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:-
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.
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 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
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)
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.
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.
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.
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.
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.
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.
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.