http://groups.yahoo.com/group/aspartameNM/message/1090
aspartame, MSG, excitotoxins, NMDA glutamate receptors, multiple
sclerosis: Blaylock: Martini: Murray 2004.06.09 rmforall
Rich Murray: I have corrected typos and spelling, and added spacing
to improve readability. I found abstracts for 7 of the 9 references, and
added more abstracts that show a vigorous scientific advance, with
scores of scientists and studies. These studies may well be relevant
to very recent research that aspartame hurts memory in rats:
http://groups.yahoo.com/group/aspartameNM/message/1088
Murray, full plain text & critique:
chronic aspartame in rats affects memory, brain cholinergic receptors,
and brain chemistry, Christian B, McConnaughey M et al, 2004 May:
2004.06.05 rmforall
http://www.rense.com/general53/ms.htm
The connection between MS and aspartame
Russell L. Blaylock, M.D. Neurosurgeon 2004.06.07
http://www.russellblaylockmd.com
Recently, much controversy has surrounded a claim that aspartame
may produce an MS-like syndrome.
A current review of recent peer-reviewed scientific studies have
disclosed a pathophysiological mechanism to explain this connection.
As far back as 1996 it was shown that the lesions produced in the
myelin sheath of axons in cases of multiple sclerosis were related to
excitatory receptors on the primary cells involved, called
oligodendroglia.
Recent studies have now confirmed what was suspected back then.
The loss of myelin sheath on the nerve fibers characteristic of the
disease are due to the death of these oligodendroglial cells at the site
of the lesions (called plaques). Further, these studies have shown
that the death of these important cells is as a result of excessive
exposure to excitotoxins at the site of the lesions.
Normally, most of these excitotoxins are secreted from microglial
immune cells in the central nervous system.
This not only destroys these myelin-producing cells, it also breaks
down the blood-brain barrier (BBB), allowing excitotoxins in the
blood stream to enter the site of damage.
Aspartame contains the excitotoxin aspartate as 40% of its
molecular structure. Numerous studies have shown that consuming
aspartame can significantly elevate the excitotoxin level in the blood.
[ Rich Murray: A Searle Laboratories team in 1976 reported that
in 4 monkeys fed aspartame, by 12 hours: "...the major fraction
(70%) of the [aspartate] label appeared in the expired air (Fig.6)...
Urinary and fecal 14C [ aspartate derived ] amounted to 4--6%
of the administered [ aspartate ] label."
This gives a total of a maximum 76% excreted aspartate
from the aspartame, indicating that 24% of this excitotoxin
was retained in the body.
It is reasonable to conclude that daily use of aspartame must lead to
substantial accumulation of this excitotoxin, aspartate, in body tissues.
Their 1979 review said: "Aspartame... is hydrolyzed in the gut to yield
aspartic acid, phenylalanine, and methanol....
Aspartate may also be incorporated into body constitutents such as
other amino acids, proteins, pyrimidines, asparagine, and
N-acetylaspartic acid."
J Environ Pathol Toxicol. 1979 Mar-Apr; 2(4): 979-85.
A review of the metabolism of the aspartyl moiety of aspartame in
experimental animals and man.
Ranney RE, Oppermann JA.
Department of Drug Metabolism and Radiochemistry,
Searle Laboratories, Skokie, Illinois.
Aspartame (3-amino-N-(alpha-carboxyphenethyl) succinamic acid,
methyl ester; the methyl ester of aspartylphenylalanine, SC-18862)
is hydrolyzed in the gut to yield aspartic acid, phenylalanine,
and methanol.
This review of the literature describes the metabolic paths
followed by aspartate in its conversion to CO2
or its incorporation into body constituents.
About 70 percent of 14C from [asp-14C]-aspartame is
converted in the monkey to 14CO2.
Some of the aspartate is converted at the intestinal mucosal level to
alanine by decarboxylation.
This amino acid may be oxidized to CO2 by entering the
tricarboxylic acid cycle via pyruvate and acetyl CoA.
In addition, transamination of aspartate to oxaloacetate
permits this product also to enter the tricarboxylic acid cycle.
Aspartate may also be incorporated into body constitutents such as
other amino acids, proteins, pyrimidines, asparagine,
and N-acetylaspartic acid.
It is concluded that the aspartate moiety of aspartame
is metabolized in a manner similar to that of dietary aspartic acid.
Publication Types: Review PMID: 376770 ]
There is a common situation during which the excitotoxin
exposure is even greater.
When aspartate (as aspartame) is combined in the diet with
monosodium glutamate (MSG) blood levels are several fold higher
than normal.
With the BBB damaged, as in MS, these excitotoxins can freely enter
the site of injury, greatly magnifying the damage.
So, we see that dietary excitotoxins, such as aspartame and MSG,
can greatly magnify the damage produced in multiple sclerosis.
Likewise, excitotoxins have been shown to breakdown the BBB as well.
Of equal concern is observation that we know that about 10% of the
population (based on autopsy studies of elderly) have MS lesions without
ever developing the full blown disease,
a condition called benign MS.
A diet high in excitotoxins, such as aspartame, can convert this benign,
subclinical condition into full-blown clinical MS.
The amount of excitotoxins consumed in the average American diet is
considerable, as shown by several studies.
In addition, the toxin methanol is also in the aspartame molecule.
Methanol is an axon poison.
Combined toxicity of the aspartate and the methanol adds up to
considerable brain toxicity, and can convert benign, subclinical MS
into full-blown MS.
Once the MS becomes full-blown, further consumption of
excitotoxins magnifies the toxicity, increasing disability and death.
Recent studies have also shown that even single exposures to these
food-based excitotoxins can produce prolonged worsening of
neurological lesions.
In addition, it has been demonstrated that autoimmune reactions
(as occurs with MS) greatly magnifies the toxicity of aspartate
and glutamate (the excitotoxins).
We also know liquid forms of excitotoxins are significantly more
toxic because of rapid absorption and higher blood levels.
In the face of this connection between excitotoxicity and the
pathophysiology of MS, it would be ludicrous to allow further use
of this excitotoxin containing sweetener.
TREATMENT FOR MS:
It is now known the cause for the destruction of the myelin in the
lesions is overactivation of the microglia in the region of the myelin.
An enzyme that converts glutamine to glutamate, called glutaminase,
increases tremendously, thereby greatly increasing excitotoxicity.
Mercury also activates microglia, even in subtoxic doses.
Any dietary excitotoxin can activate the microglia, thereby greatly
aggravating the injury.
This includes the aspartate in aspartame.
The methanol adds to this toxicity as well.
Now, the secret to treatment appears to be shutting down, or at least
calming down, the microglia.
It has been found that the antibiotic minocycline powerfully shuts
down the microglia.
I tried this treatment on a friend of mine who just came down with
fulmanant MS.
He was confined to a wheelchair.
I had him placed on minocycline and now, just a few weeks later,
he is walking.
The good news is that other things also calm the microglia --
the most potent are: silymarin, curcumin and ibuprophen.
Phosphatidylcholine helps re-myelinate the nerve sheaths that are
damaged, as does B12, B6, B1, vitamin D, folate, vitamin C,
natural vitamin E (mixed tocopherols) and L-carnitine.
DHA plays a major role in repairing the myelin sheath.
Vitamin D may even prevent MS, but it acts as an immune modulator,
preventing further damage -- the dose is 2000 IU a day.
Magnesium, as magnesium malate, is needed
in a dose of 500 mg 2X a day.
They must avoid all excitotoxins, even natural ones in foods --
such as soy, red meats, nuts, mushrooms and tomatoes.
Avoid all fluoride and especially all vaccinations, since these
either inhibit antioxidant enzymes or trigger harmful immune reactions.
Dr. Blaylock is a recently retired board-certified neurosurgeon
with more than twenty six years experience. He is a recently retired
Clinical Assistant Professor of Neurosurgery at the Medical University
of Mississippi. Author of thirty scientific papers on various medical
subjects, chapters in three medical textbooks and a booklet on multiple
sclerosis, he recently completed a booklet on bioterrorism and is the
author of "Excitotoxins: The Taste That Kills",
"Health & Nutrition Secrets to Save Your Life", and
"Natural Strategies for Cancer Patients".
http://www.russellblaylockmd.com/
He serves on the editorial staff of The Journal of American Physicians
and Surgeons, the Journal of the American Nutraceutical Association,
and acts as a medical advisor to the American Nutraceutical Association.
His excellent newsletter can be gotten at
http://www.blaylockreport.com/
He lives in Ridgeland, Mississippi.
References and additional abstracts:
1. Neurobiol Dis. 1999 Dec; 6(6): 475-85.
AMPA and kainate receptors each mediate excitotoxicity in
oligodendroglial cultures.
Sanchez-Gomez MV, Matute C.
Departamento de Neurociencias, Universidad del Pais Vasco,
Leioa, Vizcaya, 48940, Spain.
Sanchez-Gomez MV has 11 abstracts in PubMed since 1992
on this line of research, while Matute C has 63 abstracts since 1985.
Carlos Matute Almau +34-946-012-865 onpmaalc@lg.ehu.es;
Recent studies indicate that oligodendrocytes are vulnerable to
excitotoxic insults mediated by glutamate receptors.
The present study was carried out to characterize the type of glutamate
receptors triggering cell death in optic nerve oligodendrocyte cultures.
Acute activation of either AMPA or kainate receptors was toxic to
oligodendrocytes, an effect that was prevented by CNQX.
However, exposure to agonists of the NMDA and metabotropic
glutamate receptors did not impair cell viability.
Dose-response curves showed that toxicity was mediated
by three distinct populations of receptors:
an AMPA-type receptor and high- and low-affinity kainate-type
receptors.
Expression and immunocytochemical studies suggested that the
glutamate receptor subunits give rise to the native receptors
in each population.
In all instances, Ca(2+) entry was a major determinant
of glutamate receptor excitotoxicity.
However, its influence varied for each receptor subtype.
These results indicate that aberrantly enhanced activation of
AMPA and/or kainate receptors may be involved
in demyelinating diseases.
Copyright 1999 Academic Press. PMID: 10600403
J Neurosci. 2003 Oct 22; 23(29): 9519-28.
Caspase-dependent and caspase-independent oligodendrocyte
death mediated by AMPA and kainate receptors.
Sanchez-Gomez MV, Alberdi E, Ibarretxe G, Torre I, Matute C.
Departamento de Neurociencias, Universidad del Pais Vasco,
E-48940 Leioa, Vizcaya, Spain.
Department of Neurosciences, Faculty of Medicine and Dentistry,
University of the Basque Country, Leioa, Vizcaya, Spain
Carlos Matute Almau +34-946-012-865 onpmaalc@lg.ehu.es;
Oligodendrocytes are vulnerable to excitotoxic signals mediated
by AMPA receptors and by high- and low-affinity kainate receptors.
Here we investigated the nature of the cell death triggered by activation
of these receptors in primary cultures of oligodendrocytes
from the rat optic nerve.
Activation of AMPA receptors at both submaximal and maximal
concentrations of the agonist induced massive calcium entry,
mitochondrial depolarization, and a rise in the level of reactive oxygen
species that correlated with a decrease in the levels of reduced
glutathione.
In addition, excitotoxicity initiated by submaximal, but not maximal,
activation of AMPA receptors was prevented by caspase-3 blockade
and by the concomitant blockade of caspases 8 and 9.
In turn, maximal activation of high- or low-affinity kainate receptors
induced mitochondrial events and toxicity levels similar to those observed
with submaximal activation of AMPA receptors.
In contrast to AMPA receptor-mediated insults, calcineurin inhibition
or caspase-9 blockade was sufficient to prevent cell death triggered
by both types of kainate receptors.
Consistent with these results, prolonged glutamate receptor activation in
freshly isolated optic nerves caused selective activation of caspase-3
and chromatin condensation in oligodendrocytes.
Overall, the evidence presented here indicates that oligodendrocyte
death by excitotoxicity is mediated
by caspase-dependent and -independent mechanisms.
PMID: 14573531
free full text http://www.ehu.es/ingles/paginas/prin_i.htm
Glia. 2002 Sep; 39(3): 304-13.
Multiple angiotensin receptor subtypes
in normal and tumor astrocytes in vitro.
Fogarty DJ, Sanchez-Gomez MV, Matute C.
Department of Neurosciences, Faculty of Medicine and Dentistry,
University of the Basque Country, Leioa, Vizcaya, Spain.
Carlos Matute Almau +34-946-012-865 onpmaalc@lg.ehu.es;
A role for neuropeptide receptors in glial tumorigenesis has recently
been proposed.
Although angiotensin receptors are known to mediate proliferative
effects in many cell types, including brain astrocytes, the possible
participation of these receptors in glial tumorigenesis remains unknown.
In the present study, we have examined the expression of the molecularly
defined angiotensin receptor subtypes AT(1a), AT(1b), and AT(2) in
normal perinatal rat astrocytes
and in a panel of tumor adult astrocytoma cells,
using the reverse transcriptase-polymerase chain reaction (RT-PCR).
Subsequently, we compared the mitogenic effect of the angiotensins
A(1-8), A(2-8), A(3-8) and the heptapeptide "metabolite" A(1-7),
on both normal and tumor astrocytes,
measured in terms of the incorporation of tritiated thymidine.
Our results indicate that AT(1a), AT(1b), and AT(2) angiotensin
receptor mRNA is commonly expressed by many of these cells.
Of notable exception is the astrocytoma U373 which was not found
to express AT(1) or AT(2) mRNA.
Chronic (24-h) incubation of cells with A(1-8) and A(1-7) lead to the
induction of mitogenesis, even in the AT(1) and AT(2) mRNA negative
astrocytoma cell line U373.
Moreover, pharmacological analysis indicated that the observed
mitogenic effects are not mediated by the AT(1) or AT(2) type
receptors, but rather by a novel, specific A((1-7)) angiotensin
receptor, since mitogenesis was shown
to be partially blocked by the A(1-7) analogue D-Ala(7)A(1-7)
and by the protease inhibitor orthophenanthroline (100 microM).
Using Fura-2 spectrophotometry, we found that activation of this
receptor does not alter intracellular calcium levels;
however, preincubation with the protein kinase kinase inhibitor
U0126 (10 microM) was found to inhibit these mitogenic effects
partially.
Overall, these results which demonstrate that normal and tumor
astrocytes express a greater variety of angiotensin receptor subtypes
than previously thought,
support the idea that A(1-7) and its receptor signaling system may
play an important role in shaping the astrocyte population during
development.
Moreover, the untimely expression of this A((1-7)) receptor
may represent an important etiological component in the development
of brain astrocytomas.
Copyright 2002 Wiley-Liss, Inc. PMID: 12203396
free full text http://www.ehu.es/ingles/paginas/prin_i.htm
Carlos Matute, Elena Alberdi, Gaskon Ibarretxe,
Maria Victoria Sanchz-Gomez.
Excitotoxicity in glial cells.
European J. Pharmacology 2002; 447: 239-246.
Carlos Matute Almau +34-946-012-865 onpmaalc@lg.ehu.es;
Excitotoxicity results from prolonged activation of glutamate receptors
expressed by cells in the central nervous system (CNS).
This cell death mechanism was first discovered in retinal ganglion cells
and subsequently in brain neurons.
In addition, it has been recently observed that CNS glial cells can also
undergo excitotoxicity.
Among them, oligodendrocytes are highly vulnerable to glutamate signals
and alterations in glutamate homeostasis may contribute to demyelinating
disorders.
We review here the available information on excitotoxity in CNS glial
cells and its putative relevance to glio-pathologies. PMID: 12151015
Trends Neurosci. 2001 Apr; 24(4): 224-30.
The link between excitotoxic oligodendroglial death and demyelinating
diseases.
Matute C, Alberdi E, Domercq M, Perez-Cerda F, Perez-Samartin A,
Sanchez-Gomez MV.
Departamento de Neurociencias, Universidad del Pais Vasco,
48940 Leioa, Spain. Carlos Matute Almau +34-946-012-865
onpmaalc@lg.ehu.es;
Oligodendrocytes, the myelinating cells of CNS axons, are highly
vulnerable to excitotoxic signals mediated by glutamate receptors of the
AMPA and kainate classes.
Receptors in these cells are commonly activated by glutamate that is
released from axons and glial cells.
In addition, oligodendrocytes contribute to the control of extracellular
glutamate levels by means of their own transporters.
However, acute and chronic alterations in glutamate homeostasis
can result in overactivation of AMPA and kainate receptors
and subsequent excitotoxic oligodendroglial death.
Furthermore, demyelinating lesions caused by excitotoxins
can be similar to those observed in multiple sclerosis.
This, together with the effect of AMPA and kainate receptor
antagonists in ameliorating the neurological score of animals with
experimental autoimmune encephalomyelitis
(an animal model of multiple sclerosis), indicates that
oligodendrocyte excitotoxicity could be involved in the pathogenesis of
demyelinating disorders. Publication Types: Review Review Literature
PMID: 11250007
Adv Exp Med Biol. 1999; 468: 97-107.
On how altered glutamate homeostasis may contribute to demyelinating
diseases of the CNS.
Matute C, Domercq M, Fogarty DJ, Pascual de Zulueta M,
Sanchez-Gomez MV.
Departamento de Neurociencias Universidad del Pais Vasco,
Vizcaya, Spain.
Carlos Matute Almau +34-946-012-865 onpmaalc@lg.ehu.es;
Glial cells communicate reciprocally with neurons in multiple ways,
both in synaptic and non-synaptic regions of the central nervous system.
In the latter, neuron to glial and glial to glial signals can be mediated by
neurotransmitters.
Here, we review the presence and some of the functional properties of
glutamate transporters and receptors in oligodendrocytes.
In addition, we present data illustrating that alterations in glutamate
homeostasis can be excitotoxic to oligodendroglia and that the tissue
lesions caused by overactivation of glutamate receptors resemble those
observed in demyelinating diseases such as multiple sclerosis.
Overall, this information indicates that aberrant glutamate signaling may
contribute to the development of some white matter pathologies.
Publication Types: Review Review, Tutorial PMID: 10635022
2. J Neurosci Res. 1996 Nov 15; 46(4): 427-37.
Pathophysiology of oligodendroglial excitotoxicity.
Yoshioka A, Bacskai BJ, Pleasure DE.
Division of Neurology, Children's Hospital of Philadelphia, PA 19104, USA.
DAVID E PLEASURE pleasure@email.chop.edu; 215-590-2090
Oligodendrocyte-like cells (OLD) derived from the rat oligodendroglial
precursor line, CG-4, express Ca(2+)-permeable
non-methyl-D-aspartate glutamate receptor channels (GluR).
Exposure to kainate, an L-glutamate analogue,
markedly elevates OLC Ca2+ influx and cytosolic [Ca2+],
and results in damage to
both OLC plasma membrane and OLC nuclear DNA.
Two observations indicate that kainate-induced OLC internucleosomal
DNA nicking is not simply a delayed consequence of cell necrosis:
1) there is no temporal lag between onset of plasma membrane injury and
of DNA nicking; and
2) aurintricarboxylic acid, an endonuclease inhibitor, blocks
kainate-induced damage to the plasma membrane.
N-acetyl-L-cysteine also inhibits OLC kainate injury, suggesting that
reactive oxygen species participate in OLC excitotoxicity.
Kainate-induced OLC Ca2+ influx and excitotoxicity are blocked by
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA),
indicating that these kainate effects are mediated by AMPA-GluR.
AMPA and L-glutamate
fail to elicit OLC damage unless cyclothiazide,
an AMPA-GluR desensitization blocker, is present.
OLC express both the "flip" and "flop" forms of GluR2,
GluR3, and GluR4 mRNAs, but neither flip nor flop GluR1 mRNA.
These data, together with the restriction of the desensitization-blocking
activity of cyclothiazide to GluR containing flip-encoded GluR subunits,
and the sharply diminished Ca2+ permeability of GluR
ontaining edited GluR2,
suggest OLC excitotoxicity is mediated by AMPA-GluR
that contain flip GluR3 and/or flip GluR4 protein subunits,
but neither flip nor flop GluR2 protein subunits.
Rapid desensitization of these GluR is likely to be important in protecting
cells of the oligodendroglial lineage from excitotoxicity. PMID: 8950702
J Biol Chem. 1997 Jan 3; 272(1): 647-56.
N-methyl-D-aspartate receptors expressed in a nonneuronal cell line
mediate subunit-specific increases in free intracellular calcium.
Grant ER, Bacskai BJ, Pleasure DE, Pritchett DB, Gallagher MJ,
Kendrick SJ, Kricka LJ, Lynch DR.
for free full text http://www.jbc.org/cgi/content/full/272/1/647
Elfrida R. Grant , Brian J. Bacskai §, David E. Pleasure §¶, Dolan B.
Pritchett ¶, Michael J. Gallagher , Shelley J. Kendrick , Larry J. Kricka
and David R. Lynch §¶** 73 references
From the Departments of Pharmacology, § Neurology, ¶ Pediatrics,
Pathology and Laboratory Medicine, University of Pennsylvania School
of Medicine, Children's Seashore House,
Philadelphia, Pennsylvania 19104
DAVID E PLEASURE pleasure@email.chop.edu 215-590-2090
N-methyl-D-aspartate (NMDA) receptors can mediate cell death
in neurons and in non-neuronal cells that express recombinant NMDA
receptors.
In neurons, increases in intracellular calcium correlate with NMDA
receptor-mediated death, supporting a key role for loss of cellular
calcium homeostasis in excitotoxic cell death.
In the present study, free intracellular calcium concentrations were
examined in response to activation of recombinant NMDA receptors
expressed in human embryonic kidney 293 cells.
Intracellular calcium was measured in transfected cell populations by
cotransfection with the calcium-sensitive, bioluminescent protein aequorin
and by single cell imaging with the fluorescent calcium indicator fluo-3.
Agonist application to NR1/2A or NR1/2B-transfected cells elicited
robust rises in intracellular calcium.
NR1/2A responses were inhibited by the noncompetitive antagonists
MK-801 and dextromethorphan and were dependent on extracellular
calcium but not on intracellular calcium stores.
In contrast, no detectable intracellular calcium responses were observed
in NR1/2C-transfected cells.
These findings indicate that NMDA receptors in the absence of other
neuron-specific factors can mediate increases in intracellular calcium with
subunit specificity and extracellular calcium dependence.
PMID: 8995308
http://jpet.aspetjournals.org/cgi/co...full/300/3/717 free full text
Pharmacology and Experimental Therapeutics.
March 2002; 300 (3): 717-723.
Excitotoxicity: Perspectives Based on N-Methyl-D-Aspartate
Receptor Subtypes
David R. Lynch and Rodney P. Guttmann
Departments of Neurology (D.R.L.), Pediatrics (D.R.L.),
and Pharmacology (R.P.G.), University of Pennsylvania and
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
lynch@pharm.med.upenn.edu; 215-590-2242
rodneyg@email.uky.edu; (859) 257-1412 x275
Since excitotoxicity has been implicated in a variety of neuropathological
conditions, understanding the pathways involved in this type of cell death
is of critical importance to the future clinical treatment of many diseases.
The N-methyl-D-aspartate (NMDA) receptor has become a primary
focus of excitotoxic research because early studies demonstrated that
antagonism of this receptor subtype was neuroprotective.
However, initial pharmacological agents were not clinically useful due to
the adverse effects of complete NMDA receptor blockade.
Understanding the biochemical properties of the multitude of NMDA
receptor subtypes offers the possibility of developing more effective and
clinically useful drugs. With the discovery of the basis of heterogeneity
of NMDA receptors through molecular biological approaches,
many new potential therapeutic targets have been uncovered,
and several model systems have been developed for the study of
NMDA receptor-mediated cell death.
This review discusses these models and the current understanding
of the relationship between NMDA receptor subtypes and excitotoxicity.
3. Mol Cell Biochem. 2003 Jan; 243(1-2): 139-45.
Prolonged glutamate excitotoxicity: effects on mitochondrial antioxidants
and antioxidant enzymes. [ strong toxicity of MSG in rat brains ]
Singh P, Mann KA, Mangat HK, Kaur G.
Neurochemistry and Neuroendocrinology Laboratory, Department of
Biotechnology, Guru Nanak Dev University, Amritsar, India.
Glutamate, a major excitatory amino acid neurotransmitter is also an
endogenous excitotoxin.
The present study examined the prolonged and delayed effects of
glutamate excitotoxicity on mitochondrial lipid peroxidation and
antioxidant parameters in different brain regions, namely,
cerebral hemisphere, cerebellum, brain stem and diencephalon.
Wistar rats (male) were exposed to monosodium glutamate (MSG)
(4 mg x g body wt(-1), i.p.) for 6 consecutive days and sacrificed
on 30th and 45th day after last MSG dose.
MSG treatment markedly decreased the mitochondrial manganese
superoxide-dismutase (Mn-SOD), catalase
and reduced glutathione (GSH) content,
and increased the lipid peroxidation (LPx), uric acid and
glutathione peroxidase (GPx) activity.
These results indicate that oxidative stress produced by glutamate in
vulnerable brain regions may persist for longer periods and mitochondrial
function impairment is an important mechanism of excitatory amino acid
mediated neurotoxicity in chronic neurodegeneration. PMID: 12619899
4. Neurobiol Dis. 2003 Dec; 14(3): 336-48.
AMPA receptors are the major mediators of excitotoxic death in mature
oligodendrocytes.
Leuchtmann EA, Ratner AE, Vijitruth R, Qu Y, McDonald JW.
Center for the Study of Nervous System Injury, Washington University
School of Medicine, Box 8518, St. Louis, MO 63108, USA.
John Wood McDonald JMcDonald@WUSTL.EDU;
+1 314 454-7825 fax: +1 314 454-5300
Myelination of axons is important for central nervous system function,
but oligodendrocytes, which constitute CNS myelin, are vulnerable
to excitotoxic injury and death.
Although mature oligodendrocytes express functional
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)
and kainate-type glutamate receptors, the relative roles of these
subtypes in excitotoxicity are not well understood.
Using recently developed selective antagonists for subtypes of
ionotropic non-NMDA receptors, we addressed this issue.
By examining the pharmacological, biochemical, and morphologic
features of kainite-induced excitotoxic death, we also determined
whether it occurs by apoptosis, necrosis, or both.
We conclude that when mature oligodendrocytes die after exposure
to kainate:
(1) AMPA receptors are the most important mediators,
(2) kainate receptors play a smaller role, and
(3) death occurs predominantly by necrosis, not apoptosis.
PMID: 14678751
5. Annals of Neurology. 2003 May; 53 5); 588 - 595.
Interleukin-1 promotes oligodendrocyte death through glutamate
excitotoxicity.
Jennifer L. Takahashi, MD 1, Fabrizio Giuliani, MD 1,
Christopher Power, MD 1, Yoshinori Imai, MD 2,
V. Wee Yong, PhD 1 3 *
1 Department of Clinical Neurosciences, University of Calgary,
Calgary, Alberta, Canada
2 National Institute of Neuroscience, Kodaira, Tokyo, Japan
3 Department of Oncology, University of Calgary, Calgary,
Alberta, Canada email: V. Wee Yong vyong@ucalgary.ca;
*Correspondence to V. Wee Yong, Neuroscience Research Group,
University of Calgary, 3330 Hospital Drive,
Calgary, Alberta T2N 4N1, Canada
Funded by: Multiple Sclerosis Society of Canada
Canadian Institutes of Health Research; Grant Number: MT H246
Glutamate excitotoxicity is implicated in the progressive loss of
oligodendrocytes in multiple sclerosis, but how glutamate metabolism
is dysregulated in the disease remains unclear.
Because there is microglia activation in all stages of multiple sclerosis,
we determined whether a microglia product, interleukin-1,
could provide the mechanism for glutamate excitotoxicity.
We found that whereas interleukin-1 did not kill oligodendrocytes
in pure culture, it produced apoptosis of oligodendrocytes in coculture
with astrocytes and microglia.
This requirement for a mixed glia environment suggests that interleukin-1
impairs the well-described glutamate-buffering capacity of astrocytes.
In support, antagonists at AMPA/kainate glutamate receptors,
NBQX and CNQX,
blocked the interleukin-1 toxicity to oligodendrocytes.
Another microglia/macrophage cytokine, tumor necrosis factor-,
also evoked apoptosis of oligodendrocytes in a mixed glia environment
in an NBQX-blockable manner.
These results provide a mechanistic link between the persistent and
insidious microglia activation that is evident in all stages of multiple
sclerosis, with the recent appreciation that glutamate excitotoxicity leads
to the destruction of oligodendrocytes in the disease.
6. Neurology. 2003 Oct 28; 61(8): 1113-20.
Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in
multiple sclerosis.
Pitt DF, Nagelmeier IE, Wilson HC, Raine CS. dfpitt@yahoo.com;
Department of Neurology, Albert Einstein College of Medicine,
Bronx, NY, USA. Cedric S. Raine jni@aecom.yu.edu;
BACKGROUND:
Excitotoxic damage is a common pathologic event in a number of
neurologic diseases occurring after accumulation of excess extracellular
glutamate in the CNS and subsequent overstimulation
of glutamate receptors.
In gray matter, astrocytes take up synaptically released glutamate
and are thus key cells in maintaining glutamate homeostasis.
In white matter, oligodendrocytes have been shown to express
glutamate transporters, but their role in extracellular glutamate
removal is unclear.
OBJECTIVE:
To investigate whether cultured human fetal oligodendrocytes
functionally express the main glutamate transporters
EAAT-1 and EAAT-2.
METHODS:
Cultures of fetal human oligodendrocytes were examined by
immunocytochemistry and [3H]glutamate uptake, and the findings were
correlated with glutamate transporter expression in normal and multiple
sclerosis (MS) CNS tissue.
RESULTS:
Both EAAT-1 and EAAT-2 were expressed
by human oligodendrocytes in vitro.
Incubation of oligodendrocytes with the proinflammatory cytokine
tumor necrosis factor-alpha (TNFalpha) reduced EAAT-1 expression
and inhibited glutamate uptake by >75%.
Furthermore, in normal human white matter, oligodendrocytes
were found to be the predominant cells to express
EAAT-1 and EAAT-2, both at the mRNA and at the protein level.
A small number of astrocytes in white matter expressed these receptors,
more so EAAT-1 than EAAT-2.
In MS white matter, oligodendrocytes lost expression of
EAAT-1 and EAAT-2 receptors in the lesion vicinity.
CONCLUSIONS:
Oligodendrocytes appear to be predominant cells for glutamate
clearance in human white matter.
Glutamate receptor expression and glutamate removal were defective
in MS white matter, possibly mediated by TNFalpha, changes that
might underlie high extracellular glutamate and an increased risk for
glutamate excitotoxicity. PMID: 1458167
7. Neuroscience. 2004; 123(2): 441-9.
Excitotoxic insults to the optic nerve alter visual evoked potentials.
Soto A, Perez-Samartin AL, Etxebarria E, Matute C.
Departamento de Neurociencias, Universidad del Pais Vasco,
E-48940 Leioa, Vizcaya, Spain.
Carlos Matute Almau +34-946-012-865 onpmaalc@lg.ehu.es;
Excitotoxic oligodendroglial death is one of the mechanisms which
has been proposed to underlie demyelinating diseases of the CNS.
We describe here functional consequences of excitotoxic lesions to the
rabbit optic nerve by studying the visual evoked potentials (VEPs)
measured in the visual cortex.
Nerves were slowly infused with the excitotoxin kainate a
subcutaneously implanted osmotic pump which delivered the
toxin through a cannula onto the optic nerve.
Records of VEPs were obtained before pump implantation and at
1, 3 and 7 days post-implantation, and weekly evaluated thereafter
for up to 4 months.
We observed that the VEPs generated by light stimuli progressively
changed in both amplitude and profile after the lesion as well as in
comparison to those generated in control animals infused with vehicle.
Histological examination of the damage caused by the excitotoxic insult
showed that large areas of the optic nerve were demyelinated and their
axons distorted.
These observations were confirmed and extended by
immunohistochemical analyses using markers to neurofilaments,
myelin basic protein and the oligodendrocyte marker APC.
The results of the present paper indicate that the consequences of
excitotoxicity in the optic nerve share functional and morphological
alterations which are found in demyelinating disorders.
In addition, this experimental paradigm may be useful to evaluate the
functional recovery of demyelinated optic nerves following various
repair strategies. PMID: 14698751
http://www.ehu.es/ingles/paginas/prin_i.htm
Neurobiol Dis. 2002 Mar;9(2):234-43.
Ca(2+) influx through AMPA or kainate receptors alone is sufficient to
initiate excitotoxicity in cultured oligodendrocytes.
Alberdi E, Sanchez-Gomez MV, Marino A, Matute C.
Departamento de Neurociencias, Universidad del Pais Vasco,
Leioa, Vizcaya, Spain.
8. Blaylock RL.
Interactions of cytokines, excitotoxins and reactive nitrogen and oxygen
species in autism spectrum disorders.
Journal of American Nutraceutical Association 6: 21-35, 2003.
[ Not in PubMed ]
9. Blaylock RL.
Chronic microglial activation and excitotoxicity secondary to excessive
immune stimulation: possible factors in Gulf War Syndrome and autism.
Journal American Physicians and Surgeons, Summer, 2004.
[ Not in PubMed ]
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http://groups.yahoo.com/group/aspartameNM/message/97
Lancet website aspartame letter 1999.07.29:
Excitotoxins 1999 Part 1/3 Blaylock: Murray 2000.01.14 rmforall
The Medical Sentinel Journal 1999 Fall; (95 references)
http://www.dorway.com/blayenn.html
Russell L. Blaylock, MD 601-982-1175 Madison, Mississippi
"Excitotoxins: The Taste that Kills", 1977, 298 p., 493 references.
"Health and Nutrition Secrets that can save your life", 2002, 459 p.,
558 + 30 references, $ 30 http://www.russellblaylockmd.com/
http://www.truthinlabeling.org/ Truth in Labeling Campaign [MSG]
Adrienne Samuels, PhD The toxicity/safety of processed
free glutamic acid (MSG): a study in suppression of information.
Accountability in Research 1999; 6: 259-310. 52-page review
P.O. Box 2532 Darien, Illinois 60561
858-481-9333 adandjack@aol.com
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