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
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.
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 comrnunicate, 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 Ø (TNFØ) in active MS, and a correlation exists between CSF levels of TNFØ 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 TNFØ 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.
Treatrnent 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.
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* Figures not included in this version