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

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

Nac
 

good question--ol CS are you around???madelyn

"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.

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]




Ron

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."

Nac
 

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

Nac/bbb
 

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

Nac
 

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

thanks Ron
 

..You are a treasure ..

Another source for cystein : the Whey !
 

Another source for cystein : the Whey ! and it is natural. Pls see following link which I partially quote. It claims it gets through BBB ...:rolleyes:
FEEDBACK GREATLY APPRECIATED

http://64.233.169.104/search?q=cache...lnk&cd=5&gl=jo
"WHEY PROTEIN & GLUTATHIONE Whey Protein contains essential amino acids which are noted to provide overall health benefits. More specifically, whey protein is very beneficial because whey protein drinks increase Glutathione (GSH) concentration in a number of tissues. Whey-based peptide studies have shown that whey protein may reduce hypertension which contributes to cardiovascular diseases. In fact, one of whey protein’s major benefits is to assist in the building of collagen. Therefore, by supplementing whey protein to your diet, it helps to accelerate the healing of fractures as well as provide overall health benefits. Whey protein is also helpful in the prevention and treatment of Osteoporosis. American Journal of Clinical Nutrition, June 2000.Whey protein increases Glutathione levels. Glutathione (GSH) is a powerful antioxidant. It is a tripeptide protein (made within the body) from three key amino acids; Cysteine, Glutamic Acid, and Glycine. The benefits of Glutathione include detoxifying many toxic chemicals and heavy metals from the body such as lead, mercury, aluminum, arsenic and cadmium, as well as the effects of alcohol and tobacco smoke. In the Immune System, Glutathione inhibits the excessive production of Cytokines that are implicated in Autoimmune Disease. Glutathione combats Free Radicals that cause allergies and aids in Chronic Fatigue. In regards to aging and life extension, old cells contain 20% less Glutathione compared to young cells, indicating it may be beneficial. In the Cardiovascular System, Atherosclerosis patients generally exhibit reduced Glutathione, indicating it may be beneficial. Brink; Life Ext., 6(2), 2000"
--
"THE EFFECTS OF WHEY PROTEIN ON NEUROTRANSMITTER FUNCTION Essential Amino Acids, the building blocks that make up proteins, play a large part in every living cell in the body. Each group of amino acids is tailored for a specific need. It is actually the amino acids rather than the proteins that are the essential nutrients. Amino acids act as neurotransmitters to carry information from one nerve cell to another. The neurotransmitter dysfunction is caused by the lack of amino acids. The dysfunction of the neurotransmitters results in depression and obesity with further results in diabetes, heart diseases, hypertension (high blood pressure), and lack of emotional control. “Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults,” Elena Volpi, Hisamine Kobayaski, Melinda Sheffield-Moore, Bettina Mittendorfer, and Robert R. Wolfe, Am J Clin Nutr 2003;78:250-8. Amino acids also act as neurotransmitters to carry information from one nerve cell to another. Amino acids enable vitamins and minerals to do their jobs properly, but if there is a deficiency in amino acids, nerve cells can’t function. There are approximately 28 amino acids. The liver produces 19 amino acids while the other 9 must be obtained from the diet which is called the essential amino acids. Prescription for Nutritional Healing, James F. Balch, M.D., Phyllis A. Balch, CNC, 1997, Page 34-35.Plainly, the neurotransmitter dysfunction is caused by the lack of amino acids. The dysfunction of the neurotransmitters results in depression and obesity with further results in diabetes, heart diseases, hypertension (high blood pressure), and lack of emotional control. The neurotransmitters are fat soluble and cannot cross the blood/brain barrier. Therefore, the amino acids that made up the neurotransmitters must cross the blood/brain barrier and then the body makes the neurotransmitters out of the amino acids and the appropriate vitamins and minerals necessary. Neurotransmitter Testing and Amino AcidTherapy, Marty Hinz, MD, NeuroResearch, Morgan Park Clinic, Duluth, Minnesota, 2002, Pages 22-24.Nutritional deficiency is a major cause of neurotransmitter dysfunction, as well as drugs such as Zoloft and Prozac. These drugs inhibit the reuptake of serotonin and so cause a loss of serotonin. Neurotoxic effects are permanent. They are caused by heavy metals, chemicals and drugs. The main drug that causes neurotoxicity is amphetamines. Neurotoxic effects are in the post-synaptic neurons. The treatment is the same as deficiency of amino acids, but it takes more of these amino acids forming serotonin to be effective at the post-sympathic neuron. Neurotransmitter Testing and Amino Acid Therapy, Marty Hinz, MD, NeuroResearch, Morgan Park Clinic, Duluth, Minnesota, 2002, Pages 22-24"

I drink whey protein. It's my favorite protein drink. I'd read that whey helps diabetics stabilize blood sugar, even when ingested with a high carb meal. I posted the study on the old board. My friend is diabetic, and the whey protein definitely helps her.

I don't understand that. I thought those AD's increased serotonin which is a good thing for depression. :confused:

I'm sure there are other reasons!

: Anticancer Res. 2003 Mar-Apr;23(2B):1411-5.
The antioxidant system.
Bounous G, Molson JH.



The glutathione (GSH) antioxidant system is the principal protective mechanism of the cell and is a crucial factor in the development of the immune response by the immune cells. Experimental data demonstrate that a cysteine-rich whey protein concentrate represents an effective cysteine delivery system for GSH replenishment during the immune response.

Animal experiments showed that the concentrates of whey protein also exhibit anticancer activity. They do this via the GSH pathway, the induction of p53 protein in transformed cells and inhibition of neoangiogenesis.

PMID: 12820403 [PubMed - indexed for MEDLINE]

***************

Elevated glutathione as a therapeutic strategy in Alzheimer's disease -
DA Butterfield, CB Pocernich, J Drake - Drug Development Research, 2002

GSH levels are increased with strict adherence to a diet rich in whey proteins. ....whether they're increased in the brain is probable but needs demonstration.

....The bioavailability of NAC given orally is less than 20%.

Lots of good info here:

http://www3.interscience.wiley.com/c...17480/PDFSTART

Wow. Nice to see such an avid discussion about this. I have MS and posted about this on an MS forum (not the board here) -- not one response! :eek:

I look forward to reading all the back and forth more carefully -- hope you don't mind that I poked my head in here. :)

Anytime!

paula

Bioavailability
 

Thanks IMark, must find a source of whey protein in the UK.
If NAC is used as a source of cysteine since NAC is more readily absorbed by the body, yet according to ZF's reference, "....The bioavailability of NAC given orally is less than 20%", then there must be a natural substance in whey protein to assist bioavailability.
Looks like natural sources are often best, so whey protein rather than NAC, and Mucuna pruriens instead of sinemet, (since mucuna P. seems to contain a natural decarboxylation inhibitor, rather than the synthetic carbidopa in sinemet)
Like Zuchini Flower, I found a couple of strange comments in IMarks paper,
"The neurotransmitters are fat soluble and cannot cross the blood/brain barrier." The more fat soluble (lipophilic) a molecule is, the easier to cross the BBB.
I also feel that "Neurotoxic effects are permanent" is wrong, look at Rick's example of AD patients regaining their memory in minutes. If the damage is permanent, we can never be cured.
Ron

Nac Bbb Etc
 

Dr. Russell Blaylock (author of "Excitotoxins: the Taste that Kills" and son of a PD victim) says that NAC is probably good for the brain but that cysteine is dangerous in the same way as MSG/glutamate is. It depends on where you are talking about and what the concentrations are. MSG knocks me for a loop. I go completely off with freezing for 4 to 8 hours and it takes a couple of days to recover. Nasty stuff.

From http://www.whale.to/a/blaylock5.html

In this brief discussion of a most complicated and evolving subject, I have had to omit several important pieces of the puzzle. For example, I have said little about the functional components of the receptor systems, the glutamate transporter and its relation to ALS and Alzheimer's dementia, receptor decay with aging and disease, membrane effects of lipid peroxidation products, membrane fluidity, effects of chronic inflammation on the glutamate/free radical cycle, stress hormones and excitotoxicity, the role of insulin excess on the eicosanoid system, or the detailed physiology of the glutamatergic system. I have also only briefly alluded to the toxicity of aspartame and omitted its strong connection to brain tumor induction.

But, I have tried to show the reader that there is a strong connection between dietary and endogenous excitotoxin excess and neurological dysfunction and disease. Many of the arguments by the food processing industry have been shown to be false. For example, that dietary glutamate does not enter the brain because of exclusion by the blood-brain barrier, has been shown to be wrong, since glutamate can enter by way of the unprotected areas of the brain such as the circumventricular organs. Also, as we have seen, chronic elevations of blood glutamate can breech the intact blood-brain barrier. In addition, there are numerous conditions under which the barrier is made incompetent.

As our knowledge of the pathophysiology and biochemistry of the neurodegenerative diseases increases, the connection to excitotoxicity has become stronger.(21) This is especially so with the interrelationship between excitotoxicity and free radical generation and declining energy production with aging. Several factors of aging have been shown to magnify this process. For example, as the brain ages its iron content increases, making it more susceptible to free radical generation. Also, aging changes in the blood brain barrier, microvascular changes leading to impaired blood flow, free radical mitochondrial injury to energy generating enzymes, DNA adduct formation, alterations in glucose and glutamate transporters and free radical and lipid peroxidation induced alterations in the neuronal membranes all act to make the aging brain increasingly susceptible to excitotoxic injury.

Over a lifetime of free radical injury due to chronic stress, infections, trauma, impaired blood flow, hypoglycemia, hypoxia and poor antioxidant defenses secondary to poor nutritional intake, the nervous system is significantly weakened and made more susceptible to further excitotoxic injury. We know that a loss of neuronal energy generation is one of the early changes seen with the neurodegenerative diseases. This occurs long before clinical disease develops. But, even earlier is a loss of neuronal glutathione functional levels.

A word about ascorbic acid: Few are aware of the importance of adequate ascorbate levels for CNS function and neural protection against excitotoxicity. We are finding out that ascorbic acid plays a vital role in neurobehavioral regulation and the dopaminergic system as well, which may link ascorbate supplementation to improvements in schizophrenia.

Our knowledge of this process opens up new avenues for treatment as well as prevention of excitotoxic injury to the nervous system. For example, there are many nutritional ways to improve CNS antioxidant defenses and boost neuronal energy generation, as well as improve membrane fluidity and receptor integrity. By using selective glutamate blocking drugs or nutrients, one may be able to alter some of the more devastating effects of Parkinson's disease. For example, there is evidence that dopamine deficiency causes a disinhibition (overactivity) of the subthalamic nucleus and that this may result in excitotoxic injury to the substantia nigra.(22) By blocking the glutamatergic neurons in this nucleus, one may be able to reduce this damage. There is also evidence that several nutrients can significantly reduce excitotoxicity. For example, combinations of coenzyme Q10 and niacinamide have been shown to protect against striatal excitotoxic lesions. Methylcobolamine, phosphotidylserine, picnogenol and acetyl-L-carnitine all protect against excitotoxicity as well.

Of particular concern is the toxic effects of these excitotoxic compounds on the developing brain. It is well recognized that the immature brain is four times more sensitive to the toxic effects of the excitatory amino acids as is the mature brain. This means that excitotoxic injury is of special concern from the fetal stage to adolescence. There is evidence that the placenta concentrates several of these toxic amino acids on the fetal side of the placenta. Consumption of aspartame and MSG containing products by pregnant women during this critical period of brain formation is of special concern and should be discouraged. Many of the effects, such as endocrine dysfunction and complex learning, are subtle and may not appear until the child is older. Other hypothalamic syndromes associated with early excitotoxic lesions include immune alterations and violence dyscontrol.

Over 100 million American now consume aspartame products and a greater number consume products containing one or more excitotoxins. There is sufficient medical literature documenting serious injury by these additives in the concentrations presently in our food supply to justify warning the public of these dangers. The case against aspartame is especially strong.

Oral NAC 100% effective as a Cys precursor
 

Hi,

I recently found an article at the Journal of Animal Science that dealt specifically with this issue of NAC bioavailability that I think might be insightful.

Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine
R. N. Dilger and D. H. Baker

"It is apparent that considerable confusion exists with regard to the meaning of the term "NAC bioavailability." Previous pharmacokinetic studies (Borgström et al., 1986Go; Olsson et al., 1988Go; De Caro et al., 1989Go) have focused on the amount of an oral NAC dose that reaches the bloodstream as NAC itself. Little emphasis has been placed on the chemical modification of NAC (i.e., deacetylation) within the gut lumen and enterocyte during absorption. Therefore, pharmacokinetic studies suggesting that less than 10% of oral NAC is absorbed into portal blood as NAC per se are misleading. Our approach, however, was based on the assumption that beneficial effects of NAC do not result from NAC itself, but rather from NAC delivering Cys for in vivo functions (e.g., glutathione synthesis). Thus, the ability of NAC (the test precursor) to provide Cys relative to Cys itself (the standard nutrient) was assessed in assay 2. The results of this study (Table 3Go) clearly showed that oral NAC was 100% effective as a Cys precursor."

*to read more please go to http://jas.fass.org/cgi/content/full/85/7/1712

Thank you for a great discussion!

In health,

Paul