neurological conditions, it does seem that some clever people at UCLA, and elsewhere, seem to think there is potential.  Their suggested mode of action is not the same as mine, they think DAAOI and I was thinking DJ-1.

Kvx.y-channelASD, Navx.y-channelASD, Cavx.y-channelASD and channelASD-channelepsy phenotype

Perugia is an ancient university city in Central Italy.  If you live in North America you may recall it in connection with a high profile murder trial.  You probably would not expect it to produce clever insights into autism.

In fact, Italy is a rare country outside the US that has leading autism researchers.

Today’s post is to draw your attention to very insightful paper about some of the ion channel dysfunctions in autism.  This paper is about those concerning potassium.

The nice touch was their suggestion that we could classify some people with ASD, some with epilepsy and some people with both, by their ion channel dysfunction.

So if like some people, you have a dysfunction of the L-type calcium channel Ca_v1.2, you would become:-

Ca_v1.2-channelASD

Somebody with Dravet Syndrome (epilepsy) with ASD, would become:-

Na_v1.1channelASD-channelepsy

The underlying assumption by the authors is that a type of single ion channel dysfunction, generally triggered by the underlying gene being dysfunctional, and may account for many cases of “autism”.

This is interesting, but I tend to believe that multiple ion channel dysfunctions (channelopathies) are present and in some cases the underlying gene itself is not the problem.  Ion channels and transporters are proteins and each type is indeed expressed by its gene, but the degree to which that gene is expressed is also determined by many other factors.  So over/under expression of, for example, an ion transporter might well not correspond to any genetic error.

We have already seen that in addition to ion channels there are also various types of ion transporter/exchangers. Two very important ones in autism are NKCC1 and KCC2, they determine the chloride concentration within brain cells.  Too many NKCC1 transporters and/or too few KCC2 transporters mean that the level of chloride is too high.  This then causes an ongoing dysfunction of the neurotransmitter GABA.  So in this case the route problem is not a dysfunction of the transporter rather there are just too many of them.

NKCC1 is also expressed in many regions of the brain during early development, but not in adulthood.^[5] This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA and glycine from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as NKCC1 transporters are predominantly active, internal chloride concentrations in neurons is raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, outward driving force for this ions increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential for chloride, given by the Nernst equation. Later in development expression of NKCC1 is reduced, while expression of a KCC2 K-Cl cotransporter increased, thus bringing internal chloride concentration in neurons down to adult values

So we could call this common autism phenotype NKCC1 over expression.

Then the type of autism I am interested in would become:-

Ca_v1.2-channelASD with NKCC1 over expression

This assumes that no potassium or sodium channels are affected.

Back to Potassium Ion Channelopathies


Here is the paper from Perugia:-

Update on the implication of potassium channels in autism: K+ channel autism spectrum disorder

 .. a mounting body of evidence indicates that ion channel dysfunction may well enhance autism susceptibility also when other contributing alleles are coinherited.

Direct and indirect defects in K+  channels have been implicated in ASDs pathogenesis, likely altering crucial neural network processes in several brain areas including the cerebellum, a structure that emerges as critically involved in determining the core features of ASDs. Abnormal synaptic transmission and dendritic spine pathology play crucial roles in ASDs. Notably, the activity of many thousands synapses is controlled by a single astrocyte. Thus, aberrant astrocyte dependent synaptic functions and CNS development, induced by defective ion channels, represent an interesting causative hypotheses for ASDs

Kv4.2 – ChannelASD

The presence of Kv4.2 channels in hippocampus appears fundamental, mostly at early developmental stage when neuronal activity drives synaptic maturation and network refinement. At hippocampal synapses, the gradual reduction in GluN2B/GluN2A subunit ratio, during post-natal development, is correlated with AMPA expression and synaptic maturation. Ablation of Kv4.2 in mice abolished this phenomenon and resulted in a higher number of silent synapses in the adulthood.  Given the importance of Kv4.2 in brain development and functioning, defects of this channel have been unsurprisingly correlated with a broad spectrum of neurological disorders. Gene deletion in mice leads to increased susceptibility to convulsant stimuli  and truncating mutation of Kv4.2 in humans leads to temporal lobe epilepsy

Kv4.2 channel expression may also participate in establishing the conditions for the development of ASDs, given that Kv4.2 mRNA can bind to the fragile X mental retardation protein (FMRP), which is associated to fragile X syndrome (FXS), the most common monogenic cause of autism and inherited intellectual retardation

Kv7.3 – ChannelASD

KCNQ3 and KCNQ2 gene mutations segregate with various forms of Kv7.3/Kv7.2-channelepsies

  

KCa1.1 – ChannelASD

The calcium-activated K+ 230 (KCa) channels are highly conserved across species, and widely expressed in the human brain.

KCa1.1 loss-of function mutations likely alter pyramidal neurons excitability and result in impairment of neural networks in hippocampus, an area implicated in cognition, mood disorders and ASD. However, these mutations may also affect cerebellar PNs excitability, development, learning and memory processes, suggesting that KCa1.1 channels dysfunction may impact these crucial neurophysiological processes occurring within the cerebellum and result in the psychomotor development and cognition features of ASD

Recently, KCa1.1 channels have been implicated in ASD on a different ground, since their activity is regulated by FMRP, whose mutation produces FXS.

Notably, FMRP can also bind to Na+-activated K+ channel Slack  (i.e. KCa4.1), and thus regulate its activity.

Interestingly, intellectual disability only occurs in those patients who carry mutations in Slack channels, further suggesting a role for this channel type in both epilepsy and cognitive disorders

Inwardly-rectifying K+ channels

Inwardly-rectifying K+ (Kir) channels take their name from the greater conductance at potentials negative to EK, while at more positive values the outward flow of K+  ions is variably inhibited by cytoplasmic polyamines and Mg2+, by means of affinity dependent blockade

Kir2.1 – ChannelASD

Loss-of-function mutations in the KCNJ2 gene are responsible for the rare Andersen-Tawil syndrome a  condition characterized by long QT-syndrome, cardiac arrhythmia, skeletal abnormalities, periodic paralysis, mood disorders and seizures

genetically-induced Kir2.1 defects, beside causing SQT3 syndrome, may possibly result in functional impairment of neural networks where this channel type  resides and contribute to ASDs pathogenesis

I do think Kir2.1 is interesting because it seems to be related hypokalemic sensory overload, which if a key feature of many people’s ASD and indeed ADHD.

Interestingly, a reader with the above Andersen-Tawil syndrome and relatives with ASD, told me how many of them smoke and feel much better by doing so.

Direct block of inward rectifier potassium channels by nicotine.

Abstract

Nicotine has been shown to depolarize membrane potential and to lengthen action potential duration in isolated cardiac preparations. To investigate whether this is a consequence of direct interaction of nicotine with inward rectifier K(+) channels which are a key determinant of membrane potentials, we assessed the effects of nicotine on two cloned human inward rectifier K(+) channels, Kir2.1 and Kir2.2, expressed in Xenopus oocytes and the native inward rectifier K(+) current I(K1) in canine ventricular myocytes. Nicotine suppressed Kir2.1-expressed currents at varying potentials negative to -20 mV, with more pronounced effects on the outward current between -70 and -20 mV relative to the inward current at hyperpolarized potentials (below -70 mV). The inhibition was concentration dependent. For the outward currents recorded at -50 mV, the IC50 was 165 +/- 18 microM. Similar effects of nicotine were observed for Kir2.2. A more potent effect was seen with I(K1) in canine myocytes. Significant blockade ( approximately 60%) was found at a concentration as low as 0.5 microM and the IC50 was 4.0 +/- 0.4 microM. The effects in both oocytes and myocytes were partially reversible upon washout of nicotine. Antagonists of nicotinic receptors (mecamylamine, 100 microM), muscarinic receptors (atropine, 1 microM), and beta-adrenergic receptors (propranolol, 1 microM) all failed to restore the depressed currents, suggesting that nicotine acted directly on Kir channels, independent of catecholamine release. This property of nicotine may explain its membrane-depolarizing and action potential duration-prolonging effects in cardiac cells and may contribute in part to its ability to promote propensity for cardiac arrhythmias

Some people with ASD find nicotine patches helpful.  This could help for various reasons, but if they are Kir2.1 – ChannelASD, then likely it is blocking the misbehaving potassium channels.