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Showing posts with label Natto. Show all posts
Showing posts with label Natto. Show all posts

Thursday, 5 May 2016

Low Bone Density in Autism and Brain Calcification (Bone-Vascular Axis + Altered Calcium Homeostasis), – a role for Vitamin K2, or something more potent?







Today’s post with a long tittle is a spin-off from looking at the health benefits of the Mediterranean Diet.  This often quoted diet really does make you live longer and healthier; scientists are again trying to understand exactly why.  This sent me looking at various things, one of which was vitamin k, which is abundant in the Mediterranean diet.  It turns out that another healthy diet, one found in Japan, may have incorporated an even better source of this vitamin, since it is high in vitamin K2 rather than K1.

I thought this post would just end up being about general health, rather than autism specifically, but as I did more digging it seems highly credible that some people’s autism could be improved simply by adjusting their calcium homeostasis.

This will not come as a surprise to one of our readers who discovered that giving oral calcium supplements to her son with Asperger’s triggered a major regression towards Classic autism. Fortunately it was reversed by stopping the supplementation.

You likely have an older relative with osteoporosis, which is caused by decreased bone density.  Osteoporosis is defined as a bone density of 2.5 standard deviations below that of a young adult.

Osteoporosis is a condition caused by loss of calcium homeostasis, meaning that bones are losing too much calcium to the blood.  Not surprisingly this calcium has to go somewhere and researchers have come up with the idea of the bone-vascular axis, to explain that this calcium ends up causing vascular calcification, particularly in the heart.

Because so many Americans have heart disease, the condition is very well funded and studied.  You can measure the level of calcium deposits (calcification) in the heart and you can measure bone density.

Many people with osteoporosis (loss of calcium in the bones) suffer from vascular calcification.

People who have a diet high in vitamin K and particularly vitamin K2 have much lower incidence of diseases of the bone-vascular axis and therefore live longer.

In Japan high dose vitamin K2 is a registered drug to treat osteoporosis.  In the West K2 exists as a drug, but not for osteoporosis or calcification.

In the rest of the world it is available as a supplement in very low doses.

In the Western world of evidence-based medicine it appears Japanese evidence does not count.  This is not the first time I have encountered this.

In the west people with osteoporosis might be prescribed calcium supplements that have added vitamin D to promote absorption.

Fortunately there also some interesting drugs that have been developed to affect calcium homeostasis.  Some are now cheap generics.








Bone-vascular axis in Autism

This is an autism blog, so we already know that in autism there is excess calcium found in those samples held in brain banks.

There was also a very recent study:-



Background: Intracranial calcifications are observed in many diseases including those with viral and bacterial infections, vascular pathology, toxic injury, brain tumors, teratomas, lissencephaly, in children with Fahr’s disease, and very often in parasitic infections (Rabbitt et al 1969).
Objectives: Our neuropathological studies of autistic subjects brains have revealed the presence of dystrophic changes with calcification. The aim of this study was to determine the prevalence of this type of encephalopathy in autistic and control cohorts.

Methods: The brain hemispheres of 13 autistic and 14 control subjects 4 to 64 years of age were fixed in 10% formalin, dehydrated and embedded in celloidin and cut into 200 μm- or 50 μm-thick coronal serial sections
Results: Dystrophy with calcification was found in all of the 13 autistic and 14 control brains examined. Dystrophic changes disrupt the continuity of the cortical ribbon and white matter in the frontal, temporal and occipital lobes but only on the lateral side of the brain. The pathology spreads from the leptomeningeal vessels to the cortex and white matter and was detectable by postmortem MRI and histopathological examination. Microscopic examination revealed linear dystrophic lesions free of neurons but with signs of neuronal degeneration at the border between the dystrophic and normal cortex. There was no sign of activation of astrocytes or macrophages within the dystrophic and adjacent brain tissue. The dominant component of the dystrophic lesions was calcium deposits.

Conclusions: Similar morphology of lesions in control and autistic subjects 4 to 64 years of age suggests that dystrophic calcifications undergo relatively limited modifications with age. However, the presence of degenerated neurons and vessels with degenerated smooth muscle cells in the border zone between the lesion and cortex suggests the process of brain tissue damage continues to progress decades after the original causative events. Multifocal dystrophy with calcification in all the examined brains of autistic and control subjects reflects a common pathological mechanism with yet undetermined subclinical or clinical manifestations.





What about reduced bone density in autism?  Well I thought nobody would have looked, but they have.



Studies Link Autism to Low Bone Density and Increased Fractures


The increased risk was greatest among girls and women affected by autism spectrum disorder:
* Girls with autism had eight times the hip-fracture rate of other girls.
* Women with the disorder had ten times the rate of spinal fracture of other women.
* Boys with autism had double the hip-fracture rate of other boys.
* Men and women with autism (ages 23 to 50) had nearly 12 times the hip fracture rate of other adults.
* Women with autism also had double the rate of arm, wrist and hand fractures.


Bone Density in Peripubertal Boys with Autism Spectrum Disorders


Brief Report: Bone Fractures in Children and Adults with Autism Spectrum Disorders



So it looks like more severe autism (autistic girls have 8 times higher fracture rate) in particular is linked with reduced bone density. Girls with autism tend to have more severe autism, at least until recently. This is what you would have expected, the more severe the autism the more disturbed the calcium homeostasis and likely bone-vascular axis.

Is there excess calcium in the hearts of people with autism? I guess nobody thought to look.  People will severe autism tend not to live into old age and so data will be limited.

Since you can study and measure calcification non-invasively, some researcher with time on his/her hands might want to correlate reduced bone density with calcification in the brain/heart.

Given the critical role calcium signaling plays in signaling within the brain, it is clear that excess physical calcium has the potential to disturb all the finely balance flows of Ca2+ ions that control many aspects of brain function.

In particular the excess Ca2+ affects mitochondria, which is known to be disturbed in many people with autism.  The mechanism here is the mitochondrial aspartate/ glutamate carrier (AGC).


Altered calcium homeostasis in autism-spectrum disorders: Evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1



Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient–control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/ glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca 2+). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca 2+ chelator ethylene glycol tetraacetic acid; neocortical Ca 2+ levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca 2+ -containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca 2+ levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca 2+ homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.




Other diseases of brain calcification

There are conditions known to be caused by brain calcification.

Vascular Calcification



Vascular Calcification


Clinically, vascular calcification is now accepted as a valuable predictor of coronary heart disease.  Achieving control over this process requires understanding mechanisms in the context of a tightly controlled regulatory network, with multiple, nested feedback loops and cross talk between organ systems, in the realm of control theory. Thus, treatments for osteoporosis such as calcitriol, estradiol, bisphosphonates, calcium supplements, and intermittent PTH are likely to affect vascular calcification, and, conversely, many treatments for cardiovascular disease such as statins, antioxidants, hormone replacement therapy, angiotensin-converting enzyme inhibitors, fish oils, and calcium channel blockers may affect bone health. As we develop and use treatments for cardiovascular and skeletal diseases, we must give serious consideration to the implications for the organ at the other end of the bone-vascular axis.



Fahr disease

Idiopathic Basal Ganglia Calcification, also known as Fahr disease, is a rare, genetically dominant, inherited neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. Through the use of CT scans, calcifications are seen primarily in the basal ganglia and in other areas such as the cerebral cortex

Brain calcifications induce neurological dysfunction that can be reversed by a bone drug



Perivascular calcifications within the brain form in response to a variety of insults. While considered by many to be benign, these calcium phosphate deposits or "brain stones" can become large and are associated with neurological symptoms that range from seizures to parkinsonian symptoms. Here we hypothesize that the high concentrations of calcium in these deposits produce reversible, toxic effects on neurons that can be overcome with "bone" drugs that chelate solid phase calcium phosphates. We present preliminary findings that suggest a direct association between progressive neurological symptoms and brain calcification and the symptomatic improvement of seizures, headaches, and parkinsonian symptoms in patients treated with the bisphosphonate drug disodium etidronate, normally used to treat bone diseases. Future, longitudinal epidemiological studies and randomized trials will be needed to determine the true relationship between brain stones and neurological disorders as well as the utility of bisphosphonates in their prevention and treatment.



Possible therapies for brain calcification


Etidronic Acid

Etidronic acid (Didronel ®) is a bisphosphonate used to strengthen bone, treat osteoporosis, and treat Paget's disease of bone.
Bisphosphonates primarily reduce osteoclastic activity, which prevents bone resorption, and thus moves the bone resorption/formation equilibrium toward the formation side and hence makes bone stronger on the long run. Etidronate, unlike other bisphosphonates, also prevents bone calcification. For this reason, other bisphosphonates, like alendronate, are preferred when fighting osteoporosis. To prevent bone resorption without affecting too much bone calcification, etidronate must be administered only for a short time once in a while, for example for two weeks every 3 months. When given on a continuous basis, say every day, etidronate will altogether prevent bone calcification. This effect may be useful and etidronate is in fact used this way to fight heterotopic ossification. But in the long run, if used on a continuous basis, it will  cause osteomalacia.


Alendronic acid

Alendronic acid  — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis, osteogenesis imperfecta, and several other bone diseases. It is marketed alone as well as in combination with vitamin D (2,800 IU and 5,600 IU, under the name Fosamax+D). Merck's U.S. patent on alendronate expired in 2008 and the drug is now available as a generic. This is the most widely prescribed bisphosphonate medicine in the United States .


Vitamin K2

Vitamin K is a group of structurally similar, fat-soluble vitamins the human body requires for complete synthesis of certain proteins that are prerequisites for blood coagulation that the body needs for controlling binding of calcium in bones and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and promote calcification of arteries and other soft tissues.

Vitamin K2 is an approved drug therapy in Japan for dysfunctional calcium homeostasis where calcium is lost from your bones (osteoporosis)  and added to the lining of your arteries.

The mechanism involves something called osteocalcin, but is not fully understood.

Osteocalcin originates from osteoblastic synthesis and is deposited into bone or released into circulation, where it correlates with measures of bone formation. The presence of 3 vitamin K-dependent γ carboxyglutamic acid residues is critical for osteocalcin’s structure, which appears to regulate the maturation of bone mineral. In humans, the percentage of the circulating osteocalcin that is not γ-carboxylated (percent ucOC) is used as a biomarker of vitamin K status.

Osteocalcin also plays a yet to be understood role in the glucose metabolism and insulin sensitivity.  Indeed a clinical trial in humans has confirmed this effect exists.

Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial

To summarize, we have demonstrated for the first time that vitamin K2 supplementation for 4 weeks increased insulin sensitivity in healthy young men, which seems to be related to increased cOC rather than modulation of inflammation. Small sample size limits firm interpretation on β-cell function. Our results are consistent with previous studies that demonstrated improved glucose intolerance or relieved insulin resistance by treatment with vitamin K1  or vitamin K2 , respectively.

 

 

So while the mechanism remains unclear, vitamin K2 does much more than is commonly thought.

It is thought that the amount of vitamin K2 in diet is too low to keep calcium where it should be and the suggested daily amount in diet is too low.



Vitamin K in the treatment and prevention of osteoporosis and arterial calcification



PURPOSE:

The role of vitamin K in the prevention and treatment of osteoporosis and arterial calcification is examined.

SUMMARY:

Vitamin K is essential for the activation of vitamin K-dependent proteins, which are involved not only in blood coagulation but in bone metabolism and the inhibition of arterial calcification. In humans, vitamin K is primarily a cofactor in the enzymatic reaction that converts glutamate residues into gamma-carboxyglutamate residues in vitamin K-dependent proteins. Numerous studies have demonstrated the importance of vitamin K in bone health. The results of recent studies have suggested that concurrent use of menaquinone and vitamin D may substantially reduce bone loss. Menaquinone was also found to have a synergistic effect when administered with hormone therapy. Several epidemiologic and intervention studies have found that vitamin K deficiency causes reductions in bone mineral density and increases the risk of fractures. Arterial calcification is an active, cell-controlled process that shares many similarities with bone metabolism. Concurrent arterial calcification and osteoporosis have been called the "calcification paradox" and occur frequently in postmenopausal women. The results of two dose-response studies have indicated that the amount of vitamin K needed for optimal gamma-carboxylation of osteocalcin is significantly higher than what is provided through diet alone and that current dosage recommendations should be increased to optimize bone mineralization. Few adverse effects have been reported from oral vitamin K.

CONCLUSION:

Phytonadione and menaquinone may be effective for the prevention and treatment of osteoporosis and arterial calcification.



Vitamin K2 reduces coronary heart disease:-

Dietary Intake of Menaquinone (Vitamin K2) Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study



In conclusion, our findings suggest a protective effect of menaquinone intake against CHD, which could be mediated by inhibition of arterial calcification. Adequate intake of foods rich in menaquinones, such as curds and (low-fat) cheese, may contribute to CHD prevention.



















Reduce AGC Activity


Another option would be to reduce activity of AGC (mitochondrial aspartate/glutamate carrier) in the brain.  This is the realm of  mouse experiments.

In most neurodegenerative diseases there is too little AGC activity.   AGC is necessary for neuronal functions and is involved in myelinogenesis, so we again have to think about multiple sclerosis (MS).  MS is characterized by the loss of the ability to regenerate the myelin layer, so called remyelination. Autism is characterized by unusual myelination. 

Sulfatide is a major component in the nervous system and is found in high levels in the myelin sheath in both the peripheral nervous system and the central nervous system. Myelin is typically composed of about 70 -75% lipids, and sulfatide comprises 4-7% of this 70-75%.[2] When lacking sulfatide, myelin sheath is still produced around the axons; however, when lacking sulfatide the lateral loops and part of the nodes of Ranvier are disorganized, so the myelin sheath does not function properly.[5] Thus, lacking sulfatide can lead to muscle weakness, tremors, and ataxia

Dysregulation of myelin sulfatides is a risk factor for cognitive decline with age. Vitamin K is present in high concentrations in the brain and has been suggested to  regulate the sulfatide metabolism.  That would suggest that low levels of vitamin K (from diet and produced by bacteria in the intestines) might reduce sulfatide levels and hence impair myelination.
So this would appear to suggest an overlap in the effect of vitamin K and AGC activity. 

We also discover that AGC is regulated by CREB in response to pathological inflammation.  Inflammation is a recurring theme in autism.

It turns out that CREB regulates numerous genes/proteins that are dysfunctional in autism, including:-
·        Somatostatin, also known as growth hormone–inhibiting hormone (GHIH)
·        Brain-derived neurotrophic factor BDNF
·        VGF nerve growth factor.  VGF expression is induced by NGF, CREB and BDNF and regulated by neurotrophin-3.
·        genes involved in the mammalian circadian clock(PER1, PER2).


CREB (cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences calledcAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.

Genes whose transcription is regulated by CREB include: c-fos, BDNF, tyrosine hydroxylase, numerous neuropeptides (such  assomatostatin,  enkephalin, VGF, corticotropin-releasing hormone),[2] and genes involved in the mammalian circadian clock(PER1, PER2).

CREB is closely related in structure and function to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are expressed in many animals, including humans.

CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory.[5] CREB downregulation is implicated in the pathology of Alzheimer's disease and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer’s disease.[6] CREB also has a role in photoentrainment in mammals.


Somatostatin, also known as growth hormone–inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion.



For our reader in Gdansk and parents of kids who do not sleep :-


Involvement in Circadian Rhythms

Entrainment of the mammalian circadian clock is established via light induction of PER. Light excites melanopsin-containing photosensitive retinal ganglion cellswhich signal to the suprachiasmatic nucleus (SCN) via the Retinohypothalamic tract (RHT). Excitation of the RHT signals the release of glutamate which is received by NMDA receptors on SCN, resulting in a calcium influx into the SCN. Calcium induces the activity of Ca2+/calmodulin-dependent protein kinases, resulting in the activation of PKA, PKC, and CK2.  These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression. The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor for Per1 and Per2, two genes that regulate the mammalian circadian clock. This induction of PER protein can entrain the circadian clock to light/dark cycles inhibits its own transcription via a transcription-translation feedback loop which can advance or delay the circadian clock. However, the responsiveness of PER1 and PER2 protein induction is only significant during the subjective night.



Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1.



Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.


The mitochondrial aspartate/glutamate carrier isoform 1 gene expression is regulated by CREB in neuronal cells



The aspartate/glutamate carrier isoform 1 is an essential mitochondrial transporter that exchanges intramitochondrial aspartate and cytosolic glutamate across the inner mitochondrial membrane. It is expressed in brain, heart and muscle and is involved in important biological processes, including myelination. However, the signals that regulate the expression of this transporter are still largely unknown. In this study we first identify a CREB binding site within the aspartate/glutamate carrier gene promoter that acts as a strong enhancer element in neuronal SH-SY5Y cells. This element is regulated by active, phosphorylated CREB protein and by signal pathways that modify the activity of CREB itself and, most noticeably, by intracellular Ca2+ levels. Specifically, aspartate/glutamate carrier gene expression is induced via CREB by forskolin while it is inhibited by the PKA inhibitor, H89. Furthermore, the CREB-induced activation of gene expression is increased by thapsigargin, which enhances cytosolic Ca2+, while it is inhibited by BAPTA-AM that reduces cytosolic Ca2+ or by STO-609, which inhibits CaMK-IV phosphorylation. We further show that CREB-dependent regulation of aspartate/glutamate carrier gene expression occurs in neuronal cells in response to pathological (inflammation) and physiological (differentiation) conditions. Since this carrier is necessary for neuronal functions and is involved in myelinogenesis, our results highlight that targeting of CREB activity and Ca2+ might be therapeutically exploited to increase aspartate/glutamate carrier gene expression in neurodegenerative diseases.



Vitamin K2 and Myelin



Dysregulation of myelin sulfatides is a risk factor for cognitive decline with age. Vitamin K is present in high concentrations in the brain and has been implicated in the regulation of sulfatide metabolism. Our objective was to investigate the age-related interrelation between dietary vitamin K and sulfatides in myelin fractions isolated from the brain regions of Fischer 344 male rats fed one of two dietary forms of vitamin K: phylloquinone or its hydrogenated form, dihydrophylloquinone for 28 days. Both dietary forms of vitamin K were converted to menaquinone-4 in the brain. The efficiency of dietary dihydrophylloquinone conversion to menaquinone-4 compared to dietary phylloquinone was lower in the striatum and cortex, and was similar to those in the hippocampus. There were significant positive correlations between sulfatides and menaquinone-4 in the hippocampus (phylloquinone-supplemented diet -12mo and 24mo; dihydrophylloquinone -supplemented diet - 12mo) and cortex (phylloquinone-supplemented diet -12mo and 24 mo). No significant correlations were observed in the striatum. Furthermore, sulfatides in the hippocampus were significantly positively correlated with MK-4 in serum. This is the first attempt to establish and characterize a novel animal model that exploits the inability of dietary dihydrophylloquinone to convert to brain menaquinone-4 to study the dietary effects of vitamin K on brain sulfatide in brain regions controlling motor and cognitive functions. Our findings suggest that this animal model may be useful for investigation of the effect of the dietary vitamin K on sulfatide metabolism, myelin structure, and behavior functions.
Low sulfatide content in brain myelin has been recently linked with the disruption of myelin integrity [14,21], whereas the disruption of myelin integrity was implicated as an essential contributor to cognitive deficit [6, 7, 43, 44]. Although our findings of dietary-associated decreases in myelin sulfatides suggest a potential disruption in myelin integrity in evaluated brain regions, it is currently unknown whether such disruption would be sufficient to modify motor and cognitive functions controlled by these brain regions.

In summary, this is the first study to demonstrate the effect of dietary vitamin K on sulfatides and MK-4 in the purified brain myelin. It remains to be determined whether long-term and/or higher dietary dK consumption would be sufficient to affect brain-region-specific changes in the: (a) number and/or metabolic activity of oligodendrocytes; (b) rate of myelin formation and loss, (c) activity of genes responsible for the synthesis of myelin constituents. Furthermore, the behavioral consequences of altered sulfatide concentrations through manipulation of dietary vitamin K remain to be assessed.




Vitamin K Biological properties relevant for an effect in MS – Vitamin K is a group of fat-soluble vitamins, needed for posttranslational modification of proteins involved in blood coagulation and bone metabolism. It includes two natural groups of vitamer chemicals: K1 (phylloquinone) and K2 (menaquinone). In addition to its effects of coagulation and bone metabolism, it has been demonstrated that oligodendrocyte precursors and immature neurons are protected from oxidative injury by vitamin K2 (61). Vitamin K has no known function in the immune system in humans. Trials in animal models – One study has been performed in the EAE-model (62). The authors reported that the severity of EAE was significantly ameliorated by the prophylactic administration of vitamin K2, although it was not effective when given after the onset. The authors reported that the vitamer seemed to work by inhibition of inflammatory cellular infiltration. Human trials – No human trials have been performed on the effect of vitamin K on MS disease activity or prevention.


Vitamin K as an antioxidant


Novel Role of Vitamin K in Preventing Oxidative Injury to Developing Oligodendrocytes and Neurons




Oxidative stress is believed to be the cause of cell death in multiple disorders of the brain, including perinatal hypoxia/ischemia. Glutamate, cystine deprivation, homocysteic acid, and the glutathione synthesis inhibitor buthionine sulfoximine all cause oxidative injury to immature neurons and oligodendrocytes by depleting intracellular glutathione. Although vitamin K is not a classical antioxidant, we report here the novel finding that vitamin K1 and K2 (menaquinone-4) potently inhibit glutathione depletion-mediated oxidative cell death in primary cultures of oligodendrocyte precursors and immature fetal cortical neurons with EC50 values of 30 nM and 2 nM, respectively. The mechanism by which vitamin K blocks oxidative injury is independent of its only known biological function as a cofactor for γ-glutamylcarboxylase, an enzyme responsible for posttranslational modification of specific proteins. Neither oligodendrocytes nor neurons possess significant vitamin K-dependent carboxylase or epoxidase activity. Furthermore, the vitamin K antagonists warfarin and dicoumarol and the direct carboxylase inhibitor 2-chloro-vitamin K1 have no effect on the protective function of vitamin K against oxidative injury. Vitamin K does not prevent the depletion of intracellular glutathione caused by cystine deprivation but completely blocks free radical accumulation and cell death. The protective and potent efficacy of this naturally occurring vitamin, with no established clinical side effects, suggests a potential therapeutic application in preventing oxidative damage to undifferentiated oligodendrocytes in perinatal hypoxic/ischemic brain injury.

In summary, we demonstrate for the first time that oxidative cell death induced by GSH depletion in primary OL precursors and in primary cortical neurons can be prevented by nanomolar concentrations of vitamin K1 and MK-4. The cytoprotective effect of K vitamins in this model is independent of their known biological role in carboxylation. They do not prevent the loss of intracellular GSH caused by cystine depletion but markedly inhibit ROS accumulation and, thus, cell death. These results suggest a new approach to developing potential preventative and therapeutic strategies for neurological diseases in which GSH depletion-induced oxidative stress plays a role.



L-Carnitine and Calcium Chelation

I think we have established the link between excess calcium and some types of mitochondrial dysfunction.

Regular readers will know that one important element in autism mitochondrial therapies, like Dr Kelley’s and others, is the supplement L-carnitine, which in responders seems to show effect very quickly.

Is it a coincidence that one of the properties of this supplement is as a chelator of calcium?

L-carnitine is a calcium chelator: a reason for its useful and toxic effects in biological systems


Chelation normally refers to removing harmful metals from the body.  In the case of calcium we just want to put it back in the bones, not remove it from the body.

The study earlier in this post appear to show that the brain calcium deposits do not grow over time, for some reason calcium got deposited very early in life and just stays there.  The deposits do not grow but do continue to do damage.  So considering them like brain stones might be helpful.   Therapies do exist for such brain stones, as we saw using drugs developed for osteoporosis.



Conclusion

Excess calcium maybe one of those few simple concepts in autism that you do not need a PhD to fully understand.  It may also be at the root cause of further complex dysfunctions where that PhD really would be useful.

I think some of those CREB-associated dysfunctions and indeed some mitochondrial problems might just disappear if any existing excess calcium was removed.

If you can go to the doctor to measure calcification in your heart, why not do it for your brain?  Coronary Calcium Scans are common and take about 10 minutes.

 If there is no brain calcification, great. 

If it brain calcification exists, then treat it, just like the doctor would treat Grandma’s osteoporosis.

Measure bone density; all women over 65 are recommended to have a DXA scan.  So the technology is already here.

Vitamin K2 is seen as very safe, but you might need to eat a lot of Natto if you have calcification, probably better used for prevention.

Why do the Harvard researchers who have noted low bone density in autism not make a few further connections and understand the implications and treatment options?
There were also interesting issues that arose regarding multiple sclerosis (MS), but that is not really an issue for this blog.

Vitamin K2 looks like yet another good thing for people with type 1 or type 2 diabetes.

I have to add vitamin K2 to my growing list of possible dementia therapies, before I forget. It affects myelin sulfatides, which are one cause cognitive decline in the elderly.



Final Words

This did become rather a lengthy post.

Vitamin K2 is likely highly beneficial for many people, but just how much you need to decalcify a brain is unknown.  I suspect far more than in your average supplement.
 
Perhaps the dosage in the Japanese K2 drug would have an impact.  The Western RDA is 0.075 mg a day;  in Japan they used 45mg in trials, a dose 600 times larger.

Cheap generic bisphosphonate drugs might be better and then K2 for maintenance therapy?

Some serious scientific investigation looks warranted, given the therapies are sitting on the shelf.   Don’t hold your breath.