Glutathione and the Role of Inflammation in MS

[jackD]

Excess Glutamate and insufficient Glutathione does lots of damage in the 2nd stage of MS.


http://home.ix.netcom.com/~jdalton/ms-two-stages.pdf (DO NOT PANIC!!!) THIS IS ONLY TWO(2) PAGES LONG!~!!!!!!!!~!!!!!!!



Increase glutathione - reduce glutamate levels

--------------------------------------------------------------------------------

One of the best ways to counter Glutamate excitotoxicity and resulting neuron deaths is to increase glutathione levels.

Unfortunately, glutathione supplements taken orally are very poorly absorbed and have not raised glutathione levels in the blood. So save your money.

The glutathione precursor, N-acetyl-cystine(commonly just called NAC) provides sufficient sulphur containing amino acid (a duo or dimer of cysteine) to boost glutathione levels.

NAC is readily absorbed and boosts glutathione levels quite well.

Glutathione contains the following 3 amino acids linked together: Glutamate—cysteine--glycine.

There are some foods that that boost glutathione levels. I do not know all of them but a few are Asparagus, avocados, and walnuts which are known to be a rich sources of glutathione.

http://www.nutritionadvisor.com/glutathione_foods.php

Also broccoli, brussels sprouts, cabbage and cauliflower all contain cyanohydroxybutene which increases glutathione levels.
Avocados, peaches, bueberries and watermelon are also reported to raise glutathione levels.

Several spices including cinnamon, cardamom and curcumin found in turmeric raise glutathione levels.

Alpha Lipoic Acid (ALA) promotes the synthesis of glutathione in the body. Food sources of ALA include spinach, broccoli, tomatoes, peas, Brussels sprouts, and rice bran. Real Hellman’s Mayonnaise also provides 660 mg of ALA per 1 tablespoop.


jackD

[jackD]

RATS LOVE THIS STUFF!!!@!

jackD

The substance the body produces to counter Glutamate is the antioxidant glutathione. Curcumin(tumeric extract) that states that it increases the bodies production of the antioxidant glutathione.

You cannot take glutathione directly as a pill or supplement because it breaks down in the gut, But some supplements will cause the body to increase the natural production of glutathione.


Popular Botanical Supports Brain Health

A recent study investigated the effects of a popular herb in regards to cognitive deficits and oxidative damage in the brain.

Curcumin is a potent antioxidant and the principle active constituent in turmeric (Curcuma longa). In a new study, rats were treated with a chemical called streptozotocin to induce oxidative damage within the brain, which is used as an experimental model for dementia. The rats then received either 80 mg per kg of curcumin or placebo for 3 weeks.

After 2 weeks of streptozotocin treatment, the rats showed significant cognitive deficits as measured by passive avoidance and water maze tasks. The rats that received curcumin demonstrated significantly improved cognitive performance compared to the rats that did not. In addition, the group supplemented with curcumin also showed a significant decrease in markers for oxidative stress such as 4-hydroxynonenal, malonaldehyde, thiobarbituric reactive substances, hydrogen peroxide, protein carbonyl, and oxidized glutathione.

Curcumin also augmented levels of the potent antioxidant glutathione and the enzymes responsible for the regeneration of glutathione in specific areas in the brain, including the hippocampus and cerebral cortex.

Furthermore, curcumin increased the activity of the enzyme called choline acetyltransferase in the hippocampus, which is important in the synthesis of the neurotransmitter acetylcholine. Reduced levels of acetylcholine are believed to play a role in Alzheimer’s disease.

The researchers concluded, “The study suggests that curcumin is effective in preventing cognitive deficits, and might be beneficial for the treatment of sporadic dementia of Alzheimer’s type.”

Reference:

Ishrat T, Hoda MN, Khan MB, Yousuf S, Ahmad M, Khan MM, Ahmad A, Islam F. Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer’s type (SDAT). Eur Neuropsychopharmacol. 2009 Mar 27. Published Online Ahead of Print.

[jackD]

L-Theanine neuroprotective

--------------------------------------------------------------------------------

L-Theanine - Stuff in Green Tea is available as a supplement. I add an extra 200 mg to my mug of green/white tea that I drink twice each day.

jackD

Theanine is an amino acid found in green tea that produces
tranquilizing effects in the brain. In Japan, soft drinks and
chewing gum are spiked with theanine for the purpose of
inducing relaxation.

Although theanine creates a feeling of
relaxation, it doesn't shut down the brain. Studies on rodents
show that theanine enhances the ability to learn and remember.
By shutting off worry central, theanine appears to increase
concentration and focus thought.

Theanine is different than kava-kava in that it doesn't cause
drowsiness, just relaxation. Theanine increases GABA, while
caffeine decreases it. GABA doesn't just relax, it also
creates a sense of well-being. Theanine's ability to increase
this brain chemical can literally put you in a better mood.
Theanine also increases levels of dopamine, another brain
chemical with mood-enhancing effects.

Protecting neurons
In studies on neurons in cell culture, theanine significantly
reverses glutamate-induced toxicity. In vivo studies show the
same effect in rodents. Glutamate-induced neuro-toxicity is a
major cause of degenerative brain disease.

Many Americans suffer from slightly elevated blood pressure,
but don't know they have it. Chronic high blood pressure
inflicts damage on the delicate cerebral vascular network and
increases the risk of stroke. Theanine has been shown to help
lower blood pressure.

Theanine readily crosses the blood-brain barrier and changes
brain chemistry in a way that has been compared to
aromatherapy. Studies show that theanine is a non-toxic,
highly desirable mood modulator.


1: Biol Pharm Bull. 2002 Dec;25(12):1513-8.

Neuroprotective effects of the green tea components theanine and catechins.

Kakuda T.

Central Research Institute, Itoen, Ltd, Shuzuoka, Japan.

The neuroprotective effects of theanine and catechins contained in green tea are
discussed. Although the death of cultured rat cortical neurons was induced by
the application of glutamic acid, this neuronal death was suppressed with
exposure to theanine. The death of hippocampal CA1 pyramidal neurons caused by
transient forebrain ischemia in the gerbil was inhibited with the ventricular
preadministration of theanine. The neuronal death of the hippocampal CA3 region
by kainate was also prevented by the administration of theanine. Theanine has a
higher binding capacity for the AMPA/kainate receptors than for NMDA receptors,
although the binding capacity in all cases is markedly less than that of
glutamic acid.

The results of the present study suggest that the mechanism of
the neuroprotective effect of theanine is related not only to the glutamate
receptor but also to other mechanisms such as the glutamate transporter,
although further studies are needed. One of the onset mechanisms for
arteriosclerosis, a major factor in ischemic cerebrovascular disease, is
probably the oxidative alteration of low-density lipoprotein (LDL) by active
oxygen species. The oxidative alterations of LDL were shown to be prevented by
tea catechins. Scavenging of *O(2)(-) was also exhibited by tea catechins.

The neuroprotective effects of theanine and catechins contained in green tea are a
focus of considerable attention, and further studies are warranted.
Publication Types:
Review
Review, Tutorial

PMID: 12499631 [PubMed - indexed for MEDLINE]

[jackD]

This was a big surprise!! Low dose naltrexone (LDN) lowers glutamate!!

jackD

http://elaine-moore.suite101.com/glutam ... nts-a76493

[jackD]

It would be a great idea to just take a "MAGIC" pill and lower our glutamate levels to save our axon/neurons. I do not think one exists.

There are numerous supplements that may do this job.

I have posted some of them. I would welcome any additional ones you folks can find.

jackD

Pflugers Arch. 2010 Jul;460(2):525-42. Epub 2010 Mar 14.

Glutamate receptors, neurotoxicity and neurodegeneration.

Lau A, Tymianski M.
SourceDivision of Applied and Interventional Research, Toronto Western Research Institute, 399 Bathurst Street, Toronto, ON, Canada, M5T 2S8.

Abstract
Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration.

As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching.

Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research.

However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and others.

Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury.

This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.

PMID: 20229265 [PubMed - indexed for MEDLINE]

[jackD]

Nice to see that "good old reliable Vitamin D3 (Cholecalciferol)" also protects against neurotoxicity by glutamate.

jackD

p.s. Rats love this stuff too!!!



J Neurosci Res. 2006 May 15;83(7):1179-89.

Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons.

Taniura H, Ito M, Sanada N, Kuramoto N, Ohno Y, Nakamichi N, Yoneda Y.
SourceLaboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan.

Abstract
The vitamin D receptor (VDR) is believed to mediate different biologic actions of vitamin D3, an active metabolite of vitamin D, through regulation of gene expression after binding to specific DNA-response element (VDRE) on target genes. To further understand roles of both vitamin D3 and VDR in the central nervous system, we examined VDRE binding in nuclear extracts prepared from discrete rat brain regions and cultured rat cortical neurons by electrophoretic mobility shift assay. The highest activity of VDRE binding was found in the cerebellum among other brain regions examined, but sequence specific by taking into consideration the efficient competition with excess unlabeled VDRE but not with mutated VDRE. On in situ hybridization analysis, cells stained for VDR mRNA were abundant in neuron-enriched areas of cerebral cortex, hippocampus and cerebellar cortex in the mouse brain.

Chronic treatment of vitamin D3 increased the expression of microtubule-associated protein-2, growth-associated protein-43 and synapsin-1 in cultured rat cortical neurons, suggesting a trophic role of vitamin D3 in differentiation and maturation of neurons.

Neuronal cell death by brief glutamate exposure was significantly protected in cultured cortical neurons chronically treated with vitamin D3.
Parallel studies showed that VDR mRNA was significantly upregulated 12-24 hr after brief glutamate exposure in cultured neurons chronically treated with vitamin D3, but not in those with vehicle alone.

Our results suggest that vitamin D3 may play a role in mechanisms relevant to protective properties against the neurotoxicity of glutamate through upregulation of VDR expression in cultured rat cortical neurons.
Copyright 2006 Wiley-Liss, Inc.

PMID: 16521124 [PubMed - indexed for MEDLINE]

[jackD]

This provides GOOD reasons to take other supplements that lower the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta.

jackD

Interferon Beta reduces Glutamate neurotoxicity

--------------------------------------------------------------------------------

Brain Res. 2007 Nov 7;1179:140-6. Epub 2007 Sep 4.

Interferon-beta is neuroprotective against the toxicity induced by activated microglia.

Jin S, Kawanokuchi J, Mizuno T, Wang J, Sonobe Y, Takeuchi H, Suzumura A.
SourceDepartment of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.

Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system characterized by demyelination, T lymphocyte infiltration, and neuronal degeneration. Interferon-beta (IFN)-beta reduces symptoms of the relapsing-remitting form of MS. In this study, we investigated whether IFN-beta is neuroprotective against the toxicity induced by activated microglia in cortical neurons and microglia co-cultures.

IFN-beta suppressed the production of glutamate and superoxide by activated microglia to 70% and 75% of lipopolysaccharide stimulation, respectively, and prevented microglial-induced neuronal cell death. Although IFN-beta enhanced the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and nitric oxide (NO) by activated microglia, these molecules did not directly induce neurotoxicity in cultured cortical neurons. IFN-beta did not prevent neuronal cell death induced by the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) or ionotropic glutamate receptor agonists such as N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA).

These results suggest that IFN-beta may be a useful agent counteracting neurotoxicity associated with activated microglia.

PMID: 17905201 [PubMed - indexed for MEDLINE]

[jackD]

This form of B-12 is very nuroprotective.

jackD

Eur J Pharmacol. 1993 Sep 7;241(1):1-6.

Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons.

Akaike A, Tamura Y, Sato Y, Yokota T.
SourceDepartment of Neuropharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, ***uyama University, Japan.

Abstract
The effects of methylcobalamin, a vitamin B12 analog, on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free medium for 1 h. Glutamate cytotoxicity was prevented when the cultures were maintained in methylcobalamin-containing medium.

Glutamate cytotoxicity was also prevented by chronic exposure to S-adenosylmethionine, which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and S-adenosylmethionine also inhibited the cytotoxicity induced by N-methyl-D-aspartate or sodium nitroprusside that releases nitric oxide. In cultures maintained in a standard medium, glutamate cytotoxicity was not affected by adding methylcobalamin to the glutamate-containing medium. In contrast, acute exposure to MK-801, a NMDA receptor antagonist, prevented glutamate cytotoxicity.

These results indicate that chronic exposure to methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.

PMID: 7901032 [PubMed - indexed for MEDLINE]

[jackD]

Rats do not like this stuff..

jackD

1: Ann N Y Acad Sci. 2004 Dec;1031:127-42.

Tocotrienol: the natural vitamin E to defend the nervous system?

Sen CK, Khanna S, Roy S.

Davis Heart & Lung Research Institute, 473 West 12th Avenue, The Ohio State
University Medical Center, Columbus, Ohio 43210, USA. sen-1@medctr.osu.edu

Vitamin E is essential for normal neurological function. It is the major
lipid-soluble, chain-breaking antioxidant in the body, protecting the integrity
of membranes by inhibiting lipid peroxidation. Mostly on the basis of symptoms
of primary vitamin E deficiency, it has been demonstrated that vitamin E has a
central role in maintaining neurological structure and function. Orally
supplemented vitamin E reaches the cerebrospinal fluid and brain. Vitamin E is a
generic term for all tocopherols and their derivatives having the biological
activity of RRR-alpha-tocopherol, the naturally occurring stereoisomer compounds
with vitamin E activity. In nature, eight substances have been found to have
vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-,
beta-, gamma- and delta-tocotrienol. Often, the term vitamin E is synonymously
used with alpha-tocopherol. Tocotrienols, formerly known as zeta, , or
eta-tocopherols, are similar to tocopherols except that they have an isoprenoid
tail with three unsaturation points instead of a saturated phytyl tail. Although
tocopherols are predominantly found in corn, soybean, and olive oils,
tocotrienols are particularly rich in palm, rice bran, and barley oils.

Tocotrienols possess powerful antioxidant, anticancer, and cholesterol-lowering
properties. Recently, we have observed that alpha-tocotrienol is multi-fold more
potent than alpha-tocopherol in protecting HT4 and primary neuronal cells
against toxicity induced by glutamate as well as by a number of other toxins. At
nanomolar concentration, tocotrienol, but not tocopherol, completely protected
neurons by an antioxidant-independent mechanism. Our current work identifies two
major targets of tocotrienol in the neuron: c-Src kinase and 12-lipoxygenase.

Dietary supplementation studies have established that tocotrienol, fed orally,
does reach the brain. The current findings point towards tocotrienol as a potent
neuroprotective form of natural vitamin E.

]PMID: 15753140 [PubMed - indexed for MEDLINE]

[jackD]

The why and how glutamate is so harmful to MS folks.

jackD

ps Source of info gone from WEB.

Can a neuron be excited to death? Some interesting new findings about glutamate suggest that this excitatory neurotransmitter not only talks to neurons, but can also scream at them, strangle their dendrites, and even assassinate them.

One of the key glutamate receptors is called NMDA, named after its selective ligand N-methyl-d-aspartate. Once glutamate binds to its NMDA receptor, this opens an ion channel in the neuronal membrane so the nerve can drink calcium. Sipping calcium is exciting to a neuron and a normal reaction when glutamate is speaking pleasantly.

Too much glutamate can behazardous to your health

When glutamate screams at a neuron, it reacts by drinking more calcium. Imbibing too much calcium can anger intracellular enzymes, which then generate nasty chemicals called free radicals. A small commune of free radicals can crash the chemical party in the postsynaptic dendrite and strangle it.

Why would the neuron allow this to happen? It is possible that the brain needs this excitotoxic mechanism so that glutamate can act as a gardener in the brain, pruning worn out branches from dendrite trees so that healthy new sprouts might prosper. However, this also equips glutamate with a powerful weapon that can be misused to cause various pathologic states.

When glutamate decides to act as an abusive bully, neurons may seize, panic, become manic, or become psychotic. Furthermore, such symptoms of calcium intoxication may be followed by an unfortunate glutamate hangover in the form of destroyed dendrites that can never be excited again.

Glutamate as endogenous assassin.

At the far end of the excitotoxic spectrum, glutamate's molecular mischief can run rampant and actually murder entire neurons by overwhelming calcium poisoning and free-radical mayhem. Certain illnesses such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease (amyotrophic lateral sclerosis), and even schizophrenia may hire glutamate as a methodical assassin, eliminating a whole subpopulation of pre-designated neurons. This is a systematic process consistent with the pace of such neurodegenerative disorders. In the case of stroke, glutamate may form an army of hit-men, and then massacre an entire region of distressed ischemic neurons in the midst of a catastrophic molecular mess.

In summary, glutamate's actions can range across a vast spectrum. It can be a friendly neuronal conversationalist or a screaming hypothetical mediator of symptoms of mental illness. After an abusive tirade, glutamate may even strangle the dendrite it excited. As excitotoxicity escalates, glutamate can become a serial murderer of neurons, wiping them out in a devastating cumulative process over months and years. At an extreme, glutamate is a mass murderer, wreaking the destruction of localized neurons during the chaos of stroke.

[NHE]

Excess Glutmate and insufficient Glutathione does lots of damage in the 2nd stage of MS.

Biogen's new oral drug for MS, BG-12, achieves immunomodulation via glutathione depletion. http://www.thisisms.com/forum/general-d ... ml#p179598

This aspect of BG-12 seems a bit counterintuitive.

NHE

[Quest56]

Excess Glutmate and insufficient Glutathione does lots of damage in the 2nd stage of MS.

Very interesting, a pubmed post from today is related:

Glutamate and Multiple Sclerosis

[Liberation]

...

[ikulo]

Whey is a big promoter of glutathione. It comes in very delicious chocolate flavors!

http://articles.mercola.com/sites/artic ... ments.aspx

[jackD]

Well - at least they are aware of the problem and doing some reviews and research.

jackD

Pflugers Arch. 2010 Jul;460(2):525-42. Epub 2010 Mar 14.

Glutamate receptors, neurotoxicity and neurodegeneration.

Lau A, Tymianski M.

Division of Applied and Interventional Research, Toronto Western Research Institute, 399 Bathurst Street, Toronto, ON, Canada, M5T 2S8.

Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration. As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching. Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research. However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and others.

Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury.

This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.


PMID: 20229265 [PubMed - indexed for MEDLINE]