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New antioxidant, N-acetylcysteine amide (AD4), able to cross BBB

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Unread 01-12-2008, 11:27 AM   #1
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Default New antioxidant, N-acetylcysteine amide (AD4), able to cross BBB

Yissum and Eucalyptus Sign Licensing Agreement for the Development of a Small Molecule for the Treatment of Neurodegenerative Diseases


JERUSALEM--(BUSINESS WIRE)--Jan 8, 2008 - Yissum Ltd., the technology transfer company of the Hebrew University of Jerusalem, today announced that it has licensed an orally-available small molecule for several biological indications including the treatment of neurodegenerative diseases to Eucalyptus Ltd. The molecule is an antioxidant that overcomes the blood-brain barrier.

"This invention, by Professor Daphne Atlas, jointly developed with Dr. Daniel Offen and Professor Eldad Melamed, is a breakthrough in the treatment of oxidative stress, which plays a major role in CNS disorders," stated Nava Swersky Sofer, CEO of Yissum. "We are delighted to collaborate with Professor Ashley Bush, CSO, Eucalyptus, a leading expert in Alzheimer's research to take our invention into the clinic for the benefit of patients."



Under the terms of the agreement, Eucalyptus has acquired worldwide exclusive rights to develop and commercialize the molecule and Yissum together with Ramot, the technology transfer company of Tel Aviv University, and Mor Research Applications, the technology transfer company of Clalit Health Services, will receive upfront payments, milestone payments in accordance with development progress and royalties from sales of final products.

The molecule, N-acetylcysteine amide (AD4), is an antioxidant for the prevention and treatment of Parkinson's, Alzheimer's, multiple sclerosis and other neurodegenerative diseases that are linked to oxidative stress, and also has broader applications in biology. Oxidative stress, induced by free radicals, plays an important role in the progression of neurodegenerative and age-related diseases, causing damage to proteins, DNA, and lipids. For example, increasing evidence correlates Parkinson's disease with the accumulation of oxidative damage in specific neurons in the brain. AD4 is administered orally, and is able to cross the blood-brain barrier, thus overcoming a major obstacle of central nervous system (CNS) directed drugs.

Pre-clinical data showed the ability of AD4 to protect cells in culture from oxidative damage. Furthermore, the molecule was shown to protect neuronal cells from damage in rodent models of both Parkinson's disease and multiple sclerosis. The low toxicity of AD4, as evidenced in the lab, together with its neuroprotective function and high bioavailability make it highly suitable for the treatment of CNS disorders.

The molecule was invented by Daphne Atlas, Ph.D., Professor of Neurochemistry at the Hebrew University of Jerusalem, Israel. The work was performed in collaboration with Dr. Daniel Offen, Ph.D. from the Tel Aviv University, Israel and Eldad Melamed, MD, Professor and Chairman of the Department of Neurology at the Rabin Medical Center, Petah Tiqva, Israel.

"In our aging society, in which neurodegenerative diseases have become more common, there is a growing need for safe and effective drugs for age-related diseases. AD4 which overcomes the blood-brain barrier, is an excellent candidate for both the prevention and treatment of various neurodegenerative disorders," commented Prof. Daphne Atlas.

Professor Ashley Bush, CSO, Eucalyptus, added "We are excited to be able to progress the pioneering work of our Israeli collaborators towards commercialization. I am very confident that AD4 will be therapeutically useful for several major neurological disorders, certain major psychiatric conditions as well as several other biological applications. I expect this to be a rapid development project."

About Yissum

Yissum was founded in 1964 to protect the Hebrew University's intellectual property and commercialise it. $1 Billion in annual sales are generated by products based on Hebrew University technologies licensed out by Yissum. Ranked among the top technology transfer companies in the world, Yissum has registered 5000 patents covering 1400 inventions; licensed out 400 technologies and spun out 60 companies. Yissum's business partners span the globe and include companies such as Novartis, Microsoft, Johnson & Johnson, Merck, Intel, Teva and many more. For further information please visit www.yissum.co.il.

Contact

Yissum Ltd.
Tsipi Haitovsky, Media Liaison, +972-52-598-9892
tsipih@netvision.net.il
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Unread 01-12-2008, 12:36 PM   #2
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Default What is the difference from N-Acetyl-Cysteine (NAC) ?

With reference to another related thread? : http://neurotalk.psychcentral.com/sh...acetylcysteine
Two questions spring to my mind as a layman on such topics:
1) Is this new drug different from NAC?
2) Does this mean that NAC do not cross BBB?
(There is a lot going on and the light shed by the more knowledgable members is very valuable and greatly appreciated.)
I M A R K

Last edited by imark3000; 01-12-2008 at 12:54 PM. Reason: spelling
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Unread 01-12-2008, 03:29 PM   #3
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Default Nac

good question--ol CS are you around???madelyn
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Unread 01-23-2008, 08:09 PM   #4
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"Systemic administration of NAC can deliver cysteine to the brain and raise GSH levels in the CNS"......


European Journal of Neuroscience

Volume 27 Issue 1 Page 20-30, January 2008

Oxidative stress on EAAC1 is involved in MPTP-induced glutathione depletion and motor dysfunction

* Koji Aoyama,
* Nobuko Matsumura,
* Masahiko Watabe and
* Toshio Nakaki

ABSTRACT:


Excitatory amino acid carrier 1 (EAAC1) is a glutamate transporter expressed on mature neurons in the CNS, and is the primary route for uptake of the neuronal cysteine needed to produce glutathione (GSH).

Parkinson's disease (PD) is a neurodegenerative disorder pathogenically related to oxidative stress and shows GSH depletion in the substantia nigra (SN). Herein, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an experimental model of PD, showed reduced motor activity, reduced GSH contents, EAAC1 translocation to the membrane and increased levels of nitrated EAAC1.

These changes were reversed by pre-administration of n-acetylcysteine (NAC), a membrane-permeable cysteine precursor.

Pretreatment with 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, also prevented both GSH depletion and nitrotyrosine formation induced by MPTP. Pretreatment with hydrogen peroxide, l-aspartic acid β-hydroxamate or 1-methyl-4-phenylpyridinium reduced the subsequent cysteine increase in midbrain slice cultures. Studies with chloromethylfluorescein diacetate, a GSH marker, demonstrated dopaminergic neurons in the SN to have increased GSH levels after NAC treatment.

These findings suggest that oxidative stress induced by MPTP may reduce neuronal cysteine uptake, via EAAC1 dysfunction, leading to impaired GSH synthesis, and that NAC would exert a protective effect against MPTP neurotoxicity by maintaining GSH levels in dopaminergic neurons.

INTRO:


Parkinson's disease (PD) is a progressive, late-onset disorder resulting from dopaminergic neurodegeneration in the substantia nigra (SN). Although the precise pathogenesis of PD is still unclear, oxidative stress plays an important role in the underlying mechanism (Halliwell, 1992).

In patients with PD, the SN shows high levels of oxidative by-products (Dexter et al., 1989; Yoritaka et al., 1996; Alam et al., 1997) and iron (Dexter et al., 1987), which can react with hydrogen peroxide (H2O2) via the Fenton reaction to form hydroxyl radicals (Youdim et al., 1989) and low glutathione (GSH) levels (Perry & Yong, 1986; Sian et al., 1994).

GSH plays a critical role in protecting cells from oxidative stress and xenobiotics, as well as maintaining the thiol redox state. However, brain GSH declines with ageing (Maher, 2005), and GSH depletion enhances oxidative stress leading to neuronal degeneration (Schulz et al., 2000; Bharath et al., 2002). Although patients with PD exclusively show GSH loss in the SN, the precise mechanism has not yet been clarified.

GSH is a tripeptide composed of glutamate, cysteine and glycine. Cysteine is the rate-limiting substrate for GSH synthesis in neurons (Dringen et al., 1999). In primary neuron culture, approximately 90% of total cysteine uptake is mediated by sodium-dependent systems, mainly excitatory amino acid transporters (EAATs), also known as system XAG- (Shanker et al., 2001; Chen & Swanson, 2003; Himi et al., 2003b). There are five EAATs, termed GLAST, GLT-1, EAAC1, EAAT4 and EAAT5 (Danbolt, 2001). GLAST and GLT-1 are localized primarily to astrocytes; EAAC1, EAAT4 and EAAT5 to neurons. EAAT4 and EAAT5 are restricted to cerebellar Purkinje cells and the retina, respectively, whereas EAAC1 is widely expressed in the CNS (Maragakis & Rothstein, 2004). Knockdown expression of GLAST or GLT-1 in rats using antisense oligonucleotides increased the extracellular glutamate concentration, whereas EAAC1 knockdown had no effect on extracellular glutamate (Rothstein et al., 1996). Astrocyte glutamate transporters are limited to glutaminergic synapses, whereas EAAC1 is detected diffusely over cell bodies and processes (Rothstein et al., 1994).

These findings suggest that clearing extracellular glutamate is not a major role of EAAC1. EAAC1 can also transport cysteine at a rate comparable to that of glutamate, with an affinity 10–20-fold higher than that of GLAST or GLT-1 (Zerangue & Kavanaugh, 1996).

A recent study demonstrated age-dependent neurodegeneration with decreased GSH content, increased oxidant levels and increased susceptibility to oxidative stress in EAAC1-deficient mice (Aoyama et al., 2006). Notably, these EAAC1-deficient mice also showed an age-dependent decrease in neuronal number in the SN (Chan et al., 2005; Berman et al., 2007). However, to our knowledge there have been no studies examining EAAC1 in any of the PD models.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known as an exogenous neurotoxin, which induces mitochondrial dysfunction leading to increased oxidative stress, dopamine depletion in the striatum and parkinsonism (Langston et al., 1983).

Herein, we report that oxidative stress may reduce neuronal cysteine uptake via EAAC1 leading to impaired GSH synthesis in the MPTP mouse model of PD.

DISCUSSION:

Neurons rely mainly on extracellular cysteine for GSH synthesis (Dringen et al., 1999), because neurons have no means of direct GSH uptake. Extracellular supplies of the other amino acids, glutamate and glycine, do not increase GSH synthesis (Almeida et al., 1998; Dringen et al., 1999), as intracellular concentrations are already sufficient (Dringen, 2000). Cystine is an oxidized form of two cysteines with a disulfide linkage and is utilized as a substrate for GSH synthesis in some cell types (Bannai & Kitamura, 1980).

However, mature neurons utilize cysteine but not cystine for GSH synthesis (Sagara et al., 1993; Kranich et al., 1996). Because cystine is not an EAAC1 substrate (Kanai & Hediger, 1992) and mature neurons do not have cystine transporters, i.e. system xc–, which is expressed in regions facing the CSF, a role in redox buffering of the cysteine/cystine balance in the CSF has been suggested (Sato et al., 2002).

Recently, mice lacking this cystine transporter were reported to show no changes in brain GSH contents (Sato et al., 2005). Therefore, the availability of cysteine, but not other amino acids, is critically important for neuronal GSH synthesis.

Previous reports demonstrated that glutamate transporters are vulnerable to oxidative stress and that glutamate uptake is inhibited by preincubation with peroxynitrite or H2O2in vitro (Trotti et al., 1998). However, little is known about the influence of oxidative stress on the capacity of EAAC1 to function as a cysteine transporter.

Previous studies have suggested that glutamate uptake is regulated by the redox state of sulfydryl groups on cysteine residues of EAAC1 and that oxidation of the ‘redox site’ by H2O2 decreases glutamate uptake (Trotti et al., 1997a, b). Our data from acute slice culture experiments demonstrate that preincubation with H2O2 reduces subsequent cysteine uptake in the midbrain. Similarly, the marked reduction of cysteine uptake observed in the presence of LAβHA, but not DHK, suggests that EAAC1 is the primary cysteine transporter in the midbrain, as has been demonstrated in the hippocampus (Aoyama et al., 2006). These findings suggest that oxidative stress may impair neuronal GSH synthesis via EAAC1 dysfunction in the midbrain.

Peroxynitrite is a potent oxidant generated by the reaction between superoxide anion and nitric oxide (Kuhn et al., 2004), and plays a major role in MPTP neurotoxicity (Schulz et al., 1995). MPTP neurotoxicity is dependent on its metabolism to MPP+, which can specifically enter dopaminergic neurons via the dopamine transporter (Javitch et al., 1985) to inhibit complex I of the mitochondrial respiratory chain, and thus leads to reactive oxygen species production and ATP depletion (Tipton & Singer, 1993). Dopamine transporter-deficient mice preserved nearly normal striatal dopamine levels when exposed to neurotoxic doses of MPTP (Gainetdinov et al., 1997), while dopamine transporter over-expressing mice showed enhanced MPTP neurotoxicity (Donovan et al., 1999). These indicate that MPTP is a neurotoxin specific to dopaminergic neurons in vivo. In this study, we showed pretreatment with MPP+ to decrease subsequent cysteine uptake in midbrain slices and SH-SY5Y cells, and also to reduce GSH levels in dopaminergic neurons of the SN. These results indicate that MPTP neurotoxicity would be enhanced by inhibiting neuronal cysteine uptake leading to impaired GSH synthesis.

A previous report demonstrated MPTP neurotoxicity to be attenuated in nNOS-deficient mice (Przedborski et al., 1996). Therefore, it is important to elucidate the mechanism underlying peroxynitrite-mediated neurotoxicity in the MPTP model. Nitrotyrosine is a permanent marker of peroxynitrite attack on proteins (Beckman, 1994) and is found in post mortem PD brain samples (Good et al., 1998). In the MPTP model, tyrosine nitration inactivates TH, a key dopamine synthesis enzyme, and is found in α-synuclein, a major component of Lewy bodies (Kuhn et al., 2004). Peroxynitrite can oxidize cysteine residues and/or nitrate tyrosine residues on glutamate transporters, and thereby impair their function (Trotti et al., 1997b, 1998). To date, no direct evidence of EAAC1 nitration has been obtained. In this study, we found an increased amount of nitrotyrosine on EAAC1 and colocalization at the plasma membrane in the SN of MPTP-treated mice. Pretreatment with 7-NI, a selective inhibitor of nNOS, prevented the nitrotyrosine formation and GSH depletion induced by MPTP. These results may explain the decrease in GSH, which occurs with EAAC1 dysfunction in the midbrains of MPTP-treated mice. A 30% decline in total GSH appears to be rather large for a partial impairment of neuronal EAAC1 by oxidative stress. Because GSH contents may vary among TH-positive neurons, TH-negative neurons and glial cells, the apparently large decline in total GSH might suggest a predominant GSH distribution in TH-positive neurons in the midbrain.

A previous study demonstrated that MPTP administration decreased the striatal GLT-1 level after 21 days (Holmer et al., 2005). In our study, total EAAC1 amounts were unchanged, while amounts of EAAC1, though nitrated, on the plasma membrane were increased in the midbrains of MPTP-treated mice. Redistribution of EAAC1 to the membrane surface has been demonstrated to be regulated by protein kinase C, particularly protein kinase C subtype α (Davis et al., 1998).

Indeed, protein kinase C activation induced by peroxynitrite has been identified in fibroblasts (Bapat et al., 2001), pulmonary artery endothelial cells (Phelps et al., 1995) and the myocardium (Pagliaro et al., 2001). Interestingly, in this study, treatment with 7-NI, which blocks peroxynitrite formation, did not influence the EAAC1 redistribution to the membrane surface induced by MPTP. This redistribution might be induced by signals other than peroxynitrite. Further study is needed to elucidate the mechanism of the trafficking system in this model.

NAC acts as a precursor for GSH synthesis by supplying cysteine (De Vries & De Flora, 1993) and activates the GSH cycle (De Flora et al., 1991). NAC enters the cell readily (Mazor et al., 1996) and is then deacetylated to form l-cysteine regardless of whether EAAC1 is present (Himi et al., 2003a; Aoyama et al., 2006). NAC exerts a direct chemical effect as an antioxidant, although with less potency than that of GSH (Hussain et al., 1996).

Systemic administration of NAC can deliver cysteine to the brain and raise GSH levels in the CNS (Pocernich et al., 2000). Therefore, NAC would exert its protective effects against oxidative stress mainly by serving as a substrate for GSH synthesis. Our slice culture results showed NAC to act as an effective precursor for GSH synthesis in dopaminergic neurons. There are no reports demonstrating GSH-related protective effects of NAC against MPTP neurotoxicity using behavioral, biochemical or histochemical analysis in vivo, although one study demonstrated NAC treatment to restore the striatal dopamine level in MPTP-treated mice (Perry et al., 1985).

Our present results demonstrate that NAC pre-administration ameliorates motor dysfunction in addition to restoring GSH levels in MPTP-treated mice. We also found the nitrotyrosine level on EAAC1 to be reduced in the midbrains of NAC/MPTP-treated mice as compared with MPTP-treated mice. Although whether NAC would be clinically beneficial in PD is as yet unknown, its low toxicity and ease of administration warrant further investigation of this compound.
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Unread 01-24-2008, 03:21 AM   #5
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Default NAC amide

I fiddled with my keyboard to try and draw the structures,
(CS, did I get it right?) No, the computer has removed the space between 2 bonds, but you get the idea.
Frustrating, I spent an hour on it!!
I think it is the conversion of NAC, an amino acid into its amide
The carboxylic acid group -COOH in NAC is converted to CONH2 in the amide

CH3-C=O
l
NH-CH-C=O
l l
CH2 OH
l
SH

N-acetylcysteine


CH3-C=O
l
NH-CH-C=O
l l
CH2 NH2
l
SH

N-acetylcysteine amide
They are different molecules, and presumably the amide form makes it more fat soluble (lipophilic) so it can cross the BBB

See also

Biomed Chromatogr. 2006 May;20(5):415-22. Links
Separation and quantification of N-acetyl-l-cysteine and N-acetyl-cysteine-amide by HPLC with fluorescence detection.Wu W, Goldstein G, Adams C, Matthews RH, Ercal N.
Department of Chemistry, University of Missouri-Rolla, Rolla, MO 65409, USA.

N-acetyl-l-cysteine (NAC) is a well-known antioxidant that is capable of facilitating glutathione (GSH) biosynthesis and replenishing intracellular GSH under oxidatively challenging circumstances. N-acetyl-cysteine-amide (NACA), the amide form of NAC, is a newly designed and synthesized thiol-containing compound which is believed to be more lipophilic and permeable through cell membranes than NAC. The metabolic and antioxidant effects of these compounds in vitro and in vivo are under investigation. However, an analytical method that can separate and quantify both compounds simultaneously is not yet available, to the best of our knowledge. Because of their structural similarities, the two compounds are difficult to separate using earlier HPLC methods which were designed for NAC quantification. Therefore, the goal of this work was to develop an HPLC method with fluorescence detection for simultaneous quantification of NAC and NACA in biological blood and tissue samples. A gradient HPLC program with fluorescence detection (lambda(ex) = 330 nm, lambda(em) = 376 nm) using N-(1-pyrenyl)maleimide (NPM) as the derivatizing agent was developed. The calibration curves were linear over a concentration range of 25-5000 nm (r(2) > 0.997). The coefficients of variation for within-run precision and between-run precision ranged from 0.67 to 5.23% and for accuracy ranged from 0.98 to 10.54%; the percentage relative recovery ranged from 94.5 to 102.8%. This new method provides satisfactory separation of NAC and NACA, along with other biological thiols, in 20 min with a 5 nm limit of detection (LOD) per 5 microL injection volume.

PMID: 16167305 [PubMed - indexed for MEDLINE]




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Last edited by Ronhutton; 01-24-2008 at 03:49 AM. Reason: Structures came out all jumbled
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Unread 01-24-2008, 06:52 AM   #6
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Default Nac/bbb

Thank you very much Ron. I am not technical but do you think NAC will not cross BBB to brain cells?
Also what do you make out of the following research ??

http://www.medicalnewstoday.com/articles/88119.php

David Farb, PhD, recently had an abstract selected that was highlighted by the Society for Neuroscience (SFN). The abstract details how antioxidants influence dopamine release from striatal synaptosomes. It was presented at SFN's 37th annual meeting November 7th in San Diego, California.

Farb is the professor and chairman of the Department of Pharmacology & Experimental Therapeutics at Boston University School of Medicine. He is also the director of the Biomolecular Pharmacology Training Program, the interdepartmental program in biomedical neuroscience, and heads the Laboratory of Molecular Neurobiology.

Farb's abstract details the relationship between antioxidants and dopamine. Antioxidants can protect the central nervous system from oxidative damage. The level of oxidation and reduction of molecules reflects conditions within the nervous tissue. Increased levels of oxidative damage are believed to be involved in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and stroke.

In the brain, neurons communicate with each other via synaptic connections in which signals are transmitted by the release of chemical neurotransmitters from presynaptic axon terminals. Farb and fellow BUSM researchers examined the release of a specific neurotransmitter, dopamine, from isolated pre-synaptic axon terminals.

Researchers sought to determine whether the presence of antioxidant compounds could influence spontaneous dopamine release from synaptosomes. They concluded that the release of dopamine could be influenced by numerous factors, including input from other neurotransmitters as well as the reducing/oxidizing state of the cell. Inclusion of the water soluble, sulfhydryl containing antioxidant glutathione, or the glutathione precursor NAC lowered spontaneous dopamine release by 85 percent. The antioxidant vitamin E had no effect on dopamine release.

"Not all antioxidants are equivalent," said Farb. "Our results suggest that the ability of NAC or glutathione at therapeutic doses to rapidly and reversibly stabilize the release of dopamine raises the possibility that such antioxidants may have significant potential for the treatment of oxidative damage in neurodegenerative diseases."
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Unread 01-24-2008, 08:25 AM   #7
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Hi IMark,
The fact that theses researchers had to convert NAC into the amide, to get it past the BBB suggests that NAC can't pass the BBB.
Indeed a search confirmed that.
See
http://www.fasebj.org/cgi/content/full/15/1/243
where it says,
"N-acetylcysteine does not cross the blood–brain barrier"

I have little medical knowledge, I am a chemist, and had better leave the interpretation of the paper you quote, to somone better medically quailified.

Sorry my forulae came out jumbled in my other message,
Best wishes
Ron
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Unread 01-24-2008, 01:46 PM   #8
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Quote:
Originally Posted by Ronhutton View Post
Hi IMark,
The fact that theses researchers had to convert NAC into the amide, to get it past the BBB suggests that NAC can't pass the BBB.
Indeed a search confirmed that.
See
http://www.fasebj.org/cgi/content/full/15/1/243
where it says,
"N-acetylcysteine does not cross the blood–brain barrier"

I have little medical knowledge, I am a chemist, and had better leave the interpretation of the paper you quote, to somone better medically quailified.

Sorry my forulae came out jumbled in my other message,
Best wishes
Ron
Hello Ron,
I have been taking NAC for some time hoping some of it at least may cross the BBB but now I have second thoughts.
By the way the paper posted by Zflower above states :"Systemic administration of NAC can deliver cysteine to the brain and raise GSH levels in the CNS (Pocernich et al., 2000). "??

Perhapse you have further comment.

Thank you so much for you offering your knowledge generously to the forum
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Unread 01-24-2008, 03:30 PM   #9
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Hello IMark,
N-acetylcysteine can be turned into cysteine by removal of the N-acetyl group. Cysteine is a smaller molecule and can presumably cross the BBB. Cysteine and N-acetylcysteine are different chemicals.
Don't ask me why they use NAC rather than cysteine itself, there must be a reason!! Found it, the acetyl group is used in NAC to speed absorbtion by the body, once quickly absorbed, the NAC is quickly hydrolysed to cysteine. So you are doing the right thing taking NAC, it boosts the level of glutathione a powerful natural antioxidant.

If you want to see the formulae of the 2 compounds, go to
http://www.benbest.com/nutrceut/NAC.html

Ron
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Unread 01-25-2008, 05:18 AM   #10
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Default thanks Ron

Quote:
Originally Posted by Ronhutton View Post
Hello IMark,
N-acetylcysteine can be turned into cysteine by removal of the N-acetyl group. Cysteine is a smaller molecule and can presumably cross the BBB. Cysteine and N-acetylcysteine are different chemicals.
Don't ask me why they use NAC rather than cysteine itself, there must be a reason!! Found it, the acetyl group is used in NAC to speed absorbtion by the body, once quickly absorbed, the NAC is quickly hydrolysed to cysteine. So you are doing the right thing taking NAC, it boosts the level of glutathione a powerful natural antioxidant.

If you want to see the formulae of the 2 compounds, go to
http://www.benbest.com/nutrceut/NAC.html

Ron
..You are a treasure ..
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