Reduced intravenous glutathione in the treatment of Parkinson’s disease.
1. Several studies have demonstrated a deficiency in reduced glutathione (GSH) in the nigra of patients with Parkinson’s Disease (PD). In particular, the magnitude of reduction in GSH seems to parallel the severity of the disease. This finding may indicate a means by which the nigra cells could be therapeutically supported.
2. The authors studied the effects of GSH in nine patients with early, untreated PD. GSH was administered intravenous, 600 mg twice daily, for 30 days, in an open label fashion. Then, the drug was discontinued and a follow-up examination carried-out at 1-month interval for 2-4 months. Thereafter, the patients were treated with carbidopa-levodopa.
3. The clinical disability was assessed by using two different rating scale and the Webster Step-Second Test at baseline and at 1-month interval for 4-6 months. All patients improved significantly after GSH therapy, with a 42% decline in disability. Once GSH was stopped the therapeutic effect lasted for 2-4 months.
4. Our data indicate that in untreated PD patients GSH has symptomatic efficacy and possibly retards the progression of the disease.
Parkinson’s disease: a disorder due to nigral glutathione deficiency?
Amino acid analysis of autopsied human brain showed reduced glutathione (GSH) content significantly lower in the substantia nigra than in other brain regions. GSH was virtually absent in the nigra of patients with Parkinson’s disease. Oxidative degradation of L-DOPA and dopamine in vivo may generate reactive oxygen species (hydrogen peroxide, superoxide, hydroxyl radical, or singlet oxygen) which can damage membranes and other cellular components.
Since GSH is an important natural antioxidant, a deficiency of GSH in the substantia nigra could make this region vulnerable to oxidative injury. If confirmed, the hypothesis that loss of nigrostriatal dopaminergic neurons results from a regional GSH deficiency could have important therapeutic implications for the management and prevention of Parkinson’s disease.
Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson’s disease.
In Parkinson’s disease (PD), dopaminergic cell death in the substantia nigra was associated with a profound glutathione (GSH) decrease and a mitochondrial dysfunction. The fall in GSH concentration seemed to appear before the mitochondrial impairment and the cellular death, suggesting that a link may exist between these events.
The relationships between GSH depletion, reactive oxygen species (ROS) production, mitochondrial dysfunction and the mode of cell death in neuronal cells remain to be resolved and will provide important insights into the etiology of Parkinson’s disease. An approach to determine the role of GSH in the mitochondrial function and in neurodegeneration was to create a selective depletion of GSH in a neuronal cell line in culture (NS20Y) by inhibiting its biosynthesis with L-buthionine-(S,R)-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase.
This treatment led to a nearly complete GSH depletion after 24 hr and induced cellular death via an apoptotic pathway after 5 days of BSO treatment. By using the reactive oxygen species-sensitive probe 2′,7′-dichlorofluorescin, we observed that the rapid GSH depletion was accompanied, early in the process, by a strong and transient intracellular increase in reactive oxygen species evidenced after 1 hr with BSO, culminating after 3 hr when the GSH level decreased to 30% of normal. GSH depletion induced a loss of mitochondrial function after 48 hr of BSO treatment. In particular, the activities of complexes I, II and IV of the respiratory chain were decreased by 32, 70 and 65%, respectively as compared to controls.
These results showed the crucial role of GSH for maintaining the integrity of mitochondrial function in neuronal cells. Oxidative stress and mitochondrial impairment, preceding DNA fragmentation, could be early events in the apoptotic process induced by GSH depletion. Our data are consistent with the hypothesis that GSH depletion could contribute to neuronal apoptosis in Parkinson’s disease through oxidative stress and mitochondrial dysfunction.
Glutathione deficiency and Parkinson’s disease — Cause and Treatment.
Typically the treatment regimens have tried to help replenish Dopamine and help decrease tremors but, the results are generally mixed.In the Nutritional realm over the past decade or so, researchers were looking further into the disease and tried to understand the biochemical process a bit better. Over time, as with many other degenerative diseases, they were looking at oxidative stress as a contributor to the brain degeneration. With an understanding of free radical pathology and antioxidant benefit, the focus switched to helping to stop oxidative damage. Researchers soon found themselves looking at Glutathione levels in effected tissues and found them to be depleted. Is this a possible cause of the disease? Might this lead to a new line of reasoning and new treatment?
Well, it does seem that Glutathione is extremely important to the brain, and especially the Substantia Nigra. It probably has a lot to do with the disease.More importantly, therapy with Glutathione intravenously has shown some very significant results. In a variety of institutions (as well as in my office), IV treatment has helped to change the course of this disease. Patients that are having difficulty with movement are doing much better, tremors have become far less obvious, and we’ve noticed improvement in memory and concentration. Weakness, stiffness and balance have improved greatly as well.
The treatment needs to be done 2 – 3 times a week, and results are usually seen within a week or so. Intravenous access is necessary because it carries with it 100% absorption of product. Oral forms of Glutathione are not absorbed well at all. Results have been seen only with the intravenous technique.The attached articles support this view.
Looking at diseases with a “nutritional eye” has always yielded new pathways to follow and new, viable techniques of treatment.
Searching for a relationship between manganese and welding and Parkinson’s disease
Research into the causes of Parkinson disease (PD) has acceleratedrecently with the discovery of novel gene mutations. The majorityof PD cases, however, remain idiopathic and in those cases environmentalcauses should be considered.
Several recent reports have focusedon welding and manganese toxicity as potential risk factorsfor parkinsonism and some have even proposed that welding isa risk factor for PD.
The controversy has stimulated this review,the primary aim of which is to critically and objectively examinethe evidence or lack of evidence for a relationship among welding,manganese, parkinsonism, and PD.
Published on 2007-12-23 18:27:05 | Click for complete article…
Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity In Vivo A Novel Therapy for Parkinson’s Disease
Studies on postmortem brains from Parkinson’s patients reveal elevated iron in the substantia nigra (SN). Selective cell death in this brain region is associated with oxidative stress, which may be exacerbated by the presence of excess iron. Whether iron plays a causative role in cell death, however, is controversial.
Here, we explore the effects of iron chelation via either transgenic expression of the iron binding protein ferritin or oral administration of the bioavailable metal chelator clioquinol (CQ) on susceptibility to the Parkinson’s-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP).
Reduction in reactive iron by either genetic or pharmacological means was found to be well tolerated in animals in our studies and to result in protection against the toxin, suggesting that iron chelation may be an effective therapy for prevention and treatment of the disease.
Published on 2007-12-23 18:20:08 | Click for complete article…
Statins, cholesterol, Co-enzyme Q10, and Parkinson`s disease
`Statins`, drugs that lower cholesterol are widely used. Statins block cholesterol in the body and brain by inhibiting HMG-Co-A reductase. This pathway is shared by CoQ-10. An unintended consequence of the statins is lowering of CoQ-10. As CoQ-10 may play a role in PD, its possible statins may worsen PD. Such a report has appeared.
Statins came into wide use in 1997–1998, 6 years before our study began. Thus 74% of our patients on a statin had a PD duration of 1–6 years versus 56% of our patients not on a statin. A direct comparison of patients on a statin and not on a statin would bias the study in favor of the statins: patients on a statin would have a shorter disease duration and less advanced PD. Therefore we divided the patients into two groups. Group I consisted of 128 patients on a statin, and 252 not on a statin who had PD for 1–6 years. In this group, disease severity (Hoehn & Yahr Stage), levodopa dose, Co-enzyme Q10 use, prevalence of ‘wearing off’, dyskinesia and dementia were similar. Group II consisted of 45 patients on a statin and 200 patients not on a statin who had PD for 7–22 years. In this group disease severity, levodopa dose, Co-enzyme Q10 use, prevalence of wearing off, dyskinesia and dementia were similar.
Statins although they may affect Co-enzyme Q10 levels in the body and the brain, do not worsen PD at least as assessed by stage, and prevalence of wearing-off, dyskinesia, and dementia.
Published on 2007-09-09 18:03:27 | Click for complete article…
Ironing Iron Out in Parkinson’s Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6-Hydroxydopamine and Iron Chelators, Desferal and VK-28
In Parkinson`s disease (PD) and its neurotoxin-induced models,6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP), significant accumulation of iron occurs in the substantianigra pars compacta. The iron is thought to be in a labile pool,unbound to ferritin, and is thought to have a pivotal role toinduce oxidative stress-dependent neurodegeneration of dopamineneurons via Fenton chemistry. The consequence of this is itsinteraction with H2O2 to generate the most reactive radicaloxygen species, the hydroxyl radical. This scenario is supportedby studies in both human and neurotoxin-induced parkinsonismshowing that disposition of H2O2 is compromised via depletionof glutathione (GSH), the rate-limiting cofactor of glutathioneperoxide, the major enzyme source to dispose H2O2 as water inthe brain.
Further, radical scavengers have been shown to preventthe neurotoxic action of the above neurotoxins and depletionof GSH. However, our group was the first to demonstrate thatthe prototype iron chelator, desferal, is a potent neuroprotectiveagent in the 6-OHDA model. We have extended these studies andexamined the neuroprotective effect of intracerebraventricular(ICV) pretreatment with the prototype iron chelator, desferal(1.3, 13, 134 mg), on ICV induced 6-OHDA (250 µg) lesionof striatal dopamine neurons. Desferal alone at the doses studieddid not affect striatal tyrosine hydroxylase (TH) activity ordopamine (DA) metabolism. All three pretreatment (30 min) dosesof desferal prevented the fall in striatal and frontal cortexDA, dihydroxyphenylacetic acid, and homovalinic acid, as wellas the left and right striatum TH activity and DA turnover resultingfrom 6-OHDA lesion of dopaminergic neurons. A concentrationbell-shaped neuroprotective effect of desferal was observedin the striatum, with 13 µg being the most effective.
Neither desferal nor 6-OHDA affected striatal serotonin, 5-hydroxyindoleacetic acid, or noradrenaline. Desferal also protected against6-OHDA-induced deficit in locomotor activity, rearing, and exploratorybehavior (sniffing) in a novel environment. Since the lowestneuroprotective dose (1.3 µg) of desferal was 200 timesless than 6-OHDA, its neuroprotective activity may not be attributedto interference with the neurotoxin activity, but rather ironchelation. These studies led us to develop novel brain-permeableiron chelators, the VK-28 series, with iron chelating and neuroprotectiveactivity similar to desferal for ironing iron out from PD andother neurodegenerative diseases, such as Alzheimer’s disease,Friedreich’s ataxia, and Huntington`s disease.
Published on 2007-08-02 17:45:41 | Click for complete article…
Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration?
Razor sharp and high iron deposits are present in the substantia nigra (SN). Although the function of such high iron content is not known, the homeostasis of brain iron is important for normal brain function. The participation of free tissue iron in oxidative stress (OS), resulting in the formation of cytotoxic hydroxyl radical (.OH) from H2O2 (Fenton reaction) and promotion of membrane lipid peroxides by .OH can no longer be questioned as a biological phenomenon.
The highly selective increase of Fe2+ and Fe3+ and lipid peroxidation observed in parkinsonian SN points to OS in such brains. Lipid peroxidation proceeds with either Fe2+ or Fe3+ provided a mechanism exists to facilitate the interconversion of iron between its redox states. Indeed H2O2 derived from MAO B reaction and autooxidation of dopamine to melanin in the SN can drive the iron dependent Fenton reaction. Furthermore, interaction of iron with melanin may be even more important considering that melanin avidly binds Fe3+ and reduce it to Fe2+, resulting in .OH generation. Thus, without evoking environmental neurotoxins, the excessive accumulation of free iron in the SN and “melanin-trap” could be the trigger for accelerated cell death and Parkinsonism.
Published on 2007-08-02 17:43:20 | Click for complete article…
Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease.
A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson`s disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years).
A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects’ case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PD. However, more than 20 years exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83) or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD.
Occupational exposure for > 20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 1.40,9.71) was also associated with the disease. No association of occupational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD.
Published on 2007-07-15 18:16:58 | Click for complete article…
Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease.
Levels of iron, copper, zinc, manganese, and lead were measured by inductively coupled plasma spectroscopy in parkinsonian and age-matched control brain tissue. There was 31-35% increase in the total iron content of the parkinsonian substantia nigra when compared to control tissue. In contrast, in the globus pallidus total iron levels were decreased by 29% in Parkinson’s disease. There was no change in the total iron levels in any other region of the parkinsonian brain.
Total copper levels were reduced by 34-45% in the substantia nigra in Parkinson`s disease; no difference was found in the other brain areas examined. Zinc levels were increased in substantia nigra in Parkinson`s disease by 50-54%, and the zinc content of the caudate nucleus and lateral putamen was also raised by 18-35%. Levels of manganese and lead were unchanged in all areas of the parkinsonian brain studied when compared to control brains, except for a small decrease (20%) in manganese content of the medial putamen. Increased levels of total iron in the substantia nigra may cause the excessive formation of toxic oxygen radicals, leading to dopamine cell death.
Published on 2007-07-15 18:14:46 | Click for complete article…
Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity In Vivo
Studies on postmortem brains from Parkinson patients reveal elevated iron in the substantia nigra (SN). Selective cell death in this brain region is associated with oxidative stress, which may be exacerbated by the presence of excess iron. Whether iron plays a causative role in cell death, however, is controversial. Here, we explore the effects of iron chelation via either transgenic expression of the iron binding protein ferritin or oral administration of the bioavailable metal chelator clioquinol (CQ) on susceptibility to the Parkinson’s-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP). Reduction in reactive iron by either genetic or pharmacological means was found to be well tolerated in animals in our studies and to result in protection against the toxin, suggesting that iron chelation may be an effective therapy for prevention and treatment of the disease.
Published on 2007-06-06 19:05:29 | Click for complete article…
Plasma testosterone levels in Alzheimer and Parkinson diseases
Background: Testosterone deficiency, a treatable condition commonlyseen in aging men, has been linked to Parkinson disease (PD)and Alzheimer disease (AD). In normal subjects, low testosteronelevels are associated with cognitive and neuropsychiatric symptoms,yet the relationship between testosterone levels and cognitivefunction in PD and AD remains unclear.
Objective: To examine the relationship of testosterone levelsto age and cognitive function in PD and AD.
Methods: Plasma testosterone levels were determined in men enrolledin a clinical registry of subjects with PD and AD, and neuropsychologicaltesting was performed on subjects who consented. Testosteronelevels in men with PD were compared with those in men with AD.In both groups, the relationship between testosterone levelsand neuropsychological test scores was analyzed, adjusting forage and education.
Results: Linear regression analysis revealed that testosteronelevels decreased with age in male PD patients (p < 0.03)and male AD patients (p < 0.07). The rate of decline wassimilar for the two groups. In PD patients, lower testosteronelevels were associated with poorer performance on Trails B Seconds(p < 0.02).
Conclusions: There is a similar age-related decline in plasmatestosterone levels in men with either PD or AD. Previouslydescribed associations between low testosterone levels and frontallobe dysfunction in normal aged men, together with these results,suggest that the hormonal deficiency may act as a “second hit”to impair cognitive function in neurodegenerative disease.
Chemical linked to Parkinson’s disease
In the late 1970s, Eddie Abney cleaned grease from metal gauges at a Berea factory using a chemical solvent called trichloroethylene, or TCE. The chemical, which is still used today as an industrial degreaser, soaked through his cotton gloves and into his skin. It splattered on his clothes. He breathed in its vapors.
At night, when he came home, he would tell his wife that the smell was killing him.
Researchers at the University of Kentucky have linked industrial use of TCE to Parkinson’s disease, which Abney has. It was Abney, 51, who pointed researchers to a possible connection, leading to a study that was published last month in the online version of Annals of Neurology, a journal of the American Neurological Association.
The study shows a clear link between an environmental contaminant and Parkinson’s, said Don Gash, the lead researcher.
TCE has been suspected before as a cause of Parkinson’s, but the UK study shows a “clear-cut link” from exposure to the chemical to the disease’s development, Gash said. “We’ve connected the dots.”
The study found that three people who directly handled TCE at the factory where Abney worked developed Parkinson’s disease. An additional 14, who breathed in its vapors, had early symptoms of Parkinson’s, but not the disease itself. And 13 more, who were also exposed to vapors, didn’t show signs of parkinsonism but had slower fine motor skills than others their age.
As part of the study, researchers gave rats TCE. All of them showed brain damage to the same cells as Parkinson’s patients, damage done through the same cellular pathway, the mitochondria. Gash thinks the mitochondria might be the key to finding an effective treatment for Parkinson’s.
“We’re now focusing our attention on mitochondrial dysfunctions, looking at ways to intervene and promote recovery of mitochondrial functions,” Gash said.
The Berea factory where Abney worked is no longer open. It was owned by Dresser Industries, which was sold to Halliburton in 1998. In 2001, Halliburton spun off parts of Dresser Industries, including the Berea factory, into Dresser Inc., a Dallas-based company.
Linda Rutherford, general counsel for Dresser Inc., declined to comment on the UK study, because she had not seen it. She noted that the Berea factory had not used TCE since 2001, when Dresser Inc., took it over.
TCE is a clear liquid, most often used to clean grease from metal. It is found in adhesives, paint removers, typewriter correction fluids and spot removers, according to the Agency for Toxic Substances and Disease Registry, a division of the U.S. Department of Health and Human Services.
TCE does not occur naturally but it is a common contaminant of water, air and soil near factories, military installations and hundreds of waste sites around the country, according to the National Academy of Sciences.
When Abney was diagnosed with Parkinson’s in 2001, he and his wife, Susan, wondered whether TCE could have been the cause. Sometimes Parkinson’s has a genetic tie, but Eddie Abney didn’t have family history of Parkinson’s. Environmental factors had been linked to the disease: exposure to certain pesticides or recreational use of MTPT, known commonly as synthetic heroin.
But Abney wondered whether, in his case, it was TCE. He remembered the strong smell of the chemical he had worked with for more than two decades with little protection.
“I had gloves on, but they were just white cotton gloves,” Abney said. “If they got wet, they got saturated.”
A year after his diagnosis, Abney participated in a clinical drug trial for Parkinson’s disease at UK. When he told a researcher his medical history, he mentioned the exposure to TCE, and the fact that others from the factory had Parkinson’s. The researcher, Kathyrn Rutland, thought it sounded like a cluster of cases.
“We felt like there was enough there to really get started,” said Gash, the lead researcher.
Eddie Abney stopped working in 2001. Parkinson’s had made it impossible for him to do his job safely.
These days, he has trouble walking. He can move from room to room with a cane or a walker, but longer distances require a motorized wheel chair. He has trouble talking, and his words slur into one another. He can’t swallow well, and his body is stiff.
Susan Abney says she and her husband are glad to know that they weren’t wrong, that their hunch about TCE was right. But the knowledge doesn’t soothe what has happened to her husband.
“His life is completely different because of this chemical,” Susan Abney said. “Nobody told him how dangerous it was. He didn’t have the tools or the gloves or the whatever to keep him from getting sick.”