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Showing posts with label Nrf2. Show all posts
Showing posts with label Nrf2. Show all posts

Wednesday, 16 October 2019

DMF for Mitochondrial Dysfunction in Autism and Friedreich's Ataxia?


Yet more money was just donated to autism research. In 2017 the CEO of Broadcom gave $20 million to MIT and now he has given $20 million to Harvard, where he did his MBA.




Time to boost Homer's mitochondria?


I think philanthropists from the fast-moving IT sector should demand rather more from the slow-moving world of autism research.  I also think common sense is often more lacking than money.

The US Government has also just announced $1.8 billion for autism research.

Donald Trump authorized a five-year extension of the Autism Collaboration, Accountability, Research, Education and Support (CARES) Act. The 2014 act dedicated funds to children with autism spectrum disorder, but the new version includes adults.  Children with autism do indeed grow up to become adults with autism. 
Today we look at further applications of DMF, which is a cheap chemical also sold as a very expensive drug.

We learnt from Dr Kelley, from Johns Hopkins, that most regressive autism features mitochondrial dysfunction. Mitochondria within cells produce ATP (fuel) via a complex multi-step process called OXPHOS. If you lack any of the required enzyme complexes for OXPHOS, that part of your body will suffer a power shortage/outage.  Another potential problem is just too few mitochondria.

The treatment for mitochondrial disease is mainly to avoid further damage, using antioxidants.  If you know which enzyme complex is lacking, you might try and target that.

We saw a long time ago in this blog that PGC-1α is the master regulator of mitochondrial biogenesis and as such this would be a target for people with mitochondrial dysfunction.

Among other interactions, PGC-1α is affected by something called PPAR-γ (Peroxisome proliferator-activated receptor gamma), also known as the glitazone receptor.

There are many cheap drugs that target PPAR-γ, because this is also one way to treat type 2 diabetes.  We saw that Glitazone drugs have been successfully trialed in autism.

Today we look at another way to activate PGC-1α and stimulate the production of more mitochondria and increase the necessary enzyme complexes for OXPHOS.

Many people with autism in the US are diagnosed by their MAPS/DAN doctor as lacking Complex 1.

DMF has two principal effects. It affects NRF2 and HCAR2.

Many supplements sold online are supposed to activate NRF2, but may well lack potency.

Activating NRF2 turns on your antioxidant defences and so is good for people with autism, diabetes, COPD and many other conditions, but is bad for someone with cancer.

We will see later how, somewhat bizarrely, at high doses DMF reverses function and causes cell death via oxidative stress, making it a potent potential cancer therapy.  Cancer cells are highly vulnerable to oxidative stress.

In this blog we are focusing on low doses of DMF, that are NRF2 activating.

In the chart below the NFE2L2 gene encodes the transcription factor NRF2. We want the antioxidant genes turned on.

We then get another benefit because NRF2 expression also regulates NRF1 expression.

The transcription factor NRF1 is another regulator of mitochondrial biogenesis with involvements in mitochondrial replication  and transcription of mitochondrial DNA.

We then get a third benefit from DMF via activating HCAR2, this time we increase Complex I expression.  In the OXPOS multistep process to make fuel/ATP the bottleneck is usually Complex I, so Complex I is often referred to as being “rate limiting”. Complex I is the most important deficiency to fix.









Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans



The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.

                                                                                                                    
DMF for Friedreich's ataxia

Friedreich's ataxia (FA) is a genetic disease caused by mutations in the FXN gene on the chromosome 9, which produces a protein called frataxin. It causes difficulty walking, a loss of sensation in the arms and legs and impaired speech that worsens over time. Symptoms typically start between 5 and 15 years of age. Most young people diagnosed with FA require a mobility aid such as a wheelchair by their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes.

Frataxin is required for the normal functioning of mitochondria, the energy-producing factories of cells. Mutations in the FXN gene lead to a decrease in the production of frataxin and the consequent disruption in mitochondrial function.
No effective treatment exists. FA shortens life expectancy due to heart disease, but some people can live into their sixties.


Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.


High Dose DMF to treat some cancer

Some readers may recall that the protein DJ-1 is encoded by the Parkinson’s gene PARK7 and that DMF has already been proposed as a therapy for Parkinson’s disease. 

At high doses of DMF the protein DJ-1 loses its stabilization function and ends up effectively blocking NRF2. Put simply, high dose DMF turns off NRF2, making it a cancer cell killer.

Dimethyl Fumarate Controls the NRF2/DJ-1Axis in Cancer Cells: Therapeutic Applications

The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in noncancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (<25 a="" activation="" antioxidant="" cytoprotective="" dmf="" has="" mol="" nrf2="" of="" pathway.="" role="" span="" the="" through=""> At higher concentrations, however (>25 μmol/L), DMF caused oxidative stress and subsequently cytotoxicity in several cancer cell lines. High DMF concentration decreases nuclear translocation of NRF2 and production of its downstream targets. The pro-oxidative and cytotoxic effects of high concentration of DMF were abrogated by overexpression of NRF2 in OVCAR3 cells, suggesting that DMF cytotoxicity is dependent of NRF2 depletion. High concentrations of DMF decreased the expression of DJ-1, a NRF2 protein stabilizer. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antioxidant defenses, and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed in vivo in two mice models of colon cancer. Taken together, these findings implicate the effect of DJ-1 on NRF2 in cancer development and identify DMF as a dose-dependent modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants.







Proposed mechanism of DMF-induced cancer cell death. Low concentrations of DMF can induce the NRF2 antioxidant pathway, allowing NRF2 nuclear translocation and binding to the antioxidant response elements leading to the transcription of antioxidant and detoxifying enzymes, thereby promoting cell survival. High concentrations of DMF, however, induce disruption of the NRF2 stabilizer DJ-1, which in turn impairs NRF2 induction and transcriptional activities in response to DMF, induces ROS generation, GSH depletion, and hence, facilitates cancer cell death. Cys, cysteine; 2SC, succination of cysteine residues.


Conclusion

This post did not cost $20 million, it is yours for free.

It looks pretty obvious that people with autism caused by, or associated with, mitochondrial dysfunction might potentially benefit from DMF.

People with Friedreich’s Ataxia do not currently have any treatment options. Low dose DMF is free of side effects, the high doses used to treat Psoriasis and Multiple Sclerosis often cause troubling GI side effects.

DMF seems to have very many potential therapeutic applications, limited only by the cost of the pharmaceutical version of this cheap chemical. Fortunately the "autism dose" is tiny.


Related Earlier Posts







Thursday, 13 August 2015

Sulforaphane Research in Japan – Cognitive Deficits and Schizophrenia






I recently received some papers about Sulforaphane from a reader of this blog and also comments from people with schizophrenia looking for therapies

Sulforaphane is already a valued part of my autism Polypill for Monty, aged 12 with ASD.  Just google "Sulforaphane Epiphany", or use the site index tab on this blog.

Sulforaphane has been patented for various purposes by John Hopkins, however even after twenty years they have not brought to market a standardized product.  The Sulforaphane (SFN) used in their research is made in the lab and then has to be kept deep frozen.

Sulforaphane is not a stable substance and so you are wasting your money buying most supplements.  Even most types of broccoli powder, which should be a precursor to Sulforaphane (SFN), were shown to be ineffective in independent lab tests.

In Japan it seems they are far more advanced, they already have a standardized SFN-glucosinolate tablets, no mention of the need to keep them frozen.


Japanese Sulforaphane (SFN) research

What is interesting in the Japanese research into cognitive deficits in schizophrenia is that SFN shows has both prophylactic and therapeutic effects.  This suggests that even if there is no immediate benefit from taking SFN in some people, there may be some long term preventative/protective benefits.




Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

  


After giving written informed consent, participants received 3 tablets of SFN prepared by Kagome Co., Ltd. (Nagoya, Japan), totaling 30 mg of SFN-glucosinolate per day, for 8 weeks. It is known that SFN-glucosinolate is metabolized to SFN in the body.

Objective

Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti-oxidant and anti-inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia.

Methods

We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN-glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8.

Results

A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants.

Conclusion

This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia.

   
I do get comments from people with schizophrenia on this blog and there is clearly a big overlap between some schizophrenia and some autism.  More and more therapies are being shown to be effective in both; it seems to be the SFN is one of those therapies.

What would be nice would be a commercially available, standardized product that genuinely could be relied upon to produce SFN in the body.  The Japanese appear to have already mastered this.  No need for Johns Hopkins patents.

For the time being, I am happily using my Supersprouts broccoli sprout powder which does indeed seem to produce SFN.  If one day they stop making it, I have already found that you would just need to add heat stable myrosinase (in the form of daikon radish root) to otherwise ineffective broccoli sprout powder.

For those of you who tried other products claiming to contain/produce SFN, and found them ineffective, you do not know whether the child does not respond to SFN, or your product produced none.

  
Conclusion

SFN really does look worth a try, or perhaps even a second try for those who tried one of those “false” supplements.  Price does not always indicate quality.


One day I hope that the Japanese firm Kagome, chooses to sell its SFN tablets worldwide and not just their tomato ketchups and juices.  




Thursday, 29 January 2015

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:-



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.




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.