RE: Mixed Review for NAC

[Guest guest]

Bob,

According to Blaylock MD, who " wrote the book " on excitoxicity,

cysteine but not NAC is excitotoxic. Excitotoxins can have activity only

from the extracellular space, where they can activate the NMDA receptors and

trigger an excessive flow of calcium ions into the neuron. Cysteine converts

to cysteic acid and cysteine sulfinic acid outside the cell. Both of these

are potentially excitotoxic. NAC is however absorbed directly into the cell,

where it is used as a substrate in the synthesis of glutathione.

-gts

> Mixed Review for NAC

>

>

> " gts " <gts@...> said...

> > Here we see that NAC helps to protect the brain from the reactive

> aldehyde products of lipid peroxidation, and so may help protect against

> Alzheimer's disease.

>

> Here's some research regarding cysteine excitotoxicity. It appears to be

> based on cross-reaction to NMDA receptors. Those who utilize low

> prophylactic (0.5-2.0 gram) doses of cysteine or NAC (which dissociates

> into cysteine and acetyl ion) would probably consume low-dose

> methylcobalamin, lithium or dextromethorpan all of which are protective

> against excitotoxicity. I would not recommend either cysteine or NAC be

> used in pharmacologic dosages for subjects who already experience

> neurodegeneration in which excitotoxicity is a possible mechanism.

>

>

> http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve & db=P

ubMed & list_uids=11059810 & dopt=Abstract

Living requires gambling!

Bob Cruder

[Guest guest]

Bob,

According to Blaylock MD, who " wrote the book " on excitoxicity,

cysteine but not NAC is excitotoxic. Excitotoxins can have activity only

from the extracellular space, where they can activate the NMDA receptors and

trigger an excessive flow of calcium ions into the neuron. Cysteine converts

to cysteic acid and cysteine sulfinic acid outside the cell. Both of these

are potentially excitotoxic. NAC is however absorbed directly into the cell,

where it is used as a substrate in the synthesis of glutathione.

-gts

> Mixed Review for NAC

>

>

> " gts " <gts@...> said...

> > Here we see that NAC helps to protect the brain from the reactive

> aldehyde products of lipid peroxidation, and so may help protect against

> Alzheimer's disease.

>

> Here's some research regarding cysteine excitotoxicity. It appears to be

> based on cross-reaction to NMDA receptors. Those who utilize low

> prophylactic (0.5-2.0 gram) doses of cysteine or NAC (which dissociates

> into cysteine and acetyl ion) would probably consume low-dose

> methylcobalamin, lithium or dextromethorpan all of which are protective

> against excitotoxicity. I would not recommend either cysteine or NAC be

> used in pharmacologic dosages for subjects who already experience

> neurodegeneration in which excitotoxicity is a possible mechanism.

>

>

> http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve & db=P

ubMed & list_uids=11059810 & dopt=Abstract

Living requires gambling!

Bob Cruder

[Guest guest]

" gts " <gts@...> said...

> According to Blaylock MD, who " wrote the book " on

excitoxicity, cysteine but not NAC is excitotoxic. Excitotoxins can have

activity only from the extracellular space, where they can activate the

NMDA receptors and trigger an excessive flow of calcium ions into the

neuron. Cysteine converts to cysteic acid and cysteine sulfinic acid

outside the cell. Both of these are potentially excitotoxic. NAC is

however absorbed directly into the cell, where it is used as a substrate

in the synthesis of glutathione.

That's what he would wish were true. Does he by chance sell or license a

product containing NAC?

A group of enzymes collectively called acylases catalyze the attachment

or removal of acetyl groups. Unless one can guarantee that NAC doesn't

come into contact with acylase between the time it is ingested and the

time that it approaches the target neuron, one will always see an

equilibrium mix of NAC and free cysteine.

The acylases are ubiquitous, present in every tissue tested. It appears

that unless one consumes a large enough bolus of NAC to saturate the

acylases in the path between the gut and the brain the only benefit that

one derives from NAC vs cysteine is the reduced tendency to oxidize to

cystine and a reduced tendency to donate its sulfhydryl group to other

digestive contents.

See :

http://www.medscape.com/server-java/MedLineApp?/member-search/getdoc.cgi?ord=7 & s\

earchid=2 & have_local_holdings_file=0 & local_journals_only=0

Immunohistochemical localization of the acylases that catalyze the

deacetylation of N-acetyl-L-cysteine and haloalkene-derived

mercapturates.

Drug Metab Dispos 2000

Jun;28(6):625-32 (ISSN: 0090-9556)

Uttamsingh V; Baggs RB; Krenitsky DM; Anders

MW [Find other articles with these Authors]

Department of Pharmacology and Physiology, University

of Rochester Medical Center, Rochester, New York, USA.

which says...

" Both acylases were identified by immunohistochemistry in several rat

organs, including kidney, liver, lung, brain, stomach, intestines,

adrenals, pancreas, and testis, indicating that acylase activity is

widespread in rat tissues. "

[Guest guest]

Bob,

> That's what he would wish were true. Does he by chance sell or license a

> product containing NAC?

Dr. Blaylock is a board certified neurosurgeon. I believe he actually coined

the term " excitotoxin " . As far as I know he sells nothing other than his

services as a brain surgeon and of course his book on the subject of

excitotoxins. The book is titled " Excitotoxins: The Taste that Kills " . He

wrote the book after his father died with Parkinson's disease. I have a copy

in hand.

From the first abstract you posted we can see that cysteine itself is *not*

a true excitotoxin; its excitotoxic effects are mediated by some other

means. As stated in the abstract: " L-Cysteine lacks the omega carboxyl group

required for excitotoxic actions via excitatory amino acid receptors, yet it

evokes N-methyl-D-aspartate (NMDA) -like excitotoxic neuronal death and

potentiates the Ca2+ influx evoked by NMDA. "

Blaylock states that the damage from cysteine is actually from its

metabolites cysteine sulfinic acid and cysteic acid. These metabolites of

cysteine appear extracellularly; they are excitotoxic in the extracellular

space. Strictly speaking cysteine itself is non-toxic. So then for NAC to

cause toxicity it must first convert to cysteine and then to either of these

toxic metabolites, and it must do so outside of the neuron.

Quote from Blaylock's book: " In the first edition of 'Excitotoxins: The

Taste that Kills' the relation between l-cysteine and excitotoxic brain

injury was covered. Since then a multitude of people have called or written

to ask if N-Acetyl-Cysteine is also an excitotoxin. So here it is:

N-ACETYL-CYSTEINE IS NOT AN EXCITOTOXIN AND EVEN IN HIGH DOSES DOES NOT SEEM

TO DAMAGE THE BRAIN. "

[emphasis his]

- M. Blaylock M.D. " Excitotoxins: The Taste that Kills " pg 234.

Blaylock then goes on to state that NAC appears safe even at massive doses

of 4 to 6 grams.

re: acylase

I've included an abstract below which suggests that the primary acylase

activity in the brain occurs WITHIN the neuron, thus preventing the

possibility of excitoxicity. (Excitoxicity is the excess excitation of NMDA

receptors on the surface of neurons due to excessive excitatory amino acids

in the extracellular space. It cannot happen from within the cell.)

From the abstract: " These data suggest that neurons in culture, contain an

acylase activity which allows them to generate from extracellular NAC as

precursor intracellular cysteine in concentrations sufficient for

glutathione synthesis. "

Simply stated, cysteine presents no danger to the neuron once inside the

neuron, and NAC acts as substrate for cysteine inside the neuron via

acylase. Cystiene is in turn a substrate for glutathione, a powerful

antioxidant which acts to prevent rather than cause excitoxicity.

ABSTRACT:

N-acetylcysteine, but not methionine or 2-oxothiazolidine-4-carboxylate,

serves as cysteine donor for the synthesis of glutathione in cultured

neurons derived from embryonal rat brain.

Dringen R, Hamprecht B.

Physiologisch-chemisches Institut der Universitat, Tubingen, Germany.

ralf.dringen@...

The ability of neurons to metabolize sulfur-containing compounds to cysteine

was investigated using as indicator the glutathione content in neuron-rich

primary cultures derived from the brains of embryonal rats. The-glutathione

content of these cultures was doubled during a 4-h incubation in a minimal

medium containing cysteine, glutamine and glycine. In contrast, absence of

cysteine or replacement of cysteine by methionine or

2-oxothiazolidine-4-carboxylate failed to increase the glutathione content

of cultured neurons. Besides cysteine, N-acetylcysteine (NAC) also caused in

the millimolar range, a concentration-dependent increase in the neuronal

glutathione content during a 4-h incubation. These data suggest that neurons

in culture, contain an acylase activity which allows them to generate from

extracellular NAC as precursor intracellular cysteine in concentrations

sufficient for glutathione synthesis. In contrast, generation of cysteine

from 2-oxothiazolidine-4-carboxylate by the reaction of 5-oxoprolinase or

from methionine by the transsulfuration pathway appears not to take place in

these cultured neurons.

-gts

[Guest guest]

Bob,

> That's what he would wish were true. Does he by chance sell or license a

> product containing NAC?

Dr. Blaylock is a board certified neurosurgeon. I believe he actually coined

the term " excitotoxin " . As far as I know he sells nothing other than his

services as a brain surgeon and of course his book on the subject of

excitotoxins. The book is titled " Excitotoxins: The Taste that Kills " . He

wrote the book after his father died with Parkinson's disease. I have a copy

in hand.

From the first abstract you posted we can see that cysteine itself is *not*

a true excitotoxin; its excitotoxic effects are mediated by some other

means. As stated in the abstract: " L-Cysteine lacks the omega carboxyl group

required for excitotoxic actions via excitatory amino acid receptors, yet it

evokes N-methyl-D-aspartate (NMDA) -like excitotoxic neuronal death and

potentiates the Ca2+ influx evoked by NMDA. "

Blaylock states that the damage from cysteine is actually from its

metabolites cysteine sulfinic acid and cysteic acid. These metabolites of

cysteine appear extracellularly; they are excitotoxic in the extracellular

space. Strictly speaking cysteine itself is non-toxic. So then for NAC to

cause toxicity it must first convert to cysteine and then to either of these

toxic metabolites, and it must do so outside of the neuron.

Quote from Blaylock's book: " In the first edition of 'Excitotoxins: The

Taste that Kills' the relation between l-cysteine and excitotoxic brain

injury was covered. Since then a multitude of people have called or written

to ask if N-Acetyl-Cysteine is also an excitotoxin. So here it is:

N-ACETYL-CYSTEINE IS NOT AN EXCITOTOXIN AND EVEN IN HIGH DOSES DOES NOT SEEM

TO DAMAGE THE BRAIN. "

[emphasis his]

- M. Blaylock M.D. " Excitotoxins: The Taste that Kills " pg 234.

Blaylock then goes on to state that NAC appears safe even at massive doses

of 4 to 6 grams.

re: acylase

I've included an abstract below which suggests that the primary acylase

activity in the brain occurs WITHIN the neuron, thus preventing the

possibility of excitoxicity. (Excitoxicity is the excess excitation of NMDA

receptors on the surface of neurons due to excessive excitatory amino acids

in the extracellular space. It cannot happen from within the cell.)

From the abstract: " These data suggest that neurons in culture, contain an

acylase activity which allows them to generate from extracellular NAC as

precursor intracellular cysteine in concentrations sufficient for

glutathione synthesis. "

Simply stated, cysteine presents no danger to the neuron once inside the

neuron, and NAC acts as substrate for cysteine inside the neuron via

acylase. Cystiene is in turn a substrate for glutathione, a powerful

antioxidant which acts to prevent rather than cause excitoxicity.

ABSTRACT:

N-acetylcysteine, but not methionine or 2-oxothiazolidine-4-carboxylate,

serves as cysteine donor for the synthesis of glutathione in cultured

neurons derived from embryonal rat brain.

Dringen R, Hamprecht B.

Physiologisch-chemisches Institut der Universitat, Tubingen, Germany.

ralf.dringen@...

The ability of neurons to metabolize sulfur-containing compounds to cysteine

was investigated using as indicator the glutathione content in neuron-rich

primary cultures derived from the brains of embryonal rats. The-glutathione

content of these cultures was doubled during a 4-h incubation in a minimal

medium containing cysteine, glutamine and glycine. In contrast, absence of

cysteine or replacement of cysteine by methionine or

2-oxothiazolidine-4-carboxylate failed to increase the glutathione content

of cultured neurons. Besides cysteine, N-acetylcysteine (NAC) also caused in

the millimolar range, a concentration-dependent increase in the neuronal

glutathione content during a 4-h incubation. These data suggest that neurons

in culture, contain an acylase activity which allows them to generate from

extracellular NAC as precursor intracellular cysteine in concentrations

sufficient for glutathione synthesis. In contrast, generation of cysteine

from 2-oxothiazolidine-4-carboxylate by the reaction of 5-oxoprolinase or

from methionine by the transsulfuration pathway appears not to take place in

these cultured neurons.

-gts

[Guest guest]

" gts " <gts@...> said...

>From the first abstract you posted we can see that cysteine itself is

*not* a true excitotoxin; its excitotoxic effects are mediated by some

other means. As stated in the abstract: " L-Cysteine lacks the omega

carboxyl group required for excitotoxic actions via excitatory amino

acid receptors, yet it evokes N-methyl-D-aspartate (NMDA) -like

excitotoxic neuronal death and potentiates the Ca2+ influx evoked by

NMDA. "

>Blaylock states that the damage from cysteine is actually from its

metabolites cysteine sulfinic acid and cysteic acid. These metabolites

of cysteine appear extracellularly; they are excitotoxic in the

extracellular space. Strictly speaking cysteine itself is non-toxic. So

then for NAC to cause toxicity it must first convert to cysteine and

then to either of these toxic metabolites, and it must do so outside of

the neuron.

Whether excitotoxicity derives from cysteine or a metabolite is

irrelevant unless one can show that the toxic process is wholly

extracellular, that de-acetylation of NAC is wholly intra-neuronal and

that there is no reverse leakage of cysteine back out of the neuron. The

largest task, so far ignored is to explain how NAC gets to the neuron

in-vivo without suffering prior conversion to cysteine.

> N-ACETYL-CYSTEINE IS NOT AN EXCITOTOXIN AND EVEN IN HIGH DOSES DOES

NOT SEEM TO DAMAGE THE BRAIN. "

> [emphasis his]

> - M. Blaylock M.D. " Excitotoxins: The Taste that Kills " pg 234.

> Blaylock then goes on to state that NAC appears safe even at massive

doses of 4 to 6 grams.

Opinions are worthless without the references. I personally believe that

cysteine itself is safe at that dosage and have seen no in-vivo evidence

to the contrary.

> I've included an abstract below which suggests that the primary

acylase activity in the brain occurs WITHIN the neuron, thus preventing

the possibility of excitoxicity.

....

>From the abstract: " These data suggest that neurons in culture, contain

an acylase activity which allows them to generate from extracellular NAC

as precursor intracellular cysteine in concentrations sufficient for

glutathione synthesis. "

That proves exactly the point I was trying to make. Both sources have

utilized in-vitro studies which abstract the behavior of a single

tissue. A similar argument has been made regarding the beneficial

effects of gamma vs alpha tocopherol. It was based on in-vitro studies

that ignored the near-complete destruction of the gamma form in its

first pass through the liver. I maintain that orally administered NAC is

for the most part de-acetylated before it reaches the general

circulation and have seen no evidence proving otherwise.

How about we agree on the superiority of NAC for intrathecal

administration via direct catheter to the ventricles?

Bob Cruder

[Guest guest]

Bob,

> Whether excitotoxicity derives from cysteine or a metabolite is

> irrelevant unless one can show that the toxic process is wholly

> extracellular

It is wholly extracellular in its activation, Bob, by definition.

Excitoxicity occurs when excitatory amino acids (EAAs) activate, in excess,

the NMDA receptors on the surface of neurons. That is by definition. There

is no excitoxicity where there is no extracellular stimulation by EEAs of

the NMDA receptors.

The EAA itself is not directly toxic to the cell from within or without. The

damage is from excessive free-radicals released when excessive calcium ions

flow into the cell from the extracellular space, causing the neuron to fire

excessively.

So then NAC is absorbed into the cell, where it becomes cysteine via acylase

and then acts as a substrate to glutathione. No damage anywhere in that

process. In fact quite the contrary, as glutathione helps to quench any

free-radical acitivity that might ensue. Does some NAC get converted to

cysteine in the general circulation before it gets to the brain? Probably,

but the entire premise of these acetylated amino acids is that they are more

readily absorbed into cells. Would you make the same arguments against

acetyl-l-carnitine and acetyl-l-tyrosine? You are basically accusing the

supplement industry as a whole of being misguided or worse in marketing

acetylated versions of amino acids, because in your view they are no

different than the non-acetylated forms.

I'll look for some clinical evidence to support Blaylock's claim that NAC is

not excitotoxic, but given that he is the world's foremost authority on the

subject of excitotoxins I am inclined to accept his view over yours

regardless. He quite literally wrote the book on the subject of

excitotoxins.

-gts

[Guest guest]

On Wed, 13 Jun 2001 22:18:57 -0400

" gts " <gts@...> wrote:

> Bob,

>

> > Whether excitotoxicity derives from cysteine or a

> metabolite is

> > irrelevant unless one can show that the toxic process

> is wholly

> > extracellular

>

> It is wholly extracellular in its activation, Bob, by

> definition.

> Excitoxicity occurs when excitatory amino acids (EAAs)

> activate, in excess,

> the NMDA receptors on the surface of neurons. That is by

> definition. There

> is no excitoxicity where there is no extracellular

> stimulation by EEAs of

> the NMDA receptors.

>

That is a circular argument. The entire process includes the

generation of the toxin and its transport to the receptors.

It includes transport of the toxin's precursors to the

location where it is metabolized into the active toxin.

Let me repeat that I've seen no in-vivo study to show that

NAC survives in its acetylated form in the brain. I've also

seen nothing in-vivo to show that non-acetylated cysteine is

transported and metabolized in the fashion described.

What is claimed based on in-vitro studies may be the result

of the experimental situation, namely presenting a substance

at a location and a concentration that would not be possible

with a living subject.

>Would you make the same

> arguments against

> acetyl-l-carnitine and acetyl-l-tyrosine?

Both suffer less degradation in the stomach and are better

absorbed than their non-acetylated counterparts. Whether

they make it to general circulation without being

de-acetylated is a separate question.

> You are

> basically accusing the

> supplement industry as a whole of being misguided or

> worse in marketing

> acetylated versions of amino acids, because in your view

> they are no

> different than the non-acetylated forms.

>

I didn't say that. There was once a similar argument

regarding whether DHEA or DHEAS was superior for

supplementation. Both interconvert so rapidly in-vivo that

all of the claims were merely bogus attempts to claim

product differentiation. As one can prove anything with

out-of-context biblical quotations, one can also prove

anything with a contrived in-vitro study.

The recent in-vitro study " proving " that vitamin C is

pro-oxidant flies in the face of a recently completed

in-vivo study in humans where middle age to old-age subjects

had almost a 50% decrease in death rate for the quartile

with the highest ascorbate level vs those with the lowest.

Both the pro-supplement and anti-supplement side will tout

any in-vitro study and assume that we're too stupid to ask

any further questions.

> I'll look for some clinical evidence to support

> Blaylock's claim that NAC is

> not excitotoxic, but given that he is the world's

> foremost authority on the

> subject of excitotoxins I am inclined to accept his view

> over yours

> regardless. He quite literally wrote the book on the

> subject of

> excitotoxins.

It's wunnerful that we are both free to think what we wish.

Sadly, I've spent lots of money myself on books that string

together a series of in-vitro results, rarely replicated or

peer-reviewed but selected to support a conclusion to which

the author is emotionally committed.

I'll probably keep buying them but won't praise such authors

in this forum of intelligent readers.

Bob Cruder