[imark3000]

The link below seems to indicate positive role of NAC as antioxiant. However I do not undertnad the following statment:
"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."
How NAC is good while it lowers dopamine release? I hope the more knowledgable members can explain this?

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."

Farb chairs the Executive Committee for the Medical Sciences Training Program and is a member of the Bioinformatics Program. He also served as neurosciences consultant for WGBH-Boston PBS affiliate on the NOVA episode, Mirror Neurons and, as a member of the Drug Development Work Group of Mass Insight. He also co-authored the Massachusetts Technology Road Map for Drug Discovery.

Farb has served as a consultant to large and small pharmaceutical companies, intellectual property law and portfolio investment firms. He was a member of the founding Scientific Advisory Boards of CoCensys and DOV Pharmaceuticals and the Scientific Founder of Scion Pharmaceuticals (acquired by Wyeth), which commercialized his patents on high throughput electrophysiology and small molecule modulators of amino acid receptors. Farb currently serves on the SAB of DOV Pharmaceuticals and Helicon Therapeutics (pending). He holds nine issued U.S. patents and one patent issued in Australia.

Farb's current research is directed toward understanding the mechanisms of action of abused substances and steroid hormones and their interactions with excitatory and inhibitory amino acid receptors in the central nervous system. The research focuses on the mechanism of action and discovery of neuromodulators as therapeutic agents and on the structure, function, and cellular dynamics of ion channels and receptors in the brain and spinal cord. Recently, Farb's laboratory demonstrated that pregnanolone hemisuccinate inhibits reinstatement of cocaine seeking behavior and this compound has been acquired by NIDA for preclinical development in its Medications Development Program.

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Article adapted by Medical News Today from original press release.
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[imark3000]

More rational on this topic is found in following link. I have been taking NAC following this rational. I hope to have comments on this and if any body is taking NAC

http://www.ninds.nih.gov/funding/res...maries/nac.htm
N-ACETYL-CYSTEINE

N-Acetyl-Cysteine (NAC) is a precursor of glutathione (which used to prevent oxidative stress in most cells and helps to trap free radicals that can damage DNA and RNA in the body), and a protected sulfur-containing amino acid. It is a modified form of the amino acid cysteine and is commonly used in hospitals both to help break down mucus and to protect from acetaminophen toxicity. NAC shows no adverse effects more common than in placebo except perhaps headache however can cause nausea, and vomiting at higher doses.


Scientific Rationale

NAC is a precursor of glutathione and is a thiolic antioxidant. Glutathione (GSH) is markedly reduced in the substantia nigra (SN) early in PD, even before there is a detectable complex I defect. Decreased GSH has even been reported in Lewy body disease.1,2 GSH depletion has been hypothesized to result from oxidative stress. Many studies have demonstrated increased markers of oxidative damage in the SN in PD. However, experimental GSH depletion has been shown to induce a defect specifically in complex I.3

NAC also may be neuroprotective through:

scavenging reactive oxygen species
inhibiting apoptosis through interference with c-fos, c-jun, TGFb
increasing complex I, IV and V activity ( mitochondrial oxidative phosphorylation)4,5,6
Glutathione protects human neuronal cells from DA-induced apoptosis.7 However, high-dose NAC (1 g/kg IP) in rats caused a depletion of brain glutathione.8

1. Dexter DT, Ann Neurol 1994;35:38-44.
2. Jenner P. Acta Neurol Scand Suppl 1993;146:6-13.
3. Jha N. J Biol Chem 2000;275:26096-101.
4. Banaclocha, Med Hypotheses 2001;56: 472-477
5. Martinez, Life Sciences 1999; 64: 1253-1257
6. Banaclocha, Brain Res 2000; 859:173-175
7. Gabbay, Neurpharm 1996;35:571-578
8. Vina, Experientia 1983;39:164-165

Animal Model Data

RODENT: Subcutaneous (SC) NAC (500mg/kg) injected once daily for 5 days partially protected against SN dopamine depletion induced by a single SC injection of MPTP on the 3rd day in mice. Mice fed ad libitum with pellets containing 0.3% NAC had significantly lower levels of protein carbonyls18 and increased complex I activity19 in brain synaptic mitochondria. A significant increase in GSH concentrations was not detected, consistent with theories that NAC may act, in part, by acting directly as an antioxidant.

1. Perry, Neurosci Lett 1985;60:109-114
2. Banaclocha MM, Brain Res 1997;762:256-8.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

Unknown BBB penetration in humans, but there is evidence that low concentrations of NAC are achieved in the brain 2 hours after systemic administration in laboratory animals1,2 T ½ is 6.25 h after oral administration to healthy volunteers. The oral bioavailability is 9.1%.3

1. Banaclocha, Med Hypotheses 2001;56: 472-477
2. Martinez, Life Sciences 1999; 64: 1253-1257
3. Olsson, Eur J Clin Pharmacol 1988; 34:77-82

Safety/Tolerability in Humans

In a double-blind, placebo-controlled randomized trial involving 43 Alzheimer's patients given either 50 mg/kg/day orally or placebo, there were no adverse effects more common than in placebo (except perhaps headache). In APAP overdose, 140 mg/kg load followed by 70 mg/kg q4 hours x 17 doses is used. At this dosage, NAC can cause nausea, vomiting and sometimes generalized urticaria.Highest nontoxic dosage in normal volunteers was determined to be 800 mg/m2. Major toxicities at higher doses were bad taste and gastrointestinal disturbances. NAC also has been tested in HIV-infected humans. A double-blind, placebo-controlled randomized trial tested oral NAC in HIV-infected patients with evidence for decreased GSH levels in lymphocytes but without active opportunistic infections. Subjects were given 10 tablets of NAC (800mg/tablet) per day divided in 3 or 4 doses for 8 weeks. As in the Alzheimer's disease trial, adverse effects in this trial were minimal. Some subjects reduced the dose due to side effects, with the average dosage by the end of the trial being 6.3 grams/day however the reduction in "dose" was similar for the placebo arm. NAC treatment was associated with a significant increase in GSH concentration in lymphocytes.

1. Adair, Neurology 2001;57:1515-1517
2. Mosby's Drug Consult, 2002
3. Pendyala, Cancer Epid Biomarkers and prevention 1995; 4:245-251
3. De Rosa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 2000;30:915-29.

Drug Interaction Potential

UNKNOWN

Clinical Trial/Epidemiological Evidence in Human PD

NONE


Last updated February 09, 2005