Research extract - Treatment of neurodegenerative disease with N-Acetylcysteine

[pcsol at tcp.co.uk]

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:-
http://www.coa.uky.edu/ADReview/index.html
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..)
cheers
ade

To learn more about the Amalgam safety issue (or lack of) visit:-
  http://ourworld.compuserve.com/homepages/pcsol


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N-Acetyl Cysteine Report

This article submitted by on 4/13/96.

Author's Email: 

FIRST ANNUAL HEALTH SCIENCE CENTER RESEARCH WEEK
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


INTRODUCTION

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
self-care.

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.

PATIENTS AND METHODS

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. 

RESULTS

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. 

II. THE HEREDITARY ATAXIAS (N=32)

A. HEREDITARY SPINOCEREBELLAR ATAXIA (HSCA) (N=18)

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.

B. OLIVOPONTOCEREBELLAR ATROPHY (OPCA) (N=4)

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!

C. FRIEDREICH's ATAXIA (FA) (N=7)

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

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

D. ATAXIA TELANGIECTASIA (AT) (N=3)

Three siblings aged 7, 11, and 13 with AT confirmed by chromosomal
analysis and 
lymphocyte radiation fragility testing had questionable improvement in
their 
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.
These 
changes included a return of copious drooling in the youngest patient,
a
cornmon 
symptom in younger AT patients.

AT is a complex multisystem disorder characterized by ataxia, ocular 
telangiectasia, immunodeficiency involving both T and B cell
functions,
50 
to 100-fold increased cancer incidence, spontaneous chromosomal
breakage
and 
increased sensitivity to ionizing radiation14.
Recent evidence indicates that NAC treatment may be ideally suited to
treatment 
of AT, since, in addition to its potentiai as a treatment for ataxia,
in-vitro studies indicate NAC is chemopreventative, radioprotective
and 
enhances T cell functioning15-17. These AT patients have now taken NAC
for 
15 months.

III. MULTIPLE SCLEROSIS (MS) (N=10)

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
MS19. 
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
pathology20. 
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
patients, 
it is difficult to ascertain efficacy of NAC in these preliminary
studies. 
However, two MS patients with longstanding inability to speak
coherently
had 
a rather dramatic irnprovement in speech shortly after starting the
drug.
Controlled trials are necessary to ascertain if NAC can decrease the
number 
of exacerbations in MS.

IV. AMYOTROPHIC LATERAL SCLEROSIS (N=3)

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

V. HUNTINGTON'S CHOREA (HC) (N=2)

HC fibroblasts have increased sensitivity to toxic effects of
glutamate23. 
This toxicity is partially ameliorated by cystine, cysteine and 
antioxidants24. NAC is a cysteine precursor, suggesting its usage in
HC. 
Two male patients aged 43 and 44 with advanced HC were treated with
NAC 
for 2 and 3 months respectively. There was no obvious improvement in 
patient condition with NAC treatment and patients were discontinued
from 
the study. A longer trial period with less advanced patients is
necessary 
to preclude NAC usefulness in this disorder. 

DISCUSSION

Treatment with high dose NAC has produced modest improvement in
several
patients 
with neurodegenerative disorders. Where improvement has been noted, it
has usually 
been early in treatment and then tends to plateau. Some patients have
not
seen an initial improvement but remain on NAC as a possible means to
prevent 
further progression of their disorder. In some 40 patients tested
(including 
patients with HSCA, AT, FA, ALS, MS, DN and HC) pretreatment FRESA
analysis 
indicated an imbalance in antioxidant enzyme activity. Although a few
patients 
claimed some benefit from more traditional antioxidant therapies (e.g
vitamins 
A,C,E,B2, and selenium), most patients said these were without
noticeable
benefit. As suggested in Figure 2, improvement in physical condition
may 
correlate with improved free radical status. This suggests that these
enzyme
abnormalities are not primary in these disorders but occur secondary
to 
whatever gene defects trigger excess free radical activity (e.g.,
GSHpx
and 
SOD are readily destroyed by excess superoxide25). This study
indicates
the possibility that if improvement in the antioxidant status occurs,
the 
potential exists for arresting progression of the disease and in some
cases 
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
disorders.
In 
recent months, scientific reports of animal and in-vitro studies
indicate 
that NAC inhibits neuronal apoptosis26 and toxicity in models of
multiple 
sclerosis20, amyotrophic lateral sclerosis27 and diabetic necrosis28.
Some of the known actions of NAC are listed in Table 1.

REFERENCES

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3.Jesberger JA, Richardson JS. Oxygen free radicals and brain
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4.Hurd RW, Wilder BJ, Perchalski, RJ. Increased extracellular
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To learn more about the Amalgam safety issue (or lack of) visit:-
  http://ourworld.compuserve.com/homepages/pcsol