N-acetylcysteine
 

Quinone and oxyradical scavenging properties of N-acetylcysteine prevent dopamine mediated inhibition of Na+, K+-ATPase and mitochondrial electron transport chain activity in rat brain: implications in the neuroprotective therapy of Parkinson's disease.

Bagh MB, Maiti AK, Jana S, Banerjee K, Roy A, Chakrabarti S.


Source

Department of Biochemistry, Institute of Post Graduate Medical Education & Research, Dr B. C. Roy Post Graduate Institute of Basic Medical Sciences, India.


Abstract

Dopamine oxidation products such as H2O2 and reactive quinones have been held responsible for various toxic actions of dopamine, which have implications in the aetiopathogenesis of Parkinson's disease. This study has shown that N-acetylcysteine (0.25-1 mm) is a potent scavenger of both H2O2 and toxic quinones derived from dopamine and it further prevents dopamine mediated inhibition of Na+,K+-ATPase activity and mitochondrial respiratory chain function. The quinone scavenging ability of N-acetylcysteine is presumably related to its protective effect against dopamine mediated inhibition of mitochondrial respiratory chain activity. However, both H2O2 scavenging and quinone scavenging properties of N-acetylcysteine probably account for its protective effect against Na+,K+-ATPase inhibition induced by dopamine. The results have important implications in the neuroprotective therapy of sporadic Parkinson's disease since inactivation of mitochondrial respiratory activity and Na+,K+-ATPase may trigger intracellular damage pathways leading to the death of nigral dopaminergic neurons.

more
 

https://springerlink3.metapress.com/...ringerlink.com

Abstract
Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer’s disease, Parkinson’s disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down’s syndrome have been associated with several mitochondrial alterations Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.

low doses of cysteine prodrugs may be useful neuroprotectors
 

Systemic administration of N-acetylcysteine protects dopaminergic neurons against 6-hydroxydopamine-induced degeneration

Auteur(s) / Author(s)
MUNOZ Ana M. ; REY Pablo ; SOTO-OTERO Ramon ; GUERRA Maria J. ; LABANDEIRA-GARCIA Jose L. ;
Résumé / Abstract
The results of several in vitro studies have shown that cysteine prodrugs, particularly N-acetylcysteine, are effective antioxidants that increase the survival of dopaminergic neurons. N-acetylcysteine can be systemicallyadministered to deliver cysteine to the brain and is of potential use for providing neuroprotection in the treatment of Parkinson's disease. However, it has also been reported that an excess of cysteine may induce neurotoxicity. In the present study, we injected adult rats intrastriatally with 2.5 μl of 6-hydroxydopamine (7.5 μg) and N-acetylcysteine (240 mM) or cysteine (240 mM) or intraventricularly with 6-hydroxydopamine (200 μg) and subcutaneously with N-acetylcysteine (10 and 100 mg/ kg). We studied the effects of these compounds on both the nigrostriatal dopaminergic terminals and the surrounding striatal tissue. The tissue was stained with fluoro-jade (a marker of neuronal degeneration) and processed by immunohistochemistry to detect tyrosine hydroxylase, neuronal and glial markers, and the stress protein heme-oxygenase-1. After intrastriatal injection, both cysteine and N-acetylcysteine had clear neuroprotective effects on the striatal dopaminergic terminals, but also led to neuronal degeneration (as revealed by fluoro-jade staining) and astroglial and microglial activation, as well as intense induction of heme-oxygenase-1 in astrocytes and microglial cells. Subcutaneous administration of N-acetylcysteine also induced significant reduction of the dopaminergic lesion (about 30% reduction). However, we did not observe appreciable N-acetylcysteine-induced fluoro-jade labeling in striatal neurons or any of the above-mentioned changes in striatal glial cells. The results suggest that low doses of cysteine prodrugs may be useful neuroprotectors in the treatment of Parkinson's disease.

NAC has a lot going for it.
 

Rather than add to forum clutter, I am going to add onto this thread of Imad's if he doesn't mind. I have been going through my notes lately searching for promising leads. N-Acetyl Cysteine has a lot going for it. I have been using it for two weeks and it has greatly helped with weakness and fatigue and seems to be lowering my med requirement even in this heat.

If anyone has experience with this one, please feel free to post. I am going to add a series of references in the next few days in no particular order. I hope some of it helps.

NAC and addiction - possible aid in getting off Ldopa?
 

From http://www.eurekalert.org/pub_releas...-ana120502.php

There is an intersection between the worlds of drug addiction and dopamine replacement as well as addiction to those replacements. Naltrexone, dextromethorphan, and cannabis have a place in all three.

It seems that NAC may have a role there as well-

"A new approach holds promise for reducing cocaine craving

..."Our studies show that administration of an existing drug – n-acetyl cysteine, which is used to treat cystic fibrosis and several other disorders – reverses the changes in brain chemistry that appear to cause cocaine craving," said David A. Baker, a post-doctoral fellow in the laboratory of Peter W. Kalivas at the Medical University of South Carolina. ..."

"Previous studies have found that cocaine addiction interferes with the levels of the common neurotransmitter glutamate in the nucleus accumbens. Normally, the neurons are bathed in high levels of glutamate, which tends to reduce their sensitivity so that they fire less frequently. When cocaine is withdrawn after repeated exposures, however, glutamate levels plunge to about half their normal level. During the withdrawal stage, injections of small amounts of cocaine produce large increases in glutamate concentrations, but only for short periods"

This sounds much like a possible explanation if one substitutes "dopamine" for "glutamate". And large increases in glutamate for short periods might explain some dyskinesias.

Nac
 

I have been taking 600 mg of NAC daily as part of Life Extension Mix for years, long before my PD diagnosis. I Haven't noticed any benefit. Perhaps the dose is inadequate.

I have been taking 1200 mg NAC with 100mg Alpha lipoic acid for may be a couple of years. There is no way for me to tell that it is doing any thing for my PD which has been progressing steadily but I believe slowly since diagnosis about 6 years ago.
When my neuro asked me why to I take my supplements, I answered her : every body needs placebos.

Ah, the classic conundrum
 

"I don't know if it works but I dare not quit!" :D
For what it is worth, I started it two weeks ago and suspended my other supplements temporarily (enzymes and creatine). I am pleased thus far but it could be the others wearing off. :D

NAC as precursor to Glutathione
 

I take 500- 1000 mg. of NAC regularly (for 5 years). The brand I take, Jarrow, has this on it's label:
"NAC is a powerful antioxidant amino acid and a precursor in the body to the critical antioxidant glutathione.
Glutathione exerts a variety of protective effects, including detoxification and intracellular defense against oxidative stress."
My feeling is that all us PWP need as many antioxidants as possible- because of possible particular sensitivities to toxins and because of all the meds and their metabolites in our system. I think of it as taking out the garbage as often as possible.

A decent summary
 

1: Med Hypotheses. 2001 Apr;56(4):472-7.

Therapeutic potential of N-acetylcysteine in age-related mitochondrial
neurodegenerative diseases.

Banaclocha MM.

Department of Pathology, Hospital La Paz, Madrid, Spain. marbanaci@latinmail.com

Increasing lines of evidence suggest a key role for mitochondrial damage in
neurodegenerative diseases. Brain aging, Parkinson's disease, Alzheimer's
disease, Huntington's disease and Friedreich's ataxia have been associated with
several mitochondrial alterations including impaired oxidative phosphorylation.
Mitochondrial impairment can decrease cellular bioenergetic capacity, which will
then increase the generation of reactive oxygen species resulting in oxidative
damage and programmed cell death. This paper reviews the mechanisms of
N-acetylcysteine action at the cellular level, and the possible usefulness of
this antioxidant for the treatment of age-associated neurodegenerative diseases.
First, this thiol can act as a precursor for glutathione synthesis as well as a
stimulator of the cytosolic enzymes involved in glutathione regeneration.
Second, N-acetylcysteine can act by direct reaction between its reducing thiol
group and reactive oxygen species. Third, it has been shown that
N-acetylcysteine can prevent programmed cell death in cultured neuronal cells.
And finally, N-acetylcysteine also increases mitochondrial complex I and IV
specific activities both in vitro and in vivo in synaptic mitochondrial
preparations from aged mice. In view of the above, and because of the ease of
its administration and lack of toxicity in humans, the potential usefulness of
N-acetylcysteine in the treatment of age-associated mitochondrial
neurodegenerative diseases deserves investigation. Copyright 2001 Harcourt
Publishers Ltd.

Publication Types:
Review

PMID: 11339849 [PubMed - indexed for MEDLINE]