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.