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Showing posts with label mitochondria. Show all posts
Showing posts with label mitochondria. 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







Wednesday, 3 October 2018

Ketones and Autism Part 6 - Capric Acid (C10) for Mitochondrial Disease, in Particular Complex 1, plus more on Metformin



Capric Acid (C10) is so named because it smells like a goat (Goat in Latin = Caper)
Photographer: Armin Kübelbeck, CC-BY-SA, Wikimedia Commons

Rather than Goaty acid, C10 is called Capric acid, or indeed Decanoic acid (after its 10 carbon atoms). Today’s post is indirectly again about ketones, because if you eat a Ketogenic Diet (KD) you are likely to consume a fair amount of Capric acid (C10).
I have written a lot in this blog about mitochondria, even though I do not think my son has mitochondrial dysfunction. Clearly many people with autism do have a lack of one or more of the critical mitochondrial enzyme complexes that allow glucose to be converted to ATP (usable energy), by the clever process OXPHOS (Oxidative phosphorylation).

The “rate limiting” enzyme is usually Complex 1, meaning that is the one it is most important not to be short of.
Another favourite, but obscure, subject of this blog is PPAR gamma.

Peroxisome proliferator-activated receptors (PPARs) are a group of proteins that function as transcription factors regulating the expression of certain genes. Transcription factors are particularly important because they trigger numerous effects.
PPAR gamma plays a key role in fat storage and glucose metabolism, but has other functions. 

Activation of PPAR-gamma by Capric acid (C10) has been shown to increase the number of mitochondria, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase. 
So, if you have autism and impaired mitochondrial function, C10 may well give a benefit because it can increase the peak power available to your brain.


The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

Capric Acid (C10) as a PPARγ agonist

As shown in the above study the mechanism by which C10 benefits the mitochondria is via PPARγ agonism.

Here is another study confirming that C10 is indeed a PPARγ agonist.


Background: Mechanism of action of medium chain fatty acid remains unknown.

Results: Our results show that decanoic acid (C10) binds and activates PPARγ.

Conclusion: Decanoic acid acts as a modulator of PPARγ and reduces blood glucose levels with no weight gain.

Significance: This study could lead to design of better type 2 diabetes drugs.


Other PPARγ agonists
PPARγ agonists have been covered previously in this blog and we know that glitazones, a class of drugs for diabetes, do improve some types of autism. Glitazones are PPARγ agonists.

Metformin, a very widely used drug for type 2 diabetes, works differently to Glitazones, but I did suggest a while back it should help some types of autism. Last year it was indeed found to be beneficial in Fragile X.


 "Basically, it's something like a wonder drug," Sonenberg said.
The study suggests that metformin might also be used to treat other autism spectrum disorders, said Ilse Gantois, a research associate in Sonenberg's lab at McGill.
"We mostly looked at the autistic form of behaviour in the Fragile X mouse model," explained Gantois, who is co-lead author with McGill researchers Arkady Khoutorsky and Jelena Popic. "We want to start testing other mouse models to see if the drug could also have benefits for other types of autism."

Metformin is very cheap and has been used in humans for 60 years. It is another example of re-purposing a drug from Grandpa’s medicine cabinet to treat Grandson’s autism. 

Metformin has been trialled to combat obesity in idiopathic autism caused by antipsychotics. It did help with weight gain, but no comments were made about behavioural improvements, but then those studied were on antipsychotic drugs, which might mask such effects. 
Glitazone-type drugs appear more problematic than Metformin.

There are natural PPAR gamma agonists and they are often used to lower cholesterol, lower blood sugar and improve insulin sensitivity.
Sytrinol, a product containing flavanols tangeretin and nobiletin does indeed have a positive effect on some people’s autism, but for most people (but not all) the effect is lost after a few days.

Our doctor reader Maja, did suggest combining it with a PPARα agonist to see if the effect might be maintained.
This combination has indeed been researched for type 2 diabetes.               

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.


There actually is another natural substance that is an agonist of both PPARγ and PPARα, Berberine, the alkaloid long used in Chinese medicine.
In the research it is suggested that BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK”, which is not what you would want. But this may not be correct.

People who like supplements might want to follow up on Berberine.
Berberine is used by many people with diabetes and a few with autism, for all kinds of reasons, from mercury to GI problems.

Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.


Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.


                                                                                                                                     

Sources of Capric Acid (C10)
Goat milk is a good source of capric acid.
Capric acid is 8-10% of coconut oil and 4% of palm kernel oil

Capric acid is a large component (about 40%) of the less expensive MCT oil supplements.


1.2. Fatty acid composition in goat milk fat Average goat milk fat differs in contents of its fatty acids significantly from average cow milk fat, being much higher in butyric (C4:0), caproic (C6:0), caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0), palmitic (C16:0), linoleic (C18:2), but lower in stearic (C18:0), and oleic acid (C18:1) (Table 1). Three of the medium chain fatty acids (caproic, caprylic, and capric) have actually been named after goats, due to their predominance in goat milk. They contribute to 15% of the total fatty acid content in goat milk in comparison to 5% in cow milk (Haenlein, 1993). The presence of relatively high levels of medium chain fatty acids (C6:0 to C10:0) in goat milk fat could be responsible for its inferior flavour (Skjevdal, 1979). 

             
Conclusion
If someone responds well to coconut oil or cheaper MCT oil the reason may have more to do with PPAR gamma and improved mitochondrial function than anything to do with ketones and what they do.
Cheaper MCT oils are mainly a mixture of C8 and C10. To maximize the production of the ketone BHB you really want just C8, but if what you really need is a PPAR gamma agonist, to perk up your mitochondria, it is the C10 you need.
You may indeed benefit from both ketones and agonizing PPAR gamma, in which case you either follow the Ketogenic Diet, or supplement BHB, C8 and C10.
I think this explains why some people with autism reportedly respond well to teaspoon-sized doses of cheaper MCT oil or small amounts of coconut oil.
If you have Complex 1 mitochondrial dysfunction then a dose of Capric acid (C10) is likely to help.
Berberine may, or may not be, as effective as C10. I doubt we will ever know. I think C10 is the better option. 
I wonder when the Canadian researchers will publish their results showing whether Metformin is beneficial beyond Fragile X syndrome. They do not really know why it helps, but that is a repeating theme in medicine.  It is a cheap safe drug, so it would be a pity to waste time finding out if it could be repurposed for some autism.



Friday, 29 June 2018

Oxaloacetate and Pepping up Bioenergetic Fluxes in Autism and other Neurological Diseases



BHI as a dynamic measure of the response of the body to stress
In this scheme, healthy subjects have a high BHI with a high bioenergetic reserve capacity, high ATP-linked respiration (AL) and low proton leak (PL). The population of mitochondria is maintained by regenerative biogenesis. During normal metabolism, a sub-healthy mitochondrial population, still capable of meeting the energetic demand of the cell, accumulates functional defects, which can be repaired or turned over by mitophagy. Chronic metabolic stress induces damage in the mitochondrial respiratory machinery by progressively decreasing mitochondrial function and this manifests as low ATP-linked respiration, low reserve capacity and high non-mitochondrial (e.g. ROS generation) respiration. These bioenergetically inefficient damaged mitochondria exhibit increased proton leak and require higher levels of ATP for maintaining organelle integrity, which increases the basal oxygen consumption. In addition, chronic metabolic stress also promotes mitochondrial superoxide generation leading to increased oxidative stress, which can amplify mitochondrial damage, the population of unhealthy mitochondria and basal cellular energy requirements. The persistence of unhealthy mitochondria damages the mtDNA, which impairs the integrity of the biogenesis programme, leading to a progressive deterioration in bioenergetic function, which we propose can be identified by changes in different parameters of the bioenergetics profile and decreasing BHI.

Source:  The Bioenergetic Health Index: a new concept in mitochondrial translational research


Bioenergetic is today’s new buzz word; it is again all about getting maximum power output (ATP) from your mitochondria, which we looked at from a different perspective in a recent post.


A simple lack of ATP inside the brain seems to be a feature of many kinds of neurological problem. 
Oxaloacetate (OA or OAA) is another interesting potential treatment for a wide range of neurological disorders from Alzheimer’s and ALS to Huntington’s and Parkinson’s. There are no effective treatments for any of these conditions and little has changed in decades.
OAA, at high doses, and in animal studies, does have some very interesting effects, but they are perhaps too wide ranging, because some may be helpful and others not. OAA is interesting but no panacea.
OAA is sold as a supplement in low doses. It changes so many things, I think it is not surprising that some people find it beneficial, whether it is for Bipolar, ADHD or something else.
I think at higher doses, where there is a measurable impact above and beyond the OAA you have naturally in your blood, there might be some benefit as a treatment for mitochondrial disease. That would mean most regressive autism and some Childhood Disintegrative Disorder (CDD).
So we can consider OAA as another potential therapy for bioenergetic dysfunction. We have come across many potential therapies already in this blog.
Here is a schematic summary of what OAA does.



OAA effects and inter-effect relationships. OAA, a bioenergetic intermediate, affects bioenergetic flux. This produces a number of molecular changes. CREB phosphorylation and CREB activity increase, which in turn promotes the expression of PGC1 family member genes. AMPK and p38 MAP phosphorylation increase, and these activated kinases enhance PGC1α co-activator function. PGC1-induced co-activation of the NRF1 transcription factor stimulates COX4I1 production, while PGC1-induced co-activation of the ERRα transcription factor stimulates VEGF gene expression (61). OAA-induced flux changes also stimulate the pro-growth insulin signaling pathway and reduce inflammation. The pro-growth effects of increased insulin pathway signaling and increased VEGF, in conjunction with a more favorable bioenergetic status and less inflammation, cooperatively stimulate hippocampal neurogenesis.

You may recall from earlier posts that PGC-1α is the master regulator of mitochondrial biogenesis. 
The PGC-1α protein also appears to play a role in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.
The PGC-1 α protein interacts with the nuclear receptor PPARγ. PPARγ has been covered extensively in this blog; agonists of PPARγ do seem to be therapeutic in some autism. Many drugs that are used to treat Type 2 diabetes work because they are PPARγ agonists.
It is not a surprise that Oxaloacetate (OAA) lowers your blood sugar. 



Bioenergetics and bioenergetic-related functions are altered in Alzheimer's disease (AD) subjects. These alterations represent therapeutic targets and provide an underlying rationale for modifying brain bioenergetics in AD-affected persons. Preclinical studies in cultured cells and mice found that administering oxaloacetate (OAA), a Krebs cycle and gluconeogenesis intermediate, enhanced bioenergetic fluxes and upregulated some brain bioenergetic infrastructure-related parameters. We therefore conducted a study to provide initial data on the tolerability and pharmacokinetics of OAA in AD subjects. Six AD subjects received OAA 100 mg capsules twice a day for one month. The intervention was well-tolerated. Blood level measurements following ingestion of a 100 mg OAA capsule showed modest increases in OAA concentrations, but pharmacokinetic analyses were complicated by relatively high amounts of endogenous OAA. We conclude that OAA 100 mg capsules twice per day for one month are safe in AD subjects but do not result in a consistent and clear increase in the OAA blood level, thus necessitating future clinical studies to evaluate higher doses.

In addition to being proposed for the treatment of AD and diabetes, recent preclinical research has also identified OAA as a potential therapeutic agent for stroke, traumatic brain injury, amyotrophic lateral sclerosis, and glioma [15], [16], [17], [18]. The clinical safety data we now report should prove relevant to efforts intending to translate results from these preclinical studies to the clinical arena. Our study also informs our attempts to develop OAA as a treatment for AD. Overall, we conclude that although OAA 100 mg capsules twice per day for one month are safe in AD subjects, because a consistent and clear increase in the OAA plasma level was not observed future clinical studies need to evaluate higher doses.

Experimental: Oxaloacetate (OAA) active capsule containing 100 mg OAA and 100 mg ascorbate, taken daily  

Experimental: Part 2 - Oxaloacetate (OAA)2 gram/day 
Participants take 2 grams of OAA per day for period of 4 weeks

Participants take 2 capsules Jubilance 100 mg Oxaloacetate/150 mg Ascorbic Acid blend per day

Oxaloacetate is an energy metabolite found in every cell of the human body. It holds a key place in the Krebs Cycle within the mitochondria, providing energy to the cells. It is also a critical early metabolite in gluconeogenesis, which provides glucose for the heart and brain during times of low glucose. It is critical to human metabolism, proper cellular function and it is central to energy production and use in the body.
Oxaloacetate may affect Emotional PMS through multiple mechanisms. During PMS, there is a large increase in glucose utilization in the cerebellum of the brain in women who are affected with emotional mood swings. Oxaloacetate supplementation has been shown to support proper glucose levels in the body. Having an excess of oxaloacetate allows gluconeogenesis take place upon demand, thereby fueling the brain, and perhaps meeting cerebellum glucose need.
In addition to oxaloacetate's ability to support proper glucose regulation, oxaloacetate affects two chemicals in the brain, GABA and glutamate. Altering the GABA/Glutamate ratio can affect mood. Oxaloacetate supplementation can reduce glutamate levels in the brain via a process called "Glutamate Scavenging". In addition, oxaloacetate supplementation was shown to increase GABA levels in animal models. By both lowering glutamate and increasing GABA, the GABA/Glutamate ratio is affected, which may also help women with Emotional PMS.
This study will investigate oxaloacetate's effect on Emotional PMS using patient completed surveys to measure depression, anxiety, perceived stress, and aggression, and statistically compare these results against placebo (rice flour) and baseline measurements.

An interesting old paper from 1968 was recently highlighted to me by a friend, it  shows that sodium oxaloacetate is particularly effective in treating type-1 diabetes.  In type-2 diabetes the effect range from none/minor in most  to a profound effect in a minority.
The meaning of “treating” was reducing blood sugar levels.
This study was the result of identifying the active substance in the plant euonymus alatus sieb, which has known blood sugar lowering effects.



Introduced from northeast Asia in the 1860s. Widely planted as an ornamental and for highway beautification due to its reliable and very showy fall foliage coloration. Numerous cultivars are available.
Other states where invasive: CT, DE, IN, KY, MA, MD, MO, NH, NJ, OH, PA, RI, VA, WI, WV. Federal or state listed as noxious weed, prohibited, invasive or banned: CT, MA.

Here is the interesting Japanese paper from 1968: 

There are more recent studies on the Euonymus alatus plant:

Euonymus alatus (E. alatus) is a medicinal plant used in some Asian countries for treating various conditions including cancer, hyperglycemia, and diabetic complications. This review outlines the phytochemistry and bioactivities of E. alatus related to antidiabetic actions. More than 100 chemical constituents have been isolated and identified from E. alatus, including flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids. Studies in vitro and in vivo have demonstrated the hypoglycemic activity of E. alatus extracts and its certain constituents. The hypoglycemic activity of E. alatus may be related to regulation of insulin signaling and insulin sensitivity, involving PPARγ and aldose reductase pathways. Further studies on E. alatus and its bioactive compounds may help to develop new agents for treating diabetes and diabetic complications.

A total of 26 flavonoids have been isolated and identified from E. alatus. The main structure types include flavonoid, flavanone, and flavonol. The aglycones of flavonoid glycosides isolated from E. alatus include quercetin, kaempferol, naringenin, aromadendrene, and dihydroquercetin. The flavonoids are mainly distributed in the leaves and wings of E. alatus
There is no mention of oxaloacetic acid.
The active components in protecting experimental diabetic nephropathy as mentioned above have also been suggested to be concentrated in ethyl acetate and n-butanol fractions [36, 40], though the nature of these compounds is still not identified. 
Euonymus alatus (E. alatus) has been used as a folk medicine for diabetes in China for more than one thousand years. In order to identify major active components, effects of different fractions of E. alatus on the plasma glucose levels were investigated in normal mice and alloxan-induced diabetic mice. Our results show that ethyl acetate fraction (EtOAc Fr.) displayed significant effects on reducing plasma glucose. In oral glucose tolerance, EtOAc Fr. at 17.2 mg/kg could significantly decrease the blood glucose of both normal mice and diabetic mice. After 4 weeks administration of the EtOAc Fr, when compared with the diabetic control, there were significant difference in biochemical parameters, such as glycosylated serum protein, superoxide dismutase and malondial dehyde, triglyceride, and total cholesterol, between alloxan-induced diabetic mice and the control group. Additional histopathological studies of pancreatic islets also showed EtOAc Fr. has beneficial effects on diabetic mice. Chemical analysis with three-dimensional HPLC demonstrated that the major components from EtOAc Fr were flavonoids and phenolic acids, which had anti-oxidative effects on scavenging DPPH-radical in vitro. All these experimental results suggest that EtOAc Fr. is an active fraction of E. alatus and can prevent the progress of diabetes. The mechanism of E. alatus for glucose control may be by stimulating insulin release, improving glucose uptake and improving oxidative-stress.

Oxaloacetic acid
You already have Oxaloacetic acid in your body, you make it.
Oxaloacetic acid (also known as oxalacetic acid) is a metabolic intermediate in many processes that occur in animals. It takes part in the gluconeogenesis, urea cycle, glyoxylate cycle, amino acid synthesis, fatty acid synthesis and citric acid cycle. Oxaloacetate is also a potent inhibitor of Complex II.

Conclusion
This post was prompted by our reader LatteGirl, who was asking about the supplement BenaGene and ketones. BenaGene contains 100mg of OAA and the company behind it is the sponsor of some the current OAA clinical trials.
The BenaGene supplement is sold by some companies that sell ketone products, but I do not really see big connection between OAA and ketones.   
If you can materially increase the plasma level of OAA, you really would expect numerous changes to occur.
Depending on what might be wrong with you, OAA might provide a net benefit, but it all looks very hit and miss. 
Treatment of all neurological disorders from ALS, Alzheimer’s to depression currently is remarkably hit and miss. Most serious disorders have only very partially effective treatments, but they do get FDA approval nonetheless.
The OAA research suggests its effect is from “altered bioenergetic fluxes”. You might be wondering what this actually means, since it sounds like pseudoscientific mumbo jumbo. What this really means is that for one reason or another there is a shortfall in energy (ATP) to power your cells.

“Perturbed bioenergetic function, and especially mitochondrial dysfunction, is observed in brains and peripheral tissues of subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI) (1,2), a clinical syndrome that frequently represents a transition between normal cognition and AD dementia (3). Neurons are vulnerable to mitochondrial dysfunction due to their high energy demands and dependence on respiration to generate ATP (4). Mitochondrial dysfunction may, therefore, drive or mediate various AD pathologies.”

Impaired energy (ATP) production can be caused by a deficiency in one of the mitochondrial enzyme complexes (often complex 1), but it could be caused by too few mitochondria (each cell needs many) or it could be caused by a lack of fuel (glucose or ketones), or oxygen.
Glucose crosses the blood brain barrier via a transporter called GLUT1.
GLUT1 deficiency leads to epilepsy, cognitive impairment and a small head (microcephaly). It can be treated by adopting the ketogenic diet, where ketones replace glucose as the fuel for your brain and body.
Oxygen freely crosses the blood brain barrier, but sometimes there is not enough of it. To increase the amount of oxygen that is carried in the blood, mountaineers and the military sometimes use the drug Diamox, which changes the pH of your blood, among other effects.
The brain's blood supply is via microvasculature/microvessels. This does seem to be impaired in autism, according to the research, resulting in unstable blood flow to the brain. 
Thyroid hormones are generally seen as regulating your basal/resting metabolic rate, so rather like your idle on your car, when you do not press the accelerator/gas pedal.  If the idle rate is too low your car will stall in traffic.
Thyroid hormone has many other effects and these are very important in the brain, particularly during development. A lack of the T3 hormone will lead to a physically different brain, whereas in adulthood it just causes impaired function which is reversible.
Thyroid hormones T3 and T4 can cross the blood brain barrier. The prohormone T4 is converted into the active hormone T3 within the brain. Some research suggests that T4 may have a direct role in the brain, rather than simply being a source of T3.

Thyroid receptors in the brain
TRα1 encompasses 70–80% of all TR expression in the adult vertebrate brain and TRα1 is present in nearly all neurons
It appears that windows in brain development may exist where T4 itself may act on TRα1.
Thyroid Hormone (TH) endocrinology in the CNS is tightly regulated at multiple tiers. Negative feedback loops in the hypothalamus and the pituitary control T3 and T4 output by the thyroid gland itself. Further, multiple phenomenon functions together to modulate the transport of circulating TH through the BBB, and multiple transporters act together to directly alter TH availability in the CNS itself. Additionally, conversion of intracellular T4 into T3 by deiodinase 2, inactivation of both T3 and T4 by deiodinase 3, and, the ability of different TR isoforms and different coregulators to respond directly to T4 versus T3 further regulate the CNS response to TH. 


The thyroid hormone receptor subtypes TRα and TRβ are expressed throughout the brain from early development, and mediate overlapping actions on gene expression. However there are also TR-subtype specific actions. Dio3 for example is induced by T3 specifically through TRα1. In vivo T3 regulates gene expression during development from fetal stages, and in adult animals. A large number of genes are under direct and indirect regulation by thyroid hormone. In neural cells T3 may control around 5% of all expressed genes, and as much as one third of them may be regulated directly at the transcriptional level. Thyroid hormone deficiency during fetal and postnatal development may cause retarded brain maturation, intellectual deficits and in some cases neurological impairment. Thyroid hormone deficiency to the brain during development is caused by iodine deficiency, congenital hypothyroidism, and maternal hypothyroidism and hypothyroxinemia. The syndromes of Resistance to Thyroid Hormones due to receptor mutations, especially TRα, cause variable affectation of brain function. Mutations in the monocarboxylate transporter 8 cause a severe retardation of development and neurological impairment, likely due to deficient T4 and T3 transport to the brain.   

Thyroid hormones are essential for brain maturation, and for brain function throughout life. In adults, thyroid diseases can lead to various clinical manifestations (1,2). For example, hypothyroidism causes lethargy, hyporeflexia and poor motor coordination. Subclinical hypothyroidism is often associated with memory impairment. Hypothyroidism is also associated to bipolar affective disorders, depression, or loss of cognitive functions, especially in the elderly (3). Hyperthyroidism causes anxiety, irritability, and hyperreflexia. Both, hypothyroidism or hyperthyroidism can lead to mood disorders, dementia, confusion, and personality changes. Most of these disorders are usually reversible with proper treatment, indicating that thyroid hormone alterations of adult onset do not leave permanent structural defects.
The actions of thyroid hormone during development are different, in the sense that they are required to perform certain actions during specific time windows. Thyroid hormone deficiency, even of short duration may lead to irreversible brain damage, the consequences of which depend not only on the severity, but also on the specific timing of onset and duration of the deficiency (4-8).
Hypothyroidism causes delayed and poor deposition of myelin

Pep up your Bioenergetic Fluxes
Within this blog we have encountered a wide range of methods that might help put correct a deficiency in power available to the brain.
·      Improve brain microvasculature function (Agmatine)

·      Ensure central basal metabolic rate is high enough (T3 hormone)

·      Increase D2 (lower oxidative stress, kaempferol) if centrally hypothyroid

·      Increase number of mitochondria (activate PGC1alpha)

·      Ensure adequate mitochondrial enzyme complexes for OXPHOS

·      Ensure adequate glucose transport via GLUT1

While I still feel Bioenergetic Fluxes sounds like something very quack-like, it is the valid terminology and it does look important to many neurological conditions.
In Monty, aged 14 with ASD, Agmatine has worked wonders, in terms of being far more energetic. I assume the effect is via increasing eNOS (endothelial nitric oxide synthase) and this has improved blood supply. We saw that blood flow through microvasculature/microvessels is impaired in autism.  We also saw that in mouse model of Alzheimer’s, Agmatine has a similar positive effect; this also seems to apply in at least some humans with Alzheimer’s.  

Diabetes
We can certainly add Oxaloacetate to the long list of substances we have come across in this blog that may well be therapeutic in diabetes. In the case of Oxaloacetate, it is type-1 that seems to uniformly benefit, whereas in type-2 diabetes some benefit and some do not.
It is amazing that in type-1 diabetes, only insulin is routinely prescribed, when so many things can increase insulin sensitivity and reduce the severe complications of this type of diabetes.
In the case of type-2 diabetes, you can halt its progression and, for the really committed, we saw how you can reverse it.
If a common, life-threatening, condition like diabetes is not fully treated, no wonder nobody bothers to treat an amorphous condition like autism.