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.

Autism, Power Outages and the Starving Brain?

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. 

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. 

Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer's subjects

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.

A Pilot Study of Oxaloacetate in Subjects With Treated PD

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

Trial of Oxaloacetate in Alzheimer's Disease (TOAD) (TOAD)

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

Oxaloacetate Supplementation for Emotional PMS (OAA4PMS)

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.

http://tnipc.org/invasive-plants/plant-details/?id=48

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: 

Studies on Anti-diabetic Effect of Sodium Oxalcacetate

There are more recent studies on the Euonymus alatus plant:

Euonymus alatus: A Review on Its Phytochemistry and Antidiabetic Activity

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. 

Alleviating effects of active fraction of Euonymus alatus abundant in flavonoids on diabetic mice.

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888119/

“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. 

https://www.ncbi.nlm.nih.gov/books/NBK285549/

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.