Epilepsy has become one of the most common neurological disorders that affect more than 65 million people worldwide. What is troubling about epilepsy is the fact that ANYONE can develop epilepsy. There is no discrimination among males, females, races, ethnic backgrounds, and ages [1].
In the USA alone, there are currently close to 2.3 million adults and 450,000 children and adolescents living with epilepsy. An additional 150,000 people will be diagnosed with epilepsy each year. The annual financial burdens associated with the epilepsies in the USA is estimated to be $15.5 billion in direct medical expenses and lost or reduced earnings and productivity [2].
It is no coincidence that the prevalence of epilepsy has increased alongside with the exponential increase in prevalence of Metabolic Syndrome. Metabolic disturbances are now associated with epileptic seizures. It is estimated that 25% of patients with diabetes mellitus (DM) experience some form of epileptic seizure. Furthermore, diabetic patients who experience hyperglycemic ketoacidosis have been observed to have more frequent episodes of seizures [2].
Not surprisingly, Vitamin C, ascorbic acid, has been shown convincingly to reduce seizure susceptibility. What is the connection between Vitamin C, epilepsy and diabetes?
Diabetes & Epilepsy: The Glucose Connection
It is accepted that limited energy availability affects hippocampal neuronal viability during epileptic seizures [3]. The relationship between fluctuations of glucose levels, seizure susceptibility and excitotoxic cell death from epileptic seizures are complex. Excitotoxic cell death can be aggravated by energy failure, in addition to excessive glutamate release and cytosolic calcium release [4]. Many of the processes that mediate seizure-induced excitotoxic cell death are sensitive to energy availability.
In fact, the importance of glucose balance in epilepsy cannot be underestimated. Blood glucose levels in diabetic patients fluctuate greatly during the course of the day as a result of variations in insulin levels and other metabolic factors. It is believed that a threshold glucose concentration is required to support synaptic transmission [5].
Both hyper or hypoglycemic conditions have been demonstrated to exacerbate epileptic seizures [6]. More often than not, antiepileptic drugs are more effective when blood glucose is brought under control [7]. That is also why diabetes-related seizures were reduced in both Type I and Type II diabetic subjects when their glycemic status improved [8].
Abnormal glucose levels, whether too high or too low, can cause seizures. Glucose levels also affect excitotoxic cell death. Scientists bred two strains of mice to test the effect of glucose on seizure susceptibility and neuronal cell death. B6 mice were bred to be excitotoxin cell death resistant following drug-induced epileptic seizures; and FVB mice were bred to be susceptible to excitotoxin cell death following seizure episodes. What they found was quite revealing [9].
In both rodent models, the injection of glucose following drug-induced epileptic seizure offered significant protection against seizure-induced neuronal damage. FVB mice showed profound reductions in hippocampal neuronal damage following seizure episodes when these excitotoxin susceptible mice were administered glucose following administration of seizure-inducing drugs [9].
B6 mice that had normal blood glucose levels showed no sign of reduction in neurons after drug-induced seizures. Even though the B6 mice were bred to be excitotoxin cell death resistant, they could not escape significant seizure-induced cell loss when hypoglycemia was artificially induced via insulin manipulation. Similarly, diabetic hyperglycemic B6 mice also suffered massive loss of hippocampal neurons after drug-induced seizure episodes [9].
Why is the fluctuation of glucose levels so detrimental to the fate of neuronal cells?
Epilepsy, Glucose & Insulin: The Oxidative Stress Connection
Hyperglycemia is associated with enhanced plasma free radical concentration, in other words, uncontrolled oxidative stress. Increased oxidative stress under hyperglycemia can be caused by non-enzymatic glycation [10], auto-oxidation of glucose [11], and intracellular activation of polyol pathways [12].
What is the relevance of oxidative stress in glucose homeostasis?
The pancreas regulate glucose levels in the body by maintaining a tight balance between insulin and glucagon secretions. When blood glucose is low during sleep or food deprivation, glucagon is released from pancreatic α-cells to promote hepatic glycogenolysis and initiate hepatic or even renal gluconeogenesis to maintain adequate plasma glucose levels. When glucose levels are elevated after a meal for example, pancreatic β-cells will release insulin to facilitate the uptake of glucose by peripheral insulin-sensitive tissues like fat, and skeletal and cardiac muscles, reducing blood glucose levels [13].
How insulin stimulates the uptake of glucose in peripheral tissues may come as a surprise though.
Hydrogen Peroxide & Insulin Receptors
It has been known for a long time that insulin resistance is associated with increased lipid peroxidation [14]. In vitro experiments have shown that insulin increases the production of hydrogen peroxide, a reactive oxygen species [15].
Reactive oxygen species like hydrogen peroxide and superoxide anions are generally regarded as toxic byproducts of aerobic metabolism. When science first discovered that hydrogen peroxide facilitates insulin functions, it was regarded as a REDOX paradox [16].
More than four decades ago in the early 1970’s, insulin was found to stimulate the intracellular production of H2O2 in adipose tissues [17]. The addition of H2O2 to intact adipocytes was observed to stimulate the phosphorylation of the insulin receptor, resulting in the enhancement of glucose transportation in adipose tissue at 50% efficiency of insulin. The effective uptake of glucose was due to the fact that the stimulation of insulin receptor phosphorylation by H2O2 occurs more rapidly than the activation of the glucose transport system [18].
Thus hydrogen peroxide is actually an important ROS for enhancing early insulin receptor signalling in adipocytes. Yet uncontrolled oxidative stress have been found to impair insulin secretion in diabetics, resulting in glucose dysregulation [19]. Reduction in plasma antioxidants as a direct result of increased free radicals like hydrogen peroxide can damage the structure and activity of pancreatic β-cells, leading to impaired insulin secretion [19].
Diabetic patients have been demonstrated to have higher levels of ROS and lower levels of glutathione. Raising glutathione levels in those patients significantly improved glucose homeostasis [20]. In non-insulin dependent diabetics, plasma levels of oxidative stress is strongly associated with insulin activity [21].
If you believe that manipulating antioxidant levels can modulate insulin activities, you would also be in for a surprise.
Oxidative Stress, Antioxidants & the Brain
The key to how hydrogen peroxide regulates insulin signalling is dependent upon the concentration of the molecule. Whether H2O2 can exert a positive or NEGATIVE effect on insulin signal transduction depends on the amount of H2O2 present. ROS can either impair or enhance insulin signaling [22].
The brain utilizes the highest amount of oxygen compared with other organs of the body. It is therefore highly susceptible to increased oxidative stress. The brain also contains high amounts of polyunsaturated fatty acids that easily undergo lipid peroxidation, catalyzing the formation of dangerous hydroxyl radicals [23]. Uncontrolled oxidative stress in the brain can cause cellular damage and cell death via oxidation of biomolecules such as proteins, lipids and nucleotides. Protein oxidation can cause functional changes or deactivation of enzymes [24]. Lipid peroxidation can affect membrane structures that can alter membrane fluidity and membrane protein activities [25].
Oxidative stress is now widely accepted to play a critical role in the pathogenesis of numerous neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis [26], and epilepsy [27]. Metabolic dysfunctions are now associated with genetic epilepsy [28].
When challenged with excess oxidative stress, our bodies respond by increasing antioxidant defenses. The problem with this reaction is that insulin-induced H2O2 signalling would also be downregulated by increased intracellular antioxidants.
N-acetylcysteine (NAC) is an artificial molecule that mimics glutathione in the glutathione peroxidase reaction with hydrogen peroxide. NAC is actually three-orders of magnitude more effective in the enzymatic reactions with H2O2. A small increase in NAC levels above a threshold value could completely inhibit insulin-stimulated insulin receptor activation [29].
Mice bred to overexpress glutathione peroxidase (Gpx1) developed insulin resistance and associated conditions like hyperinsulinemia, hyperglycemia, obesity as well as a dramatic 70% reduction in insulin-stimulated phosphorylation of insulin receptors compared to wild type controls [30]. Whereas mice bred without Gpx1 were protected from high-fat diet-induced insulin resistance. Interestingly, these Gpx1 null mice given NAC became more insulin-resistant and had elevated levels of fasting blood glucose [31].
Obviously, using antioxidants to control insulin homeostasis presents unique challenges that may not be easy to resolve. One cannot help but question how Vitamin C, ascorbic acid would affect insulin, since most people consider vitamin C as an ‘antioxidant’. The real question is, is ascorbic acid truly just an antioxidant?
Insulin & Vitamin C, the Ultimate REDOX Balancer
Ascorbic acid is a unique molecule with an evolutionary history of over 3 billion years. Ascorbic acid has the ability to combine fast proton-electron transfers with high reactivity in enzymes that have been designed to use it. Yet ascorbic acid will remain relatively stable and unreactive until it is activated by those enzymes [32]. This remarkable attribute renders ascorbate to be the most efficient and effective reductant found in living systems, and it is for that reason most of the important biological processes in our bodies are dependent upon vitamin C, ascorbic acid.
For example, ascorbic acid is used specifically as an electron donor in the regulation of dopamine β-hydroxylase in the synthesis of the neurotransmitter dopamine [33]. During the conversion of dopamine to norepinephrine, ascorbic acid has been found to enhance norepinephrine synthesis from dopamine by neuronal cells .
One oxygen plus two electrons are required during the synthesis of norepinephrine from dopamine. Plasma membrane redox enzyme cytochrome b561 work exclusively with ascorbate and its one-electron oxidation product semidehydroasorbate to exchange electrons on the external and internal sides of the chromaffin granule (transmembrane electron transfer) during norepinephrine synthesis [34].
The only acceptor of electrons In chromaffin granules from cytochrome b561 is the ascorbate radical. That is why when other antioxidants like thiols were substituted, they failed to achieve similar stimulating effects [35]. In a similar way, ascorbic acid has a critical role in glucose homeostasis.
Ascorbic acid has the ability to regulate insulin secretion in the pancreas. In aged healthy and non-insulin dependent diabetic subjects, ascorbic acid has been shown to restore insulin action and improve insulin secretion [36].
Vitamin C, Glucose Homeostasis & Insulin: The mGPDH Connection
A clinical trial involving forty Type 2 diabetic patients who were given 0.5 g vitamin C twice daily for 4 months found chronic vitamin C administration versus placebo demonstrated significant declines in fasting plasma free radicals, insulin, LDL cholesterols and triglycerides levels. Chronic vitamin C supplementation decreased HbA1 levels; improved whole body glucose disposal and nonoxidative glucose metabolism while increasing plasma glutathione levels [37].
Vitamin C has the ability to stimulate both alpha and beta cells that produce glucagon and insulin respectively in pancreatic islets of guinea pigs, which like humans are unable to produce ascorbic acid [38]. In scorbutic guinea pigs, it was further demonstrated that the decreased insulin release was not due to insufficient insulin production, but was the effect of abnormal insulin secretion [39].
Mice bred without the ability to synthesize ascorbic acid, demonstrated impaired glucose tolerance with significantly lower levels of plasma insulin upon glucose challenges compared to wild-type mice. The gluconolactonase knock-out mice kept on a vitamin C deficient diet did not have obvious signs of scurvy, but they all exhibited worsened glucose tolerance and impaired insulin secretion after a glucose load [40].
The gluconolactonase gene that was deleted from mice in these experiments is called Senescence marker protein-30 (SMP30). In mammals including humans, the expression of this molecule declines with age in a sex-dependent manner. In mammals, SMP30 is a pleiotropic protein that acts to protect cells from apoptosis by enhancing plasma membrane Ca2+‐pump activity. In humans, SMP30 are found in the liver, kidneys, pancreas, and adrenal cortex [41]. Even though the SMP30 gene is no longer associated with ascorbic acid production in humans, loss of SMP30 function is now associated with metabolic diseases and non‐alcoholic fatty liver disease (NAFLD) [42].
How does ascorbic acid modulate insulin secretion in SMP30 knockout mice on the quantum level?
Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH)
mGPDH is a little known key enzyme in the glycerol phosphate (GP) NADH shuttle in pancreatic β-cells. This NADH shuttle system is essential for coupling glycolysis with the activation of mitochondrial energy metabolism to trigger glucose-induced insulin secretion. Therefore, mGPDH functions at the critical crossroads of glycolysis, oxidative phosphorylation and fatty acid metabolism, while controlling the rate of glucose-induced insulin secretion [43].
Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is now associated with the pathogenesis of polygenic disease and non-insulin dependent diabetes mellitus as mGPDH has significant functions in the glycerol phosphate shuttle that mediates the release of insulin from increased glucose [44]. Ascorbic acid is an essential cofactor for the activation of mGPDH [45]. That is the reason why vitamin C deficient SMP30 knockout mice showed glucose intolerance as well as lower insulin secretions. The defective shuttling of cytosolic NADH into mitochondria as a result of vitamin C deficiency could have contributed to impaired insulin secretion [43].
When glucose levels are not controlled by adequate insulin, hyperglycemia can potentially induce enhanced plasma free radical concentrations. Seizure generation has been linked to oxidative stress, which is the imbalance between antioxidants and oxidants in the body. Impairment of endogenous antioxidant elements against oxidative stress has been demonstrated to be involved in seizure generation. Metabolic and redox disruption have been demonstrated to be both cause and consequence of epileptic seizures [46].
The article “Deuterium, REDOX & Epilepsy – The Microbiome Connection” [47] discussed how oxidative stress can alter gut microbiota composition to have an indirect effect on epileptic seizure thresholds. The fact that prevalence for both metabolic diseases like Type 2 diabetes and epilepsy have been steadily increasing is probably a good indicator for elevated oxidative stress levels in modern humans.
The ubiquitous presence of man made electromagnetic radiation may be one of the major contributing factors to increased oxidative stress.
Electromagnetic Radiation (EMR), Oxidative Stress & Vitamin C
The fact that adults who show higher plasma vitamin C levels exhibited lower weight & BMI; better indicators of metabolic health including HbA1c, insulin and triglycerides, and lower levels of cognitive impairment demonstrates that ascorbic acid may be an effective antidote against oxidative stress [48].
The role of vitamin C as REDOX balancer effectively controls excess oxidative stress in the brain. Patients suffering from epilepsy may benefit from neuroprotective effects as a result of decreased lipid peroxidation from ascorbic acid supplementation [49].
Ascorbate deficiency in the brain can also result in higher susceptibility to seizures as well as cognitive impairment due to altered glutamate clearance [50]. In rodent Alzheimer’s models, deficient ascorbic acid also increased susceptibility to seizures as direct consequence of increased uncontrolled oxidative stress [51].
Electromagnetic radiation (EMR) from manmade sources has been linked to the rise in diseases including the proliferation of cancer [52], neurodegenerative disorders [53], cardiovascular diseases [54] and even infertility [55]. The current understanding is the non-thermal effects from EMR are mediated by oxidative stress generated from oxygen radicals such as superoxide anion radical, singlet oxygen , hydroxyl radical, and perhydroxyl radical, collectively known as reactive oxygen species (ROS).
All artificial electromagnetic radiation are polarized [56]. Ascorbic acid can depolarize EMR due to its birefringent qualities [57]. The ability to tunnel hydrogen and electrons gives ascorbic acid a distinct advantage in the attenuation of oxidative stress. As the perfect proton and electron donor, ascorbic acid plays a central role in the sophisticated, complex redox system designed by nature to counter and balance the destructive effects of oxygen.
An imbalance between free radical generation and sequestration leads to oxidative stress. Free radicals under certain conditions must be effectively quenched or the ensuing chain of reactions can cause mitochondrial dysfunction, cytotoxicity, DNA and mtDNA damage [58, 59, 60].
Disturbed redox status from free radical production can lead to inflammatory processes resulting in tissue damage. Excessive ROS from oxidative stress can attack cellular proteins, lipids and nucleic acids that lead to cellular dysfunctions in the form of reduced energy metabolism, altered cell signalling as well as cell cycle control, genetic mutations, decreased biological activity, immune activation and inflammation [61]. Abnormal immunity is believed to be related to oxidative imbalance. Diabetes is a prime example of organ-specific autoimmune disorders caused by oxidative stress induced inflammation [62].
It is now widely accepted that the root cause for almost all diseases is oxidative stress, and EMR is linked to the generation of diseases via the production of oxidative stress. Our bodies have evolved with a robust and complex redox system that has been able to counter oxidative stress successfully. Vitamin C (ascorbic acid, ascorbate) is at the heart of this remarkable redox system. However, the ability of ascorbic acid to facilitate this extensive redox system is now being critically challenged by our modern lifestyles.
Oxidative stress generated by pervasive artificial and natural EMR, unhealthy lifestyles can result in the depletion of ascorbate. Inadequate substrates from dietary deficiencies may also inhibit the necessary regeneration of ascorbate. Absent ascorbate, our highly developed redox systems comes to a halt, taking with it as collateral damage the life-sustaining bioenergetic balance in mitochondria, ultimately resulting in disease in every form imaginable.
The importance of ascorbic acid as a REDOX balancer in today’s world flooded with manmade EMR cannot be underestimated.
Have you had your AA today?
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