IUBio Biosequences .. Software .. Molbio soft .. Network News .. FTP

Research extract - Treatment of neurodegenerative disease with N-Acetylcysteine

pcsol at tcp.co.uk pcsol at tcp.co.uk
Tue Feb 4 10:39:50 EST 1997

The research extract below indicates that NAC may be useful 
for treating neurological disorders. The role of NAC for 
chelating Mercury is well known- NAC has a very high binding
strength for mercury, and has been shown to elevate uinary
excretion levels of Mercury. It will also help elevate
glutathione, which helps counteract the effect of
Mercury. If one considers that the primary cause of "oxidative
stress" can be shown to be environmental toxins such as Mercury
(mainly from Dental Amalgam), the inference is clear.

The conclusions in this extract make a moot point - to what extend 
does one say that the oxidants cause the disease, or merely the 
suseptability to them? Since metals like Mercury are
alien to the human metabolism (with *no* role within it)
I would lay blame firmly at the door of the oxidant..

Also see the University of Kentucky site:-
for research on the role of oxidative stress in Alzheimers,
and the benifits of (heavy-metal) chelation agents.
Also see my site for info on the NAC/Hg link..
(inc material from Ray..)

To learn more about the Amalgam safety issue (or lack of) visit:-

N-Acetyl Cysteine Report

This article submitted by on 4/13/96.

Author's Email: 

October 16-20, 1995

Treatment of neurodegenerative disease with N-Acetylcysteine

B.J.Wilder, M.D., Russell W. Hurd, M.S., Scott C. Franzcek, M.D.

Wendell R. Helveston, M.D., Basim M. Uthman, M.D.

Department of Neurology and Brain Institute, University of Florida,
Gainesville, FL 32610


Free radical mediated mechanisms have been suggested as contributing 
to the  development of several neurodegenerative diseases. Several 
excellent reviews have  recently addressed this subject1-3.
In patients with a hereditary seizure disorder, Progressive Myoclonus
Epilepsy of the Unverricht Lundborg Type (PME-UL), characterized by 
myoclonus, generalized and absence seizures and deterioration in 
mental function, we found increased activity of the antioxidant enzyme

extracellular superoxide dismutase (EC-SOD, SOD3)4-5. An increase in 
EC-SOD could potentially disrupt a balance in oxidative metabolism 
since enhanced H2O2 production without compensatory changes in 
catalase or glutathione peroxidase (GSHpx) may lead to increased 
production of more potent free radicals such as the hydroxyl radical 
(Figure 1). This was recently confirmed in animal studies by Oury 
et al.6 in which mice, transgenic for the human EC-SOD gene, had
markedly  increased susceptibility to oxygen-induced seizures.

Patients were therefore placed on antioxidant vitamins and minerals
(vitamin E, riboflavin, selenium and zinc). Over a six month period, 
parents and nursing home staff indicated there was some improvement in

patient condition, particularly in alertness. N-Acetylcysteine (NAC), 
a sulfhydryl amino acid has several characteristics promoting its 
usage as an antioxidant, including scavenging of the hydroxyl radical,

increased synthesis of reduced glutathione and diminished production 
of H2O2 (Figure 1)7-8. NAC administration was initiated and, 
at a dosage of 4-6 grams daily, produced a reduction in myoclonus,
increased mobility, and improvements in speech, alertness, and

Objective improvement in patients with PME-UL with NAC suggested its
usage in other neurodegenerative disorders. Our initial emphasis was 
the treatment of hereditary movement disorders, particularly the 
hereditary ataxias. More recently, patients with other
neurodegenerative conditions including amyotrophic lateral sclerosis 
(ALS), multiple sclerosis (MS), diabetic neuropathy and Alzheimer's 
disease have been treated with NAC. We report here results of studies 
with NAC conducted over the last 30 months.


A total of 61 patients have been treated with NAC for periods from 1 
month to 30 months. Forty eight (48) patients continue in these 
studies. Patients receive NAC either in liquid (Mucomyst or Mucosil), 
as a powder (Spectrum Chemical, Gardena, CA, USP grade), or as a 
flavoured suspension (West Labs Pharmacy, Gainesville, FL) dissolved 
in juice or cola. In this open label study, dosage is 4-6 grams/day 
for adults and 60 mg/kg/day for children divided into 2-3 doses.

Because of reports of magnesium (Mg) deficiency subsequent to 
treatment with NAC9, all patients receive supplemental Mg. In this 
report, we include patients with PME-UL (N=4), hereditary ataxias 
(N=32), multiple sclerosis (N=10), amyotrophic lateral sclerosis (N=3)

and Huntington's Chorea (N=2). At  baseline, all patients received a 
videotaped neurological exam, and the initial 40 patients received a 
FRESA analysis (FRESA Labs,  Redmond, WA) which included red blood 
cell (RBC) activity levels of GSHpx, glutathione reductase, 
glutathione transferase, catalase, superoxide dismutase (SOD1) and 
plasma selenium, zinc, manganese and copper. Disease specific 
neurophysiological, neuropsychological, ophthalmological and genetics 
testing was also performed. 


I. PME-UL (N=4)

A Florida family with 4 siblings with PME-UL have been treated at the
University of Florida for over 20 years. Molecular genetic analysis 
confirmed that the gene loci for these patients is located at 
chromosome 21 band q22.310. Treatment with phenytoin was without 
benefit and may have been deleterious11.
Patients had a steady course of deterioration with various 
combinations of phenytoin, phenobarbital, carbamezepine and other 
anticonvulsants. Valproic acid (VPA) produced marked improvement in 
these patients when introduced in 1978. 
VPA decreased myoclonus and generalized seizure activity such that
1 patient was able to attend college briefly. A possible mechanism for
the beneficial effect of VPA and negative effect of PHT is shown in 
Figure 1.

Progression of the disease continued however, and at initiation of
treatment with antioxidants, the 3 eldest were bedridden and could not
communicate, while the youngest had been in a wheelchair for over 2 
years and received meals and medications in a nursing home.

Improvement with NAC has included long periods of decreased myoclonus 
in the least affected patient such that she has been able to walk
unaided for several days at a time. This patient now lives in an 
apartment and provides for her own meals and medications. Her 3 male 
siblings have shown less, but demonstrable, improvement in seizure 
frequency and verbalization.

Objective measurements of improvement include some normalization of
somatosensory evoked potentials (SEPS). Giant SEPs (Figure 2), are a 
characteristic feature of this disorder. 



Eighteen patients with HSCA have been treated with NAC. Five siblings
(from a family of 14 children of the same parents) demonstrated 
variable signs of ataxia, dysarthria, and oculomotor disturbance. 
Genetic analysis ruled out SCA1 gene localization. All patients claim 
subjective improvement with NAC. The most severely affected sibling 
(male, age 43) has been treated with NAC for 26 months. Improvement in

eye movement control was marked. 
Prior to NAC treatment, reading speed had decreased from 300 wpm to 
less than 50 wpm and now the patient has regained more speed in 
reading. He returned to college and is now pursuing graduate studies. 
Prior to NAC, 4 of the siblings had retired from full-time work 
because of balance and fatigue problems. 
The youngest (42), a high school physics teacher, had considered 
disability retirement. Since starting NAC however, he claims fatigue 
and balance are no longer major problems.

A 67 year old patient with HSCA had steady progression of this
disorder for 25 years. Two brothers and his father died after years 
with a similar condition. Prior to initiation of NAC, balance was a 
major problem and the patient experienced 8-12 falls a day. According 
to his wife, no falls occurred following NAC treatment for a period of

almost 7 months. Dysarthria improved to the point that his
grandchildren could understand him on the telephone.


A 43 year old patient with a diagnosis of OPCA had difficulties with
balance and walking, progressive speech disturbance and diminished
proprioception and pain sensitivity. Improvement in dysarthria and 
balance were evident 1 month after NAC. At the 3 month visit, the 
patient could discriminate between hot and cold, and had regained some

touch and position sense. The patient joked that he used to enjoy 
going fishing since previously he could just watch the mosquitos bite 
him - now they hurt!


A 21 year old female with FA was referred for treatment with NAC.
analysis indicated low selenium and GSHpx activity along with other
abnormalities (Figure 3). Sirnilar antioxidant changes were found in
3 additional patients with FA (Helveston et al. in press). After 8
treatment with NAC and other antioxidants, this patient's FRESA
normal (Figure 3). During this time, there was an improvement in
and a slight decrease in ataxia.

Greater than 90% of FA patients develop a cardiomyopathy, which is a
cause of early death12. Until recent years, cardiomyopathy was a major
of childhood death in low selenium areas of China (Keshan Disease)
program of selenium supplementation of table salt was initiated in
areas and population glutathione peroxidase levels increased13.


Three siblings aged 7, 11, and 13 with AT confirmed by chromosomal
analysis and 
lymphocyte radiation fragility testing had questionable improvement in
condition after 3 months NAC. However, when 2 patients were taken off
NAC for 
a period of 2 weeks, rapid deterioration in their conditions ensued.
changes included a return of copious drooling in the youngest patient,
symptom in younger AT patients.

AT is a complex multisystem disorder characterized by ataxia, ocular 
telangiectasia, immunodeficiency involving both T and B cell
to 100-fold increased cancer incidence, spontaneous chromosomal
increased sensitivity to ionizing radiation14.
Recent evidence indicates that NAC treatment may be ideally suited to
of AT, since, in addition to its potentiai as a treatment for ataxia,
in-vitro studies indicate NAC is chemopreventative, radioprotective
enhances T cell functioning15-17. These AT patients have now taken NAC
15 months.


There is a marked elevation of the cytokine tumor necrosis factor ÿ
(TNFÿ) in 
active MS, and a correlation exists between CSF levels of TNFÿ and the

severity and progression of disease18. With cytokine activation there
is increased free radical production and this has been demonstrated in
NAC is a free radical scavenger and inhibits toxicity of TNFÿ and in
the EAE animal model of MS, inhibits the development of MS like
Ten patients with MS have taken NAC for a period of up to 16 months.
Because of 
the relapsing-remitting course of the disease occurring in many MS
it is difficult to ascertain efficacy of NAC in these preliminary
However, two MS patients with longstanding inability to speak
a rather dramatic irnprovement in speech shortly after starting the
Controlled trials are necessary to ascertain if NAC can decrease the
of exacerbations in MS.


A role of free radicals in the progression of ALS recently received
with the discovery of linkage of familial ALS (FALS) with mutations in
gene encoding CuZn SOD (SOD1)21. Levels of SOD1 are decreased in
with FALS but are often norrnal in sporadic ALS. In a patient with
FRESA analysis indicated an SOD1 activity of approximately 50% of the
end of the normal range. The remaining FRESA profile was normal. NAC
treatment has so far been unsuccessful in altering the progressive
of this patient's disease. In two patients with sporadic ALS, SOD1
was normal, but GSHpx and glutathione reductase activities were
decreased. In these patients NAC treatment may have modified the
of the disease as one patient (duration of treatment 12 months) has
remained stable with an increase in grip strength. A second patient
only marginally progressed during 17 months of treatment with NAC. 
Recently, Louwerse et al.22 reported on a double-blind trial of NAC in

111 patients with ALS. Patients with limb onset but not bulbar
onset of ALS had a 50% decrease in the one year mortality rate 
with NAC treatment. 


HC fibroblasts have increased sensitivity to toxic effects of
This toxicity is partially ameliorated by cystine, cysteine and 
antioxidants24. NAC is a cysteine precursor, suggesting its usage in
Two male patients aged 43 and 44 with advanced HC were treated with
for 2 and 3 months respectively. There was no obvious improvement in 
patient condition with NAC treatment and patients were discontinued
the study. A longer trial period with less advanced patients is
to preclude NAC usefulness in this disorder. 


Treatment with high dose NAC has produced modest improvement in
with neurodegenerative disorders. Where improvement has been noted, it
has usually 
been early in treatment and then tends to plateau. Some patients have
seen an initial improvement but remain on NAC as a possible means to
further progression of their disorder. In some 40 patients tested
patients with HSCA, AT, FA, ALS, MS, DN and HC) pretreatment FRESA
indicated an imbalance in antioxidant enzyme activity. Although a few
claimed some benefit from more traditional antioxidant therapies (e.g
A,C,E,B2, and selenium), most patients said these were without
benefit. As suggested in Figure 2, improvement in physical condition
correlate with improved free radical status. This suggests that these
abnormalities are not primary in these disorders but occur secondary
whatever gene defects trigger excess free radical activity (e.g.,
SOD are readily destroyed by excess superoxide25). This study
the possibility that if improvement in the antioxidant status occurs,
potential exists for arresting progression of the disease and in some
an improvement in patient condition.

The high level of safety and variety of antioxidant actions of NAC
suggest it as 
a very promising new tool for treatment of neurodegenerative
recent months, scientific reports of animal and in-vitro studies
that NAC inhibits neuronal apoptosis26 and toxicity in models of
sclerosis20, amyotrophic lateral sclerosis27 and diabetic necrosis28.
Some of the known actions of NAC are listed in Table 1.


1.Gotz ME, Kunig G, Riederer P, Youdim MBH. Oxidative Stress: Free
production in neural degeneration. Pharrnac Ther 63:37-122, 1994.
2.Olanow CW. A radical hypothesis for neurodegeneration. Ann Neurol 
32(Suppl):S8-S15, 1992. 
3.Jesberger JA, Richardson JS. Oxygen free radicals and brain
Intern J Neurosci 57:1-17, 1991.
4.Hurd RW, Wilder BJ, Perchalski, RJ. Increased extracellular
dismutase in Baltic Myoclonus. Epilepsia 34:8, 1993.
5.Wilder BJ, Hurd RW, Uthman BM. N-Acetylcysteine in the treatment of
disease with altered superoxide dismutase activity. Neurology 44(Suppl
12): 1994.
6.Oury TD, Ho Y-S, Piantadosi CA, Crapo JD. Extracellular superoxide
dismutase, nitric oxide, and central nervous system toxicity. Proc
Acad Sci 89:9715-9719, 1992.
7.Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of
N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl
superoxide, and hypochlorous acid. Free Radical Biol Med 6:593-597,
8.Zirnent I. Acetylcysteine: a drug that is much more than a
mucokinetic. Biomed pharrnacother 42:513-520, 19~8.
9.Scantay J. The scavenger role of preparation tiomag in antioxidant
therapy. In: Trace Metals in Man and Animals. M Anke, D Messsner, CF
Mills (eds.) Vol.8, Verlag, 
Bodstrasse, Germany, pp.849-853, 1993.
10. Lehesjoki A, Eldridge E, Eldridge J, Wilder BJ, de la Chapelle A.
Progressive myoclonus epilepsy of Unverricht-Lundborg type: A clinical
and molecular genetic 
study of a family from the United States with four affected sibs.
Neurol 43:2384-2386, 1993.
11. Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ.
disorder of childhood made worse by phenytoin. Lancet 2:838-840, 1983.
12.Lechtenberg R. Ataxia and other cerebellar syndromes. In:
Disease and Movement Disorders. 2nd Edition, J Jankovic and E Tolosa
(eds), Williams and 
Wilkins, Baltimore, 1993, pp 419-431.
13.Yang G, Chen J, Wen Z, et al. The role of selenium in Keshan
Adv Nutr Res
6:203-231, 1984.
14.Woods CG, Taylor AMR. Ataxia telangiectasia in the British Isles:
clinical and laboratory features of 76 affected individuals. Quart J
82:169-179, 1992.
15.Solen G. Radioprotective effect of N-Acetylcysteine in vitro using
the induction in DNA breaks as end point. Int J Radiat Biol
16.Mayer M, Noble M. N-acetyl-l-cysteine is a pluripotent protector
against cell death and enhancer of trophic factor-mediated cell
in vitro. Proc Natl Acad Sci 91:7496 7500, 1994.
17.Eylar E, Rivera-Quinones C, Molina C, Baez I, Molina F, Mercado CM.
enhances T-cell function and T-cell growth in culture. Intern Immunol
5:97-101, 1993.
18.Sharief K, Hentges R. Association between tumor necrosis
and disease progression in patients with multiple sclerosis. N Engl J
Med 325:467-472, 1991.
19.Glabinski A, Tawsek NS, Bartosz G. Increased generation of
radicals in the blood of MS patients. Ann Neurol Scand 88:171-177,
20.Lehmann D, Karussis D, Misrachi-Koll R, Shezen E, Ovadia H,
O. Oral
administration of the oxidant-scavenger N-acetyl-L-cysteine inhibits
acute experiemental autoimmune encephalomyelitis. Neuroimmunol
21.Rosen DR, Siddique T, Patterson D et al. Mutations in CuZn
dismutase gene are associated with familial amyotrophic lateral
sclerosis Nature 302:59-62, 1993
22.Louwerse ES, Weverling GJ, Bossuyt PMM, Meyjes FEP, Vianney deJong
JMB. Randomized,
double-blind, controlled trial of acetylcysteine in Amyotrophic
Sclerosis. Arch Neurol 52:559-564, 1995. 
23.Gray PN, May PD, Mundy L, Elkins J. L-glutamate toxicity in
Huntington's disease fibroblasts. Biochem Biophys Res Comm
95:707-714, 1980.
24.May PC, Gray PN. The mechanism of glutamate-induced degeneration of
Huntington's disease and control fibroblasts. Neurol Sci 70: 101-112,
25.Pigeolet E, Corbisier P, Houbion A, Larnbert D, Michiels C, Raes M,
Zachary M-D, 
Remacle J. Glutathione peroxidase, superoxide dismutase, and catalase
inactivation by 
peroxides and oxygen derived free radicals. Mechs Ageing Devel
51:283-297, 1990.
26.Ferrari G, YAN CYI, Greene LA. N-Acetylcysteine (D and L
stereoisomers) prevents 
apoptic death of neuronal cells. J Neuroscience 15:2857-2866, 1995.
27.Rothstein JD, Bristol LA, Hosler B, Brown, Jr RH, Kuncl, RW.
inhibition of 
superoxide dismutase produces apoptotic death of spinal neurons. Proc
Nat Acad Sci 
91:4155-41S9, 1994.
28.Sagara M, Satoh J, Zhu XP, Takhashi K, Fuzuzawa M, Muot G, Muto Y,
Toyota T. 
Inhibition with N-acetylcysteine of enhanced production of tumor
necrosis factor in 
streptozotocin-induced diabetic rats. Clin Immunol Immunopathol
71:333-337, 1994.

To learn more about the Amalgam safety issue (or lack of) visit:-

More information about the Neur-sci mailing list

Send comments to us at biosci-help [At] net.bio.net