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:-
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.
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.
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.
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®.
|
Applicant
|
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.
