ascorbic-acid and Parkinson-Disease

Similar to many other diseases, the etiology of Parkinson's disease (PD) is multifactorial and includes both genetic and environmental factors. Exposure to pesticides and the production of reactive oxygen species (ROS) in the body, mainly in electron transporter complexes 1 and 2 in the inner mitochondrial membrane, are two primary environmental risk factors for this disease. Increased accumulation of ROS and oxidative stress (OS) trigger a series of reactions that can lead to the aggregation of misfolded proteins, DNA damage, autophagy, and apoptosis, which may adversely affect cell function. These processes cause diseases such as coronary artery disease (CAD), Alzheimer's disease (AD), and PD. As indicated in previous studies, ROS is considered a critical regulator in the progression of PD. The human body contains several antioxidant molecules, such as vitamin A, vitamin C, bilirubin, and uric acid, as well as antioxidant enzymes including paraoxonase (PON), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Therefore, based on the canonical function of the antioxidant enzymes in PD, In the present review, we attempted to examine the function of antioxidant enzymes in PD.

Topics: Antioxidants; Ascorbic Acid; Glutathione Peroxidase; Humans; Parkinson Disease; Reactive Oxygen Species

The aim of the current review was to explore the association between various dietary antioxidants and the risk of developing Parkinson's disease (PD). PubMed, Scopus, Web of Science, and Google Scholar were searched up to March 2021. Prospective, observational cohort studies, nested case-control, and case-control designs that investigated the association between antioxidants and PD risk were included. A random-effects model was used to pool the RRs. The certainty of the evidence was rated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluations) scoring system. In addition, a dose-response relation was examined between antioxidant intake and PD risk. Six prospective cohort studies and 2 nested case-control (total n = 448,737 with 4654 cases), as well as 6 case-control (1948 controls, 1273 cases) studies were eligible. The pooled RR was significantly lower for the highest compared with the lowest intake categories of vitamin E (n = 7; 0.84; 95% CI: 0.71, 0.99) and anthocyanins (n = 2; 0.76; 95% CI: 0.61, 0.96) in cohort studies. Conversely, a significantly higher risk of PD was observed for higher lutein intake (n = 3; 1.86; 95% CI: 1.20, 2.88) among case-control studies. Dose-response meta-analyses indicated a significant association between a 50-mg/d increase in vitamin C (n = 6; RR: 0.94; 95% CI: 0.88, 0.99), a 5-mg/d increment in vitamin E (n = 7; RR: 0.84; 95% CI: 0.70, 0.99), a 2-mg/d increment in β-carotene (n = 6; RR: 0.94, 95% CI: 0.89, 0.99), and a 1-mg/d increment in zinc (n = 1; OR: 0.65; 95% CI: 0.49, 0.86) and a reduced risk of PD. Overall, higher intake of antioxidant-rich foods may be associated with a lower risk of PD. Future well-designed prospective studies are needed to validate the present findings. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (https://www.crd.york.ac.uk/PROSPERO, CRD42021242511).

Topics: Anthocyanins; Antioxidants; Ascorbic Acid; beta Carotene; Humans; Lutein; Observational Studies as Topic; Parkinson Disease; Prospective Studies; Risk Factors; Vitamin E; Zinc

A neuroprotective effect of dietary vitamins C and E on Parkinson's disease (PD) has been suggested, however, several human studies have reported controversial results. Therefore, we conducted a meta-analysis on the effect of vitamins C and E on the risk of Parkinson's disease.. A comprehensive literature search was conducted using the PubMed, EMBASE, Cochrane Library, and SCOPUS databases for studies published up to January 23, 2021. We included studies that reported (1) intake of vitamins C and E using validated methods; (2) assessment of odds ratio (OR), relative risk (RR), or hazard ratio (HR); and (3) patients with PD identified by a neurologist, hospital records, or death certificates. The Comprehensive Meta-Analysis Software 2 program was used for statistical analyses of the pooled data.. A total of 12 studies (four prospective cohort and eight case-control studies) were included in our meta-analysis. No significant risk reduction was observed in the high vitamin C intake group compared to low intake group. On the other hand, the high vitamin E intake group showed a significantly lower risk of development of PD than the low intake group (pooled OR = 0.799. 95% CI = 0.721 to 0.885).. We conclude that vitamin E might have a protective effect against PD, while vitamin C does not seem to have such an effect. However, the exact mechanism of the transport and regulation of vitamin E in the CNS remains elusive, and further studies would be necessary in this field.

Topics: Ascorbic Acid; Dietary Supplements; Humans; Parkinson Disease; Risk Factors; Vitamin E

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the degeneration and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been suggested that oxidative stress plays a role in the etiology and progression of PD. For instance, low levels of endogenous antioxidants, increased reactive species, augmented dopamine oxidation, and high iron levels have been found in brains from PD patients. In vitro and in vivo studies of Parkinson models evaluating natural and endogenous antioxidants such as polyphenols, coenzyme Q10, and vitamins A, C, and E have shown protective effects against oxidative-induced neuronal death. In this paper, we will review the mechanisms by which polyphenols and endogenous antioxidants can produce protection. Some of the mechanisms reviewed include: scavenging nitrogen and oxygen reactive species, regulation of signaling pathways associated with cell survival and inflammation, and inhibition of synphilin-1 and alpha-synuclein aggregation.

Topics: alpha-Synuclein; Animals; Antioxidants; Ascorbic Acid; Carrier Proteins; Cell Death; Dopamine; Dopaminergic Neurons; Humans; Inflammation; Nerve Tissue Proteins; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Polyphenols; Reactive Oxygen Species; Signal Transduction; Substantia Nigra; Ubiquinone; Vitamin A; Vitamin E

We studied the effect of vitamin C, vitamin E, and beta carotene intake on the risk of Parkinson's disease (PD). We did a systematic review and meta-analysis of observational studies published between 1966 and March 2005 searching MEDLINE, EMBASE, and the Cochrane Library. Eight studies were identified (six case-control, one cohort, and one cross-sectional). We found that dietary intake of vitamin E protects against PD. This protective influence was seen with both moderate intake (relative risk 0.81, 95% CI 0.67-0.98) and high intake (0.78, 0.57-1.06) of vitamin E, although the possible benefit associated with high intake of vitamin E was not significant. The studies did not suggest any protective effects associated with vitamin C or beta carotene. We conclude that dietary vitamin E may have a neuroprotective effect attenuating the risk of PD. These results require confirmation in randomised controlled trials.

Topics: Ascorbic Acid; beta Carotene; Carotenoids; Humans; Parkinson Disease; Risk Factors; Vitamin E

FREE RADICALS AND THE THEORY OF AGING: Severe oxidative stress progressively leads to cell dysfunction and ultimately cell death. Oxidative stress is defined as an imbalance between pro-oxidants and/or free radicals on the one hand, and anti-oxidizing systems on the other. The oxygen required for living may indirectly be responsible for negative effects; these deleterious effects are due to the production of free radicals, which are toxic for the cells (superoxide anions, hydroxyl radicals, peroxyl radicals, hydrogen peroxide, hydroperoxides and peroxinitrite anions). Free radical attacks are responsible for cell damage and the targeted cells are represented by the cell membranes, which are particularly rich in unsaturated fatty acids, sensitive to oxidation reactions; DNA is also the target of severe attacks by these reactive oxygen species (ROS).. These are represented by the enzymes and free radical captors. The latter are readily oxidizable composites. The free radical captor or neutralization systems of these ROS use a collection of mechanisms, vitamins (E and C), enzymes [superoxide dismutase (SOD), glutathion peroxidase (GPx) and others], and glutathion reductase (GSH), capable of neutralizing peroxinitrite. The efficacy of this system is dependent on the genome for the enzymatic defence systems, and on nutrition for the vitamins. Some strategies aimed at reducing oxidative stress-related alterations have been performed in animals. However, only a few can be used and are efficient in humans, such as avoidance of unfavourable environmental conditions (radiation, dietary carcinogens, smoking...) and antioxidant dietary supplementation.. Epidemiological data suggest that antioxidants may have a beneficial effect on many age-related diseases: atherosclerosis, cancer, some neurodegenerative and ocular diseases. However, the widespread use of supplements is hampered by several factors: the lack of prospective and controlled studies; insufficient knowledge on the pro-oxidant, oxidant and ant-oxidant properties of the various supplements; growing evidence that free radicals are not only by-products, but also play an important role in cell signal transduction, apoptosis and infection control.. Although current data indicate that antioxidants cannot prolong maximal life span, the beneficial impact of antioxidants on various age-related degenerative diseases may forecast an improvement in life span and enhance quality of life. The current lack of sufficient data does not permit the systematic recommendation of anti-oxidants. Nevertheless, antioxidant-rich diets with fruit and vegetables should be recommended.

Topics: Aging; Alzheimer Disease; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Carotenoids; Cataract; Chronic Disease; Disease Models, Animal; Evidence-Based Medicine; Free Radicals; Humans; Lutein; Macular Degeneration; Neoplasms; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Vitamin E

It is rare to see a day pass in which we are not told through some popular medium that the population is becoming older. Along with this information comes the "new" revelation that as we enter the next millennium there will be increases in age-associated diseases (e.g., cancer, cardiovascular disease) including the most devastating of these, which involve the nervous system (e.g., Alzheimer's disease [AD] and Parkinson's disease [PD]). It is estimated that within the next 50 years approximately 30% of the population will be aged 65 years or older. Of those between 75 and 84 years of age, 6 million will exhibit some form of AD symptoms, and of those older than 85 years, over 12 million will have some form of dementia associated with AD. What appears more ominous is that many cognitive changes occur even in the absence of specific age-related neurodegenerative diseases. Common components thought to contribute to the manifestation of these disorders and normal age-related declines in brain performance are increased susceptibility to long-term effects of oxidative stress (OS) and inflammatory insults. Unless some means is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Thus, it is extremely important to explore methods to retard or reverse age-related neuronal deficits as well as their subsequent, behavioral manifestations. Fortunately, the growth of knowledge in the biochemistry of cell viability has opened new avenues of research focused at identifying new therapeutic agents that could potentially disrupt the perpetual cycle of events involved in the decrements associated with these detrimental processes. In this regard, a new role in which certain dietary components may play important roles in alleviating certain disorders are beginning to receive increased attention, in particular those involving phytochemicals found in fruits and vegetables.

Topics: Alzheimer Disease; Animals; Ascorbic Acid; Capsicum; Carotenoids; Flavonoids; Fruit; Garlic; Ginkgo biloba; Humans; Nervous System Diseases; Panax; Parkinson Disease; Phenols; Phytotherapy; Plants, Medicinal; Polymers; Polyphenols; Tea; Vitamin E

The progression of Parkinson's disease, and the increase in the time under therapy with levodopa of this disease, leds to development of several complications, including loss of efficacy of the therapy, motor fluctuations, dyskinesias, psychiatric disorders, etc. These complications cause serious limitations to the management of the advanced disease. This article reviews the current status of the therapeutic approaches to the management of complicated Parkinson's disease.

Topics: Antiparkinson Agents; Ascorbic Acid; Combined Modality Therapy; Diet Therapy; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Humans; Levodopa; Parkinson Disease

Despite a realisation that antioxidants will not delay ageing in healthy older people, there is increasing scientific interest in the role of free radical oxidants in a number of diseases associated with older age. For most of these diseases there is suggestive theoretical and laboratory evidence but not confirmatory clinical evidence. Free radical damage seems likely to be significant in the pathophysiology of atherosclerosis, ischaemia-reperfusion injury, Parkinson's disease, cataract, some cancers and rheumatoid arthritis. Evidence to suggest a protective effect from antioxidant vitamins exists for ischaemic heart disease, cataract and some cancers. Attempts to influence the outcome of other diseases such as ischaemia-reperfusion injury, Parkinson's disease and rheumatoid arthritis have so far failed to achieve positive results. Research interest in the field is increasing although hampered by methodological difficulties and the limited financial return for drug companies. In the meantime there seems no reason to discourage older people who wish to ingest extra vitamin E and vitamin C. A diet with adequate vegetables and fruits should provide sufficient beta carotene.

Topics: Aged; Aging; Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cataract; Diet; Free Radicals; Humans; Parkinson Disease; Reactive Oxygen Species; Reperfusion Injury; Vitamin A; Vitamin E

Topics: Ascorbic Acid; Catalase; Central Nervous System Diseases; Dopamine; Female; Free Radicals; Humans; Male; Oxidants; Parkinson Disease; Superoxide Dismutase; Vitamin E

Topics: Adult; Aged; Aging; Antioxidants; Ascorbic Acid; Cell Count; Female; Free Radicals; Humans; Male; Middle Aged; Neurons; Parkinson Disease; Vitamin E

Parkinson's disease (PD) is characterized by a progressive, slow loss of dopaminergic neurones in the substance nigra. Although the cause of this neurone loss is unknown, at the present time many papers suggest oxidative stress (OS), secondary to dopaminergic metabolism, as an aetiopathogenic factor of PD. Therefore study of the part played by OS in this would permit the use of antioxidants (AO) as another possibility for treatment of the disease. It would also be a major step forward in the search for possible biological markers.. A study using spectrophotometric techniques was made of the serum levels of four biochemical indicators: catalase (CAT), malonyl aldehyde (MDA), phospholipase A2 (PLA2) and Vitamin C (VITC) in controls and in patients with PD. We found the average value for each of the variables studied in controls and in patients, taking AO treatment into account.. The effect of clinical variables on serum levels of CAT, MDA, PLA2 and VITC was analyzed. It was seen that only the clinical state of Hoen and Yahr was related to the biochemical indicators. The CAT activity and VITC concentration showed statistically significant differences between patients (independently of their AO treatment) and controls. The CAT activity was significantly less in those treated with AO. The patients with PD did not all have the same degree of OS. The effect of AO treatment on plasma markers showed changes only in one subgroup of Parkinson patients.. Our study suggests that AO treatment in this condition should be tailored to the individual patient according to the degree of OS present.

Topics: Antioxidants; Ascorbic Acid; Biomarkers; Catalase; Disease Progression; Humans; Malondialdehyde; Monoamine Oxidase Inhibitors; Oxidative Stress; Parkinson Disease; Phospholipases A; Phospholipases A2; Reactive Oxygen Species; Spectrophotometry; Vitamin E

A new formulation of a sublingual tablet with 10 mg apomorphine was examined in 13 patients with Parkinson's disease. Vitamin C (250 mg) was added sublingually to lower the salivary pH. Four patients received sublingual apomorphine and nine received sublingual apomorphine as well as vitamin C. Subcutaneous apomorphine was given to all patients. The study was designed as a randomized three-way cross-over study. Tmax, Cmax, and bioavailability (F) were determined. Clinical efficacy was assessed by hand-tapping during 30 s, walking time over 25 m, and a 4-point tremor score. The mean Tmax after subcutaneous apomorphine was 14.5 +/- 1.9 min with a mean Cmax of 19.2 +/- 3.8 ng/ml. The mean clearance of all patients was 3.8 +/- 0.6 L/min. The mean Tmax after sublingual apomorphine was 61.1 +/- 6.9 min vs. 61.7 +/- 8.2 min with vitamin C. The mean Cmax was 7.4 +/- 1.0 ng/ml (- vitamin C) vs. 4.3 +/- 1.3 ng/ml (+ vitamin C). These data resulted consequently in a not significantly different mean bioavailability, varying from 17.6% (- vitamin C) to 6.1% (+ vitamin C). The latency of onset of clinical efficacy varied between 25.0 +/- 8.5 min (- vitamin C) and 26.0 +/- 5.3 min (+ vitamin C). The duration of effect was lower (not significantly) when vitamin C was added: 88.0 +/- 12.5 min (- vitamin C) vs. 61.0 +/- 11.9 min (+ vitamin C). These data show that 10 mg apomorphine sublingually was effective in 56% of the patients. The combination with vitamin C did not significantly change the latency of onset or duration of clinical efficacy. Sublingual apomorphine should be considered as an alternative in the treatment of "off"-periods in Parkinson's disease, in particular when patients have the capacity to anticipate their off-periods.

Topics: Administration, Sublingual; Aged; Antiparkinson Agents; Apomorphine; Ascorbic Acid; Biological Availability; Cross-Over Studies; Female; Humans; Injections, Subcutaneous; Male; Metabolic Clearance Rate; Middle Aged; Neurologic Examination; Parkinson Disease; Treatment Outcome

High dosages of tocopherol and ascorbate were administered to patients with early Parkinson's disease as a preliminary open-labeled trial for the eventual controlled double-blind study evaluating antioxidants as a test of the endogenous toxin hypothesis of the etiology of Parkinson's disease. The primary endpoint of the trial was the need to treat patients with levodopa. The time when levodopa became necessary in the treated patients was compared with another group of patients followed elsewhere and not taking antioxidants. The time when levodopa became necessary was extended by 2.5 y in the group taking antioxidants. The results of this pilot study suggest that the progression of Parkinson's disease may be slowed by the administration of these antioxidants. A large multicenter, controlled clinical trial currently underway in North America evaluating tocopherol and deprenyl has the potential to confirm these results.

Topics: Adult; Aged; Ascorbic Acid; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pilot Projects; Vitamin E

Patients with PD who experience on-off effects have higher erythrocyte catechol-O-methyltransferase (COMT) activities and plasma 3-O-methyldopa concentrations than do patients without these levodopa-related motor fluctuations. We therefore administered ascorbic acid, a weak competitive inhibitor of COMT, to six PD patients with on-off effects. In this double-blind crossover investigation, ascorbic acid produced a modest improvement in functional performance. However, no fundamental change was observed in the pattern of on-off effects, severity of parkinsonism/dyskinesia, or self-assessment ratings. Ascorbic acid therapy reduced plasma concentrations of levodopa and 3-O-methyldopa but did not alter erythrocyte COMT activity. These findings are discussed in the context of the pharmacokinetic and pharmacodynamic factors that contribute to the pathogenesis of levodopa-induced dyskinesias and on-off motor fluctuations.

Topics: Aged; Ascorbic Acid; Clinical Trials as Topic; Female; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Parkinson Disease

It is estimated that half of the individuals with Parkinson's disease (PD) use some form of over-the-counter vitamin, herbal supplement or nutraceutical. The goal of this study was to survey individuals with PD about their use of the nutraceuticals and evaluate the association of the nutraceutical with the severity of symptoms.. Participants with self-reported idiopathic PD within the 2021 cohort (. The most frequently used supplements were vitamin D (71%), B12 (44%), vitamin C (38%) and fish oil (38%). None of the supplements being used were associated with statistically significant worse outcomes. Nutraceuticals associated with improved outcomes were Ginkgo biloba (GB), NAD+ or its precursors, 5-methyltetrahydrofolate, glutathione, mucuna, CoQ10, low dose lithium, curcumin, homocysteine factors, DHEA, coconut oil, vitamin C, and omega-3 fatty acids (fish oil).. These data suggest that in a real-world setting, some over-the-counter supplements are associated with fewer patient-reported symptoms. Supplements with significant associations with fewer symptoms have biological plausibility and future clinical trials should be explored.

Topics: Ascorbic Acid; Cross-Sectional Studies; Dietary Supplements; Fish Oils; Humans; Parkinson Disease; Vitamins

Liposomes are promising drug carriers for a wide range of central nervous system disorders, such as Parkinson's disease (PD), since they can protect active substances from degradation and could be administered intranasally, ensuring a direct access to the brain. Levodopa (LD), the drug commonly used to treat PD, spontaneously oxidizes in aqueous solutions and thus needs to be stabilized. Our investigation focuses on the preparation and the physico-chemical characterization of mixed liposomes to vehiculate LD and two natural substances (L-ascorbic acid and quercetin) that can prevent its oxidation and contribute to the treatment of Parkinson's disease. These co-loaded vesicles were prepared using a saturated phospholipid and structurally related cationic or analogue N-oxide surfactants and showed different properties, based on their composition. In particular, ex-vivo permeability tests using porcine nasal mucosa were performed, denoting that subtle variations of the lipids structure can significantly affect the delivery of LD to the target site.

Topics: Ascorbic Acid; Drug Carriers; Humans; Levodopa; Liposomes; Parkinson Disease

Topics: Ascorbic Acid; Diet; Humans; Parkinson Disease; Vitamin E; Vitamins

Levodopa and carbidopa are reported to be degraded by magnesium oxide (MgO), which is often used as a laxative for patients with Parkinson's disease (PD). Ascorbic acid (AsA) can stabilize levodopa and carbidopa solutions; however, the effect of AsA on the degradation of levodopa and carbidopa induced by MgO has not been fully investigated.. The effect of AsA was evaluated using in vitro examinations, compared with lemon juice, and by measuring the plasma concentration of levodopa in a patient with PD.. In vitro experiments showed that the relative concentrations of levodopa remained almost constant, and the relative concentrations of carbidopa decreased with time with addition of MgO. AsA mitigated this effect in a concentration-dependent manner, whereas the addition of lemon juice caused little change, although the pH decreased to the same extent. The results of levodopa pharmacokinetics of the patient showed that the area under the plasma concentration-time curve values from hour 0 to 8 were 53.00 μmol·h/L with regular administration and 67.27 μmol·h/L with co-administration of AsA.. AsA can mitigate the degradation of carbidopa induced by MgO and may contribute to improving the bioavailability of levodopa in patients with PD.

Topics: Antiparkinson Agents; Ascorbic Acid; Carbidopa; Humans; Levodopa; Magnesium Oxide; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by inclusions of aggregated α-synuclein (α-Syn). Oxidative stress plays a critical role in nigrostriatal degeneration and is responsible for α-Syn aggregation in PD. Vitamin C or ascorbic acid acts as an effective antioxidant to prevent free radical damage. However, vitamin C is easily oxidized and often loses its physiological activity, limiting its therapeutic potential. The objective of this study was to evaluate whether NXP031, a new compound we developed consisting of Aptamin C and Vitamin C, is neuroprotective against α-synucleinopathy. To model α-Syn induced PD, we stereotactically injected AAV particles overexpressing human α-Syn into the substantia nigra (SN) of mice. One week after AAV injection, NXP031 was administered via oral gavage every day for eight weeks. We found that oral administration of NXP031 ameliorated motor deficits measured by the rotarod test and prevented the loss of nigral dopaminergic neurons caused by WT-α-Syn overexpression in the SN. Also, NXP031 blocked the propagation of aggregated α-Syn into the hippocampus by alleviating oxidative stress. These results indicate that NXP031 can be a potential therapeutic for PD.

Topics: alpha-Synuclein; Animals; Ascorbic Acid; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Mice; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Substantia Nigra

The beneficial effects of dietary β-carotene and vitamin A on Parkinson disease (PD) have been confirmed, but some studies have yielded questionable results. Therefore, this meta-analysis investigated the effect of dietary β-carotene and vitamin A on the risk of PD.. The following databases were searched for relevant paper: PubMed, Embase, Medline, Scopus, Cochrane Library, CNKI, Wanfang Med online, and Weipu databases for the relevant paper from 1990 to March 28, 2022. The studies included were as follows: β-carotene and vitamin A intake was measured using scientifically recognized approaches, such as food frequency questionnaire (FFQ); evaluation of odds ratios using OR, RR, or HR; β-carotene and vitamin A intake for three or more quantitative categories; and PD diagnosed by a neurologist or hospital records.. This study included 11 studies (four cohort studies, six case-control studies, and one cross-sectional study). The high β-carotene intake was associated with a significantly lower chance of developing PD than low β-carotene intake (pooled OR = 0.83, 95%CI = 0.74-0.94). Whereas the risk of advancement of PD was not significantly distinctive among the highest and lowest vitamin A intake (pooled OR = 1.08, 95%CI = 0.91-1.29).. Dietary β-carotene intake may have a protective effect against PD, whereas dietary vitamin A does not appear to have the same effect. More relevant studies are needed to include into meta-analysis in the further, as the recall bias and selection bias in retrospective and cross-sectional studies cause misclassifications in the assessment of nutrient intake.

Topics: Ascorbic Acid; beta Carotene; Cross-Sectional Studies; Humans; Meta-Analysis as Topic; Parkinson Disease; Retrospective Studies; Risk Factors; Systematic Reviews as Topic; Vitamin A; Vitamin E

Ascorbic acid (AA), a major antioxidant in the central nervous system (CNS), is involved in withstanding oxidative stress that plays a significant role in the pathogenesis of Parkinson's disease (PD). Exploring the AA disturbance in the process of PD is of great value in understanding the molecular mechanism of PD. Herein, by virtue of a carbon fiber electrode (CFE) as a matric electrode, a three-step electrochemical process for tailoring oxygen-containing groups on graphene was well designed: potentiostatic deposition was carried out to fabricate graphene oxide on CFE, electrochemical reduction that assisted in removing the epoxy groups accelerated the electron transfer kinetics of AA oxidation, and electrochemical oxidation that increased the content of the carbonyl group (C═O) generated an inner-reference signal. The mechanism was solidified by

Topics: Animals; Ascorbic Acid; Graphite; Mice; Oxygen; Parkinson Disease; Reproducibility of Results

To determine whether high baseline dietary antioxidants and total nonenzymatic antioxidant capacity (NEAC) is associated with a lower risk of Parkinson disease (PD) in men and women, we prospectively studied 43,865 men and women from a large Swedish cohort.. In the Swedish National March Cohort, 43,865 men and women aged 18-94 years were followed through record linkages to National Health Registries from 1997 until 2016. Baseline dietary vitamin E, vitamin C, and beta-carotene intake, as well as NEAC, were assessed by a validated food frequency questionnaire collected at baseline. All exposure variables were adjusted for energy intake and categorized into tertiles. Multivariable Cox proportional hazard regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for PD.. After a mean follow-up time of 17.6 years, we detected 465 incidence cases of PD. In the multivariable adjusted model, dietary vitamin E (HR 0.68, 95% CI 0.52-0.90;. Our findings suggest that dietary vitamin E and C intake might be inversely associated with the risk of PD. No association was found with dietary beta-carotene or NEAC.. This study provides Class III evidence that dietary vitamin E and C intake are inversely associated with the risk of PD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; beta Carotene; Female; Follow-Up Studies; Food; Humans; Incidence; Male; Middle Aged; Parkinson Disease; Registries; Sweden; Vitamin E; Young Adult

Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson's disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention.. We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test.. We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = - 1.134, 95% CI: [- 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = - 1.750, 95% CI: [- 3.396, - 0.105], P = 0.037) and MR-Egger (beta = - 2.592, 95% CI: [- 4.623, - 0.560], P = 0.012).. We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.

Topics: Age of Onset; Ascorbic Acid; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Parkinson Disease; Polymorphism, Single Nucleotide

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. The oxidative stress and DA derived quinones have been proposed to be closely related to the progression of PD. To examine the possibility of the application of ascorbate (Asc) as a therapeutic strategy in PD, the effect of Asc on the fate of iron both in the absence and presence of DA was investigated. The results of this study indicate that, in the absence of iron, the presence of high concentrations of Asc is of great benefit in view of the alleviation in oxidative stress and formation of DA derived quinones by quenching radicals, such as O

Topics: Ascorbic Acid; Brain; Dopamine; Free Radical Scavengers; Free Radicals; Iron; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Many factors have been shown to contribute to its pathogenesis including genetic and environmental factors. Ubiquitin C-terminal hydrolase L1 (UCHL1) is also known to be involved in the pathogenesis of PD. We herein modeled the study of UCHL1 in Drosophila melanogaster and investigated its functions in PD. The specific knockdown of the Drosophila ortholog of UCHL1 (dUCH) in dopaminergic neurons (DA neurons) led to the underdevelopment and/or degeneration of these neurons, specifically in DL1 DA neuron cluster in the larval brain lobe and PPM2, PPM3, PPL2ab, and VUM DA neuron clusters in the adult brain. These defects were followed by a shortage of dopamine in the brain, which subsequently resulted in locomotor dysfunction. The degeneration of DA neurons in dUCH knockdown adult brain, which occurred progressively and severely during the course of aging, mimics the epidemiology of PD. DA neuron and locomotor defects were rescued when dUCH knockdown flies were treated with vitamin C, a well-known antioxidant. These results suggest that dUCH knockdown fly is a promising model for studying the pathogenesis and epidemiology of PD as well as the screening of potential antioxidants for PD therapeutics.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Drosophila melanogaster; Drosophila Proteins; Gene Knockdown Techniques; Humans; Male; Oxidative Stress; Parkinson Disease; Ubiquitin Thiolesterase

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain and formation of α-synuclein-containing intracellular inclusions. Excess intraneuronal iron in the SNpc increases reactive oxygen species (ROS), which identifies removing iron as a possible therapeutic strategy. Desferrioxamine B (DFOB, 1) is an iron chelator produced by bacteria. Its high Fe(iii) affinity, water solubility and low chronic toxicity is useful in removing iron accumulated in plasma from patients with transfusion-dependent blood disorders. Here, lipophilic analogues of DFOB with increased potential to cross the blood-brain barrier (BBB) have been prepared by conjugating ancillary compounds onto the amine terminus. The ancillary compounds included the antioxidants rac-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (rac-trolox, rac-TLX (a truncated vitamin E variant)), R-TLX, S-TLX, methylated derivatives of 3-(6-hydroxy-2-methylchroman-2-yl)propionic acid (α-CEHC, γ-CEHC, δ-CEHC), or 4-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)benzoic acid (carboxylic acid derivative of edaravone, EDA). Compounds 2-8 could have dual function in attenuating ROS by chelating Fe(iii) and via the antioxidant ancillary group. A conjugate between DFOB and an ancillary unit without antioxidant properties (3,5-dimethyladamantane-1-carboxylic acid (AdA

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antioxidants; Ascorbic Acid; Benzothiazoles; Blood Proteins; Deferoxamine; Disease Models, Animal; Iron; Iron Chelating Agents; Mice; Nerve Degeneration; Neurons; Parkinson Disease; Sulfonic Acids

While levodopa, carbidopa, ascorbic acid solution (LCAS) therapy has been used in patients with advanced Parkinson's disease (PD) for many years, long-term follow-up data is scarce. The present study aimed to determine the long-term retention rate for LCAS therapy, and to identify the causes of LCAS therapy withdrawal. Our study included a series of 38 patients with PD (14 men and 24 women) who underwent LCAS treatment between 2011 and 2013 to alleviate motor complications that were not satisfactorily controlled by optimized conventional anti-parkinsonian treatment at the Seoul National University Hospital. All patients were admitted to educate them about and initiate LCAS treatment for 2-5days, and were then followed up as outpatients. The mean follow-up duration was 12.8months, and three main reasons for LCAS treatment discontinuation were worsening of wearing-off symptoms (8 patients), persistent dyskinesia (4 patients), and poor drug adherence (4 patients). Fourteen patients (36.8%) maintained the LCAS treatment after 12months, and were categorized as the treatment-retention group. The mean percentage of on time without dyskinesia significantly increased from 33.6±17.6% to 57.0±27.7% after LCAS initiation (p=0.016) in the treatment-retention group. Twelve patients (31.6%) were still receiving LCAS treatment after 30months. LCAS treatment can be a non-device assisted therapeutic option for patients who have no access to advanced therapies such as deep brain stimulation and infusional treatments.

Topics: Aged; Antiparkinson Agents; Ascorbic Acid; Carbidopa; Drug Combinations; Dyskinesia, Drug-Induced; Female; Humans; Kaplan-Meier Estimate; Levodopa; Longitudinal Studies; Male; Middle Aged; Parkinson Disease; Retrospective Studies; Treatment Outcome

A neuroprotective effect of dietary antioxidants on Parkinson's disease (PD) risk has been suggested, but epidemiological evidence is limited.. To examine the associations between intake of dietary antioxidant vitamins and total antioxidant capacity and risk of PD.. We prospectively assessed the relationships of dietary antioxidant vitamins C and E, ß-carotene, and total antioxidant capacity with PD risk in two population-based cohorts (38,937 women and 45,837 men).. Intake of dietary vitamin E and ß-carotene was associated with a lower risk of PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; Antioxidants; Ascorbic Acid; beta Carotene; Diet; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuroprotective Agents; Parkinson Disease; Sex Factors; Sweden; Vitamin E

Cultured neural stem/precursor cells (NSCs) are regarded as a potential systematic cell source to treat Parkinson's disease (PD). However, the therapeutic potential of these cultured NSCs is lost during culturing. Here, we show that treatment of vitamin C (VC) enhances generation of authentic midbrain-type dopamine (mDA) neurons with improved survival and functions from ventral midbrain (VM)-derived NSCs. VC acted by upregulating a series of mDA neuron-specific developmental and phenotype genes via removal of DNA methylation and repressive histone code (H3K9m3, H3K27m3) at associated gene promoter regions. Notably, the epigenetic changes induced by transient VC treatment were sustained long after VC withdrawal. Accordingly, transplantation of VC-treated NSCs resulted in improved behavioral restoration, along with enriched DA neuron engraftment, which faithfully expressed midbrain-specific markers in PD model rats. These results indicate that VC treatment to donor NSCs could be a simple, efficient, and safe therapeutic strategy for PD in the future.

Topics: Animals; Ascorbic Acid; Behavior, Animal; Biomarkers; Cell Differentiation; Cell Proliferation; Cell- and Tissue-Based Therapy; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Epigenesis, Genetic; Female; Gene Expression Regulation; Mesencephalon; Neural Stem Cells; Neurogenesis; Parkinson Disease; Phenotype; Presynaptic Terminals; Promoter Regions, Genetic; Rats; Stem Cell Transplantation

Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5'-nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations observed in the pathophysiology of PD.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Adenosine Triphosphatases; Advanced Oxidation Protein Products; Aged; Ascorbic Acid; Biomarkers; Case-Control Studies; Catalase; Dopaminergic Neurons; Female; Ferritins; Humans; Iron; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pars Compacta; Peroxidase; Reactive Nitrogen Species; Reactive Oxygen Species; Sulfhydryl Compounds; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Transferrin

Oxidative stress is proposed to be one of the potential mechanisms leading to neurodegeneration in Parkinson's disease. However, previous epidemiologic studies investigating associations between antioxidant vitamins, such as vitamins E and C and carotenoids, and PD risk have produced inconsistent results.. The objective of this work was to prospectively examine associations between intakes of antioxidant vitamins, including vitamins E and C and carotenoids, and PD risk.. Cases were identified in two large cohorts: the Nurses' Health Study and the Health Professionals Follow-up Study. Cohort members completed semiquantitative food frequency questionnaires every 4 years.. A total of 1036 PD cases were identified. Dietary intakes of vitamin E and carotenoids were not associated with PD risk; the multivariable-adjusted relative risk comparing extreme intake quintiles were 0.93 (95% confidence interval: 0.75-1.14) and 0.97 (95% confidence interval: 0.69-1.37), respectively. Dietary vitamin C intake was significantly associated with reduced PD risk (relative risk: 0.81; 95% confidence interval: 0.65-1.01; p. Our results do not support the hypothesis that intake of antioxidant vitamins reduces the risk of PD. © 2016 International Parkinson and Movement Disorder Society.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Carotenoids; Female; Follow-Up Studies; Health Personnel; Humans; Male; Middle Aged; Nurses; Parkinson Disease; United States; Vitamin E

We demonstrate the microwave-assisted synthesis of short graphene oxide nanoribbons (GONRs) through unzipping cut multiwalled carbon nanotubes (MWCNTs). Transmission electron microscopy and dynamic light scattering spectroscopy were used to examine the length, size, and morphology, i. e. unzipping level, of our various products. The nanotube core and nanoribbon shell can be observed from short GONRs via a modified unzipping recipe. Then the short GONRs were adopted to modify the glassy carbon electrode for the electrochemical detection of ascorbic acid (AA), uric acid (UA), and dopamine (DA). Compared to other nanomaterials, cyclic voltammograms of short GONRs show higher anodic oxidation currents for AA, UA, and DA. The detection limits of three analytes are 26, 98, and 24 nM, respectively, in amperometric current-time measurements. Especially, the sensitivity for DA is improved to be 40.86 μA μM(-1) cm(-2). The improved detection signals are due to the increased active sites of the open ends of short GONRs. Moreover, the width side of short GONRs could be more active than their length side. All above-mentioned results reveal that the short GONRs can provide a novel platform for electrochemically biomarker detection of Parkinson's disease.

Topics: Ascorbic Acid; Biomarkers; Biosensing Techniques; Dopamine; Graphite; Humans; Nanotubes, Carbon; Oxides; Parkinson Disease; Uric Acid

Vitamin C is a major antioxidant and also is known as a neuromodulator in dopaminergic neurons. The aim of this study was to investigate the association between lymphocyte and plasma vitamin C levels in various stages of Parkinson's disease (PD).. Sixty-two individuals with PD (age 71 ± 8.8 y [mean ± SD]) being treated at Shizuoka General Hospital from December 2007 to August 2013 were consecutively recruited. PD severity was classified using the Hoehn-Yahr scale for staging PD. Fasting blood samples were collected, and plasma and lymphocyte vitamin C levels were measured. The association between PD severity and vitamin C levels was estimated by ordinal logistic regression with confounding variables.. The distribution of Hoehn-Yahr stages in patients was as follows: stage I, 7; II, 28; III, 16; and IV, 11. Lymphocyte vitamin C levels in patients with severe PD were significantly lower (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.80-0.97; P < 0.01) compared with those at less severe stages. Plasma vitamin C levels also tended to be lower in patients with severe PD; however, this was not significant (OR, 0.98; 95% CI, 0.96-1.00; P = 0.09).. Our findings suggest that lymphocyte vitamin C levels in the peripheral blood may be a potentially useful biomarker for the progression of PD.

Topics: Aged; Aged, 80 and over; Ascorbic Acid; Biomarkers; Disease Progression; Female; Humans; Logistic Models; Lymphocytes; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Parkinson Disease

In our overall goal to develop multifunctional dopamine D2/D3 agonist drugs for the treatment of Parkinson's disease (PD), we previously synthesized potent D3 preferring agonist D-264 (1a), which exhibited neuroprotective properties in two animal models of PD. To enhance the in vivo efficacy of 1a, a structure-activity relationship study was carried out. Competitive binding and [(35)S]GTPγS functional assays identified compound (-)-9b as one of the lead molecules with preferential D3 agonist activity (EC50(GTPγS); D3 = 0.10 nM; D2/D3 (EC50): 159). Compounds (-)-9b and (-)-8b exhibited high in vivo activity in two PD animal models, reserpinized and 6-hydroxydopamine (OHDA)-induced unilateral lesioned rats. On the other hand, 1a failed to show any in vivo activity in these models unless the compound was dissolved in 5-10% beta-hydroxy propyl cyclodextrin solution. Lead compounds exhibited appreciable radical scavenging activity. In vitro experiments with dopaminergic MN9D cells indicated neuroprotection by both 1a and (-)-9b from toxicity of MPP+.

Topics: Animals; Benzothiazoles; Biphenyl Compounds; Cell Line; Disease Models, Animal; Mice; Neuroprotective Agents; Parkinson Disease; Piperazines; Rats; Structure-Activity Relationship; Thiazoles

Topics: Ascorbic Acid; Biosensing Techniques; Dopamine; Electrodes; Graphite; Humans; Nanowires; Parkinson Disease; Uric Acid; Zinc Oxide

In the present study, the effect of l-ascorbic acid (AA) was studied on the climbing ability of the Parkinson's disease (PD) model Drosophila expressing normal human alpha synuclein (h-αs) in the neurons. These flies show locomotor dysfunction as the age progresses. AA at final concentration of 11.35 × 10(-5) M, 22.71 × 10(-5) M, 45.42 × 10(-5) M, and 68.13 × 10(-5) M was added to the diet, and the flies were allowed to feed for 21 days. AA at 11.35 × 10(-5) M did not show any significant delay in the loss of climbing ability of PD model flies. However, AA at 22.71 × 10(-5) M, 45.42 × 10(-5) M, and 68.13 × 10(-5) M showed a dose dependent significant (p < .05) delay in the loss of climbing ability of PD model flies as compared to the untreated PD flies. The total protein concentration in brain homogenate was measured in treated as well as control groups after 21 days, no significant difference was obtained between treated as well as control (PD flies and l-dopa) groups. The results suggest that AA is potent in delaying the climbing disability of the PD model flies expressing h-αs in the neurons.

Topics: Age Factors; alpha-Synuclein; Animals; Animals, Genetically Modified; Antioxidants; Antiparkinson Agents; Ascorbic Acid; Brain; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drosophila; Drosophila Proteins; Gait Disorders, Neurologic; Humans; Levodopa; Membrane Proteins; Neurons; Parkinson Disease; Transcription Factors

The development of a novel surface-enhanced resonance Raman scattering (SERRS) platform that allows fast and sensitive detection of dopamine (DA) has been reported. The iron-nitrilotriacetic acid attached silver nanoparticle (Ag-Fe(NTA)) substrate provides remarkable sensitivity and reliable repeatability. The advantages of both the surface functionalization for specific analytes and the SERRS are integrated into a single functional unit. While the silver core gives the necessary enhancing properties, the Fe-NTA receptors can trap DA adjacent the silver core and the NTA-Fe-DA complex formed provides resonance enhancement with a 632.8 nm laser. DA could be detected in pM level without any pretreatment with a reliable discrimination against AA, by utilizing low laser power (10 mW) and short data acquisition time (10 s). The high sensitivity along with the improved selectivity of this sensing approach is a significant step toward molecular diagnosis of Parkinson's disease.

Topics: Ascorbic Acid; Dopamine; Humans; Iron; Metal Nanoparticles; Nitrilotriacetic Acid; Parkinson Disease; Silver; Spectrum Analysis, Raman

Before induced pluripotent stem cells (iPSCs) can be used to treat neurologic diseases, human iPSC-derived neural cells must be analyzed in the primate brain. In fact, although mouse and human iPSCs have been used to generate dopaminergic (DA) neurons that are beneficial in rat models of Parkinson's disease (PD), human iPSC-derived neural progenitor cells (NPCs) have not been examined in primate brains. Here, we generated NPCs at different stages of predifferentiation using a feeder-free culture method, and grafted them into the brains of a monkey PD model and NOD-SCID mice. Magnetic resonance imaging (MRI), positron emission tomography (PET), immunocytochemistry, and behavioral analyses revealed that NPCs pretreated with Sonic hedgehog and fibroblast growth factor-8 followed by glial cell-derived neurotrophic factor, brain-derived neurotrophic factor, ascorbic acid, and dibutyryl cyclic AMP resulted in smaller grafts than those without these treatments, and survived as DA neurons in a monkey brain as long as six months. Thus, for the first time, we describe a feeder-free neural differentiation method from human iPSCs and an evaluation system that can be used to assess monkey PD models.

Topics: Animals; Ascorbic Acid; Carrier Proteins; Cell Differentiation; Cyclic AMP; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Intercellular Signaling Peptides and Proteins; Macaca fascicularis; Male; Mesencephalon; Mice; Nerve Tissue Proteins; Neural Cell Adhesion Molecule L1; Parkinson Disease; Radionuclide Imaging; Sialic Acids; Time Factors

Aggregation of alpha-synuclein (αS) into oligomers is critically involved in the pathogenesis of Parkinson's disease (PD). Using confocal single-molecule fluorescence spectroscopy, we have studied the effects of 14 naturally-occurring polyphenolic compounds and black tea extract on αS oligomer formation. We found that a selected group of polyphenols exhibited potent dose-dependent inhibitory activity on αS aggregation. Moreover, they were also capable of robustly disaggregating pre-formed αS oligomers. Based upon structure-activity analysis, we propose that the key molecular scaffold most effective in inhibiting and destabilizing self-assembly by αS requires: (i) aromatic elements for binding to the αS monomer/oligomer and (ii) vicinal hydroxyl groups present on a single phenyl ring. These findings may guide the design of novel therapeutic drugs in PD.

Topics: Acetylcysteine; alpha-Synuclein; Antioxidants; Apigenin; Ascorbic Acid; Deferoxamine; Dose-Response Relationship, Drug; Flavanones; Flavonoids; Humans; Iron Chelating Agents; Microscopy, Confocal; Microscopy, Fluorescence; Molecular Structure; Mutation; Parkinson Disease; Phenols; Polyphenols; Protein Multimerization; Protein Structure, Quaternary; Recombinant Proteins; Spectrometry, Fluorescence; Structure-Activity Relationship

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the nigrostriatal system and dopamine (DA) depletion in the striatum. The most popular therapeutic medicine for treating PD, 3-(3,4-Dihydroxyphenyl)-L-alanine (L-DOPA), has adverse effects, such as dyskinesia and disease acceleration. As superoxide (·O(2)(-)) and hydroxyl radical (·OH) have been implicated in the pathogenesis of PD, free radical scavenging and antioxidants have attracted attention as agents to prevent disease progression. Rodents injected with 6-hydroxydopamine (6-OHDA) intracerebroventricularly are considered to be a good animal model of PD. Zingerone and eugenol, essential oils extracted from ginger and cloves, are known to have free radical scavenging and antioxidant effects. Therefore, we examined the effects of zingerone and eugenol on the behavioral problems in mouse model and on the DA concentration and antioxidant activities in the striatum after 6-OHDA administration and L-DOPA treatment. Daily oral administration of eugenol/zingerone and injection of L-DOPA intraperitoneally for 4 weeks following a single 6-OHDA injection did not improve abnormal behaviors induced by L-DOPA treatment. 6-OHDA reduced the DA level in the striatum; surprisingly, zingerone and eugenol enhanced the reduction of striatal DA and its metabolites. Zingerone decreased catalase activity, and increased glutathione peroxidase activity and the oxidized L-ascorbate level in the striatum. We previously reported that pre-treatment with zingerone or eugenol prevents 6-OHDA-induced DA depression by preventing lipid peroxidation. However, the present study shows that post-treatment with these substances enhanced the DA decrease. These substances had adverse effects dependent on the time of administration relative to model PD onset. These results suggest that we should be wary of ingesting these spice elements after the onset of PD symptoms.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Corpus Striatum; Disease Models, Animal; Dopamine; Eugenol; Free Radical Scavengers; Glutathione; Glutathione Peroxidase; Guaiacol; Levodopa; Male; Mice; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Superoxide Dismutase

Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K(i)). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (-)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC(50) (GTP gamma S); D3 = 0.52 nM; D2/D3 (EC(50)): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity. The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson's disease (PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.

Topics: Animals; Antiparkinson Agents; Benzothiazoles; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Free Radical Scavengers; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Isoquinolines; Locomotion; Mice; Parkinson Disease; Radioligand Assay; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3; Reserpine; Structure-Activity Relationship; Thiazoles

α-Synuclein (α-syn), a presynaptic protein believed to play an important role in neuropathology in Parkinson's disease (PD), is known to bind Cu(2+). Cu(2+) has been shown to accelerate the aggregation of α-syn to form various toxic aggregates in vitro. Copper is also a redox-active metal whose complexes with amyloidogenic proteins/peptides have been linked to oxidative stress in major neurodegenerative diseases. In this work, the formation of the Cu(2+) complex with α-syn or with an N-terminal peptide, α-syn(1-19), was confirmed with electrospray-mass spectrometry (ES-MS). The redox potentials of the Cu(2+) complex with α-syn (α-syn-Cu(2+)) and α-syn(1-19) were determined to be 0.018 and 0.053 V, respectively. Furthermore, the Cu(2+) center(s) can be readily reduced to Cu(+), and possible reactions of α-syn-Cu(2+) with cellular species (e.g., O(2), ascorbic acid, and dopamine) were investigated. The occurrence of a redox reaction can be rationalized by comparing the redox potential of the α-syn-Cu(2+) complex to that of the specific cellular species. For example, ascorbic acid can directly reduce α-syn-Cu(2+) to α-syn-Cu(+), setting up a redox cycle in which O(2) is reduced to H(2)O(2) and cellular redox species is continuously exhausted. In addition, the H(2)O(2) generated was demonstrated to reduce viability of the neuroblastoma SY-HY5Y cells. Although our results ruled out the direct oxidation of dopamine by α-syn-Cu(2+), the H(2)O(2) generated in the presence of α-syn-Cu(2+) can oxidize dopamine. Our results suggest that oxidative stress is at least partially responsible for the loss of dopaminergic cells in PD brain and reveal the multifaceted role of the α-syn-Cu(2+) complex in oxidative stress associated with PD symptoms.

Topics: alpha-Synuclein; Ascorbic Acid; Cell Survival; Copper; Dopamine; Humans; Hydrogen Peroxide; Neurons; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Peptides

A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared for comparison. The cell viability of PC12 cells, Fe(2+) chelation, lipid peroxidation (LPO), free radical scavenging, and xanthine oxidase inhibition models were utilized to evaluate their antioxidative and neuron protective properties. The study revealed that the diether at C7-OH and C20-OH as well as the monoether at C7-OH, which possess aliphatic substituted acetamides, demonstrated more potent LPO inhibition and Fe(2+) chelation compared to DHS and quercetin. Conversely, the diallyl ether at C7-OH and C20-OH was more potent in protection of PC12 cells against H(2)O(2)-induced injury than DHS and quercetin. Overall, the more lipophilic alkenylated DHS analogues were better performing neuroprotective agents than the acetamidated derivatives. The results in this study would be beneficial for optimizing the therapeutic potential of lignoflavonoids, especially in neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

Topics: Alkenes; Alzheimer Disease; Amides; Animals; Drug Design; Free Radical Scavengers; Humans; Iron Chelating Agents; Lipid Peroxidation; Liver; Male; Models, Molecular; Molecular Conformation; Neurons; Neuroprotective Agents; Parkinson Disease; PC12 Cells; Rats; Silymarin; Structure-Activity Relationship; Xanthine Oxidase

A high performance liquid chromatographic assay for the quantitative determination of apomorphine in human plasma is described. Sample clean-up and concentration was optimised using solid-phase extraction on C18 cartridges, enabling rapid and sensitive determination of apomorphine and potential metabolites. The limit of apomorphine quantification, using fluorescence detection, was 0.5 ng/mL. The assay was stability-indicating, and allowed the detection of analytes in the presence of commonly co-administered anti-Parkinsonian drugs. Apomorphine was stable in frozen plasma containing 0.14% (w/v) ascorbic acid for 98 days, and through four freeze-thaw cycles. The assay has been used in clinical pharmacokinetic studies of apomorphine in patients with Parkinson's disease, and in preliminary studies of novel apomorphine delivery devices in volunteers.

Topics: Apomorphine; Ascorbic Acid; Chromatography, High Pressure Liquid; Drug Stability; Freezing; Humans; Parkinson Disease; Reproducibility of Results; Sensitivity and Specificity

We previously showed, using microdialysis, that autoxidation of exogenous L-dihydroxyphenylalanine (L-DOPA) occurs in vivo in the extracellular compartment of the freely moving rat, with a consequent formation of L-DOPA semiquinone (L-DOPA-SQ). In the present study, intrastriatal infusion of L-DOPA (1.0 microm for 200 min) increased dialysate L-DOPA concentrations (maximum increases up to 116-fold baseline values); moreover, L-DOPA-SQ was detected in dialysates. Individual dialysate concentrations of L-DOPA were negatively correlated with those of L-DOPA-SQ. Co-infusion of N-acetylcysteine (100 microm) or melatonin (50 microm) increased L-DOPA (up to 151- and 246-fold, respectively) and decreased L-DOPA-SQ (by about 53% and 87%, respectively) dialysate concentrations. Systemic L-DOPA [25 mg/kg intraperitoneally (i.p.) twice in a 12-h interval] significantly increased striatal baseline dialysate concentrations of L-DOPA and decreased dopamine (DA) and ascorbic acid (AsAc) concentrations, when compared with controls. Following systemic L-DOPA, L-DOPA-SQ was detected in dialysates. Endogenous melatonin was depleted in rats maintained on a 24-h light cycle for 1 wk. In melatonin-depleted rats, systemic L-DOPA induced a smaller increase in dialysate L-DOPA, a greater increase in L-DOPA-SQ formation, and a greater reduction in DA and AsAc dialysate concentrations. Co-administration of melatonin (5.0 mg/kg, i.p., twice in a 12-h interval) with L-DOPA, in control as well as in light-exposed rats, significantly increased dialysate L-DOPA concentrations, greatly inhibited L-DOPA-SQ formation, and restored up to the control values dialysate DA and AsAc concentrations. These findings demonstrate that endogenous melatonin protects exogenous L-DOPA from autoxidation in the extracellular compartment of the striatum of freely moving rats; moreover, systemic co-administration of melatonin with L-DOPA markedly increases striatal L-DOPA bioavailability in control as well as in melatonin-depleted rats. These results may be of relevance to the long-term L-DOPA therapy of Parkinson's disease.

Topics: Animals; Ascorbic Acid; Corpus Striatum; Dopamine; Levodopa; Light; Male; Melatonin; Microdialysis; Movement; Oxidation-Reduction; Parkinson Disease; Quinones; Rats; Rats, Wistar

Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway in vivo. However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome c within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome c is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Ascorbic Acid; bcl-2-Associated X Protein; Brain; Cardiolipins; Cell Death; Chromatography, High Pressure Liquid; Cytochromes c; Electron Transport Complex I; Genetic Techniques; Hydrogen Peroxide; Male; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Mitochondria; Models, Biological; Neurodegenerative Diseases; Neurons; Oxidative Stress; Oxygen; Parkinson Disease; Reactive Oxygen Species; Subcellular Fractions; Submitochondrial Particles; Time Factors

We determined systemic oxidative stress in Parkinson's disease (PD) patients, patients with other neurological diseases (OND) and healthy controls by measurement of in vitro lipoprotein oxidation and levels of hydro- and lipophilic antioxidants in plasma and cerebrospinal fluid (CSF). Additionally, we investigated the influence of levodopa (LD) and dopamine agonist therapy (DA) on the oxidative status in PD patients. We found increased oxidative stress, seen as higher levels of lipoprotein oxidation in plasma and CSF, decrease of plasma levels of protein sulfhydryl (SH) groups and lower CSF levels of alpha-tocopherol in PD patients compared to OND patients and controls. Levodopa treatment did not significantly change the plasma lipoprotein oxidation but LD monotherapy tended to result in an increase of autooxidation and in a decrease of plasma antioxidants with significance for ubiquinol-10. DA monotherapy was significantly associated with higher alpha-tocopherol levels. Patients with DA monotherapy or co-medication with DA showed a trend to lower lipoprotein oxidation. These data support the concept of oxidative stress as a factor in the pathogenesis of PD and might be an indicator of a potential prooxidative role of LD and a possible antioxidative effect of DA in PD treatment.

Topics: Adult; alpha-Tocopherol; Antioxidants; Antiparkinson Agents; Ascorbic Acid; Biomarkers; Brain; Dopamine; Female; Humans; Levodopa; Lipoproteins; Male; Middle Aged; Oxidative Stress; Parkinson Disease; Reference Values; Sulfhydryl Compounds; Ubiquinone; Up-Regulation

Topics: Age Factors; Ascorbic Acid; Humans; Parkinson Disease; Vitamin A; Vitamin E

A decrease in total glutathione, and aberrant mitochondrial bioenergetics have been implicated in the pathogenesis of Parkinson's disease. Our previous work exemplified the importance of glutathione (GSH) in the protection of mesencephalic neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase/complex II. Additionally, reactive oxygen species (ROS) generation was an early, contributing event in malonate toxicity. Protection by ascorbate was found to correlate with a stimulated increase in protein-glutathione mixed disulfide (Pr-SSG) levels. The present study further examined ascorbate-glutathione interactions during mitochondrial impairment. Depletion of GSH in mesencephalic cells with buthionine sulfoximine potentiated both the malonate-induced toxicity and generation of ROS as monitored by dichlorofluorescein diacetate (DCF) fluorescence. Ascorbate completely ameliorated the increase in DCF fluorescence and toxicity in normal and GSH-depleted cultures, suggesting that protection by ascorbate was due in part to upstream removal of free radicals. Ascorbate stimulated Pr-SSG formation during mitochondrial impairment in normal and GSH-depleted cultures to a similar extent when expressed as a proportion of total GSH incorporated into mixed disulfides. Malonate increased the efflux of GSH and GSSG over time in cultures treated for 4, 6 or 8 h. The addition of ascorbate to malonate-treated cells prevented the efflux of GSH, attenuated the efflux of GSSG and regulated the intracellular GSSG/GSH ratio. Maintenance of GSSG/GSH with ascorbate plus malonate was accompanied by a stimulation of Pr-SSG formation. These findings indicate that ascorbate contributes to the maintenance of GSSG/GSH status during oxidative stress through scavenging of radical species, attenuation of GSH efflux and redistribution of GSSG to the formation of mixed disulfides. It is speculated that these events are linked by glutaredoxin, an enzyme shown to contain both dehydroascorbate reductase as well as glutathione thioltransferase activities.

Topics: Animals; Antioxidants; Ascorbic Acid; Buthionine Sulfoximine; Chromans; Disulfides; Fluorescent Dyes; Glutathione; Glutathione Disulfide; Malonates; Mesencephalon; Mitochondria; Oxidative Stress; Parkinson Disease; Rats; Rats, Sprague-Dawley

Oxidative stress is an important mechanism of cell death in Parkinson's disease (PD) and brain ischemia. Vitamins C, E and A are important antioxidants and deficiency of these agents has been implicated in the mechanisms of atherosclerosis. We measured the levels of the above antioxidant vitamins in 44 patients with PD, 12 patients with vascular parkinsonism (VP), 11 patients with other parkinsonism syndromes of various causes and 39 controls. Vitamin A levels did not differ between groups. Vitamins C and E were found decreased in VP, while they were normal in PD indicating low levels of antioxidant vitamins in VP and stressing the necessity of maintaining sufficient dietary intake of these agents in the elderly.

Topics: Aged; Analysis of Variance; Antioxidants; Ascorbic Acid; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Parkinson Disease; Statistics, Nonparametric; Vitamin E

Oxidative damage has been implicated in the pathogenesis of PD. Limited and mostly retrospective epidemiologic data suggest a reduction or no change in risk of PD associated with high vitamin E intake.. To examine prospectively the associations between intakes of vitamins E and C, carotenoids, vitamin supplements, and risk of PD.. The authors documented the occurrence of PD within two large cohorts of men and women who completed detailed and validated semiquantitative food frequency questionnaires. A total of 371 incident PD cases were ascertained in the Nurses' Health Study, which comprised 76,890 women who were followed for 14 years, and the Health Professionals Follow-Up Study, which comprised 47,331 men who were followed for 12 years.. Neither intake of total vitamins E or C or use of vitamin E or vitamin C supplements or multivitamins was significantly associated with risk of PD. The risk of PD, however, was significantly reduced among men and women with high intake of dietary vitamin E (from foods only). The pooled multivariate relative risk (RR) comparing individuals in the highest quintile with those in the lowest quintile was 0.68 (95% CI, 0.49 to 0.93). Consumption of nuts was also significantly associated with a reduced risk of PD (for >or=5/week vs <1/month, pooled RR, 0.57; 95% CI, 0.34 to 0.95). Intakes of dietary vitamin C and carotenoids were not significantly associated with risk of PD.. Use of vitamin supplements and high intake of carotenoids do not appear to reduce the risk of PD. The reduction in risk of PD associated with high dietary vitamin E intake suggests that other constituents of foods rich in vitamin E may be protective. Alternatively, moderate amounts of vitamin E may reduce risk of PD, but this benefit may be lost with higher intakes.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Carotenoids; Cohort Studies; Confidence Intervals; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Parkinson Disease; Prospective Studies; Risk Factors; Vitamin E

We conducted a case-control study nested within a prospective cohort study of 13,979 residents of Leisure World Laguna Hills, a retirement community in southern California, for etiologic clues for Parkinson's disease (PD). Between 1981 (when first mailed a health survey) and 1998, we identified 395 PD cases from death certificates, hospital discharge diagnoses and a 1992 follow-up questionnaire. Six controls were individually matched on sex, birth date (+/-2 years), vital status and, if dead, death date (+/-1 year) to each case. Baseline characteristics of the 395 cases and 2,320 controls were analyzed as potential PD risk factors. The risk of PD was significantly reduced among smokers, hypertensives, coffee drinkers and alcohol consumers, and significantly increased among those with 3 or more children and with a high intake of total vitamin A and dietary vitamin C. The multivariate odds ratios (95% confidence intervals) were 0.42 (0.22-0.80) for current cigarette smokers of 1+ pack/day, 0.62 (0.48-0.80) for current users of hypertensive medication, 0.71 (0.52-0.95) for coffee drinkers of 2+ cups/day and 0.77 (0.58-1.03) for drinkers of 2+ alcoholic drinks/day. Risk increased with increasing number of children (1.25 for 1, 1.34 for 2 and 1.90 for 3+ children; p for trend = 0.0003). The increased risks among individuals in the highest third of total vitamin A intake and of dietary vitamin C intake were no longer statistically significant after adjusting for the other variables. These findings suggest several environmental factors that may be related to the development of PD and support a multifactorial etiology.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Ascorbic Acid; Caffeine; California; Case-Control Studies; Catchment Area, Health; Cohort Studies; Female; Humans; Hypertension; Male; Middle Aged; Parkinson Disease; Prospective Studies; Risk Factors; Smoking; Vitamin A

Compromised mitochondrial energy metabolism and oxidative stress have been associated with the pathophysiology of Parkinson's disease. Our previous experiments exemplified the importance of GSH in the protection of neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase/complex II. This study further defines the role of oxidative stress during energy inhibition and begins to unravel the mechanisms by which GSH and other antioxidants may contribute to cell survival. Treatment of mesencephalic cultures with 10 microM buthionine sulfoximine for 24 h depleted total GSH by 60%, whereas 3 h exposure to 5 mM 3-amino-1,2,4-triazole irreversibly inactivated catalase activity by 90%. Treatment of GSH-depleted cells with malonate (40 mM) for 6, 12 or 24 h both potentiated and accelerated the time course of malonate toxicity, however, inhibition of catalase had no effect. In contrast, concomitant treatment with buthionine sulfoximine plus 3-amino-1,2,4-triazole in the presence of malonate significantly potentiated toxicity over that observed with malonate plus either inhibitor alone. Consistent with these findings, GSH depletion enhanced malonate-induced reactive oxygen species generation prior to the onset of toxicity. These findings demonstrate that early generation of reactive oxygen species during mitochondrial inhibition contributes to cell damage and that GSH serves as a first line of defense in its removal. Pre-treatment of cultures with 400 microM ascorbate protected completely against malonate toxicity (50 mM, 12 h), whereas treatment with 1 mM Trolox provided partial protection. Protein-GSH mixed disulfide formation during oxidative stress has been suggested to either protect vulnerable protein thiols or conversely to contribute to toxicity. Malonate exposure (50 mM) for 12 h resulted in a modest increase in mixed disulfide formation. However, exposure to the protective combination of ascorbate plus malonate increased membrane bound protein-GSH mixed disulfides three-fold. Mixed disulfide levels returned to baseline by 72 h of recovery indicating the reversible nature of this formation. These results demonstrate an early role for oxidative events during mitochondrial impairment and stress the importance of the glutathione system for removal of reactive oxygen species. Catalase may serve as a secondary defense as the glutathione system becomes limiting. These findings also suggest that protein-GSH mixed disulfide formatio

Topics: Amitrole; Animals; Antioxidants; Ascorbic Acid; Catalase; Cells, Cultured; Chromans; Energy Metabolism; Enzyme Inhibitors; Glutathione Disulfide; Hydrogen Peroxide; Malonates; Mesencephalon; Neurons; Oxidative Stress; Parkinson Disease; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Nitric oxide (NO) exerts neurotrophic and neurotoxic effects on dopamine (DA) function in primary midbrain cultures. We investigate herein the role of glutathione (GSH) homeostasis in the neurotrophic effects of NO. Fetal midbrain cultures were pretreated with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), 24 h before the addition of NO donors (diethylamine/nitric oxide-complexed sodium and S-nitroso-N-acetylpenicillamine) at doses tested previously as neurotrophic. Under these conditions, the neurotrophic effects of NO disappeared and turned on highly toxic. Reduction of GSH levels to 50% of baseline induced cell death in response to neurotrophic doses of NO. Soluble guanylate cyclase (sGC) and cyclic GMP-dependent protein kinase (PKG) inhibitors protected from cell death for up to 10 h after NO addition; the antioxidant ascorbic acid also protected from cell death but its efficacy decreased when it was added after NO treatment (40% protection 2 h after NO addition). The pattern of cell death was characterized by an increase in chromatin condensed cells with no DNA fragmentation and with breakdown of plasmatic membrane. The inhibition of RNA and protein synthesis and of caspase activity also protected from cell death. This study shows that alterations in GSH levels change the neurotrophic effects of NO in midbrain cultures into neurotoxic. Under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterized by an early step of free radicals production followed by a late requirement for signalling on the sGC/cGMP/PKG pathway.

Topics: Alkaloids; Aminoquinolines; Animals; Antioxidants; Apoptosis; Ascorbic Acid; Buthionine Sulfoximine; Carbazoles; Cell Division; Cells, Cultured; Cyclic GMP-Dependent Protein Kinases; Dopamine; Enzyme Inhibitors; Free Radicals; Glutathione; Glutathione Synthase; Guanylate Cyclase; Homeostasis; Hydrazines; Indoles; Mesencephalon; Methylene Blue; Nerve Tissue Proteins; Neurons; Nitric Oxide; Nitric Oxide Donors; Nitrogen Oxides; Nucleic Acid Synthesis Inhibitors; Parkinson Disease; Penicillamine; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase

The principal neuropathological feature of Parkinson's disease is the degeneration of melanized dopamine neurons in the substantia nigra pars compacta (SNc). Characteristic pathobiochemical changes in the parkinsonian SNc include a fall of both dopamine (DA) and glutathione levels (GSH), increased activity of gamma-glutamyl transpeptidase, a key enzyme involved in the degradation of GSH to L-cysteine (CySH), together with evidence for elevated intraneuronal superoxide (O2-*), nitric oxide (NO.) and thence peroxynitrite (ONOO-) generation, and accelerated DA oxidation as indicated by a large rise of the 5-S-cysteinyldopamine (5-S-CyS-DA)/DA concentration ratio. The latter effect is consistent with an increased rate of DA oxidation by O2-* and ONOO- forming DA-o-quinone which reacts with CySH forming 5-S-CyS-DA. However, 5-S-CyS-DA is readily further oxidized to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 is rapidly accumulated by isolated intact rat brain mitochondria and selectively inhibits complex I respiration and the alpha-ketoglutarate dehydrogenase (alpha-KGDH) complex. In this study it is demonstrated that DHBT-1 also inhibits the pyruvate dehydrogenase complex (PDHC). The mechanism underlying the inhibition of all of these enzyme complexes involves bioactivation of intramitochondrial DHBT-1 by oxidation to highly electrophilic metabolites that covalently bind to active site cysteine residues. Thus, oxidative metabolites of intraneuronal 5-S-CyS-DA may contribute to impaired mitochondrial complex I and alpha-KGDH activities known to occur in the parkinsonian SNc and suggest that impaired PDHC evoked by the same metabolites may also occur in PD.

Topics: Animals; Ascorbic Acid; Catalase; Dopamine; Energy Metabolism; Glutathione; Intracellular Membranes; Male; Mitochondria; Neurons; Oxidative Stress; Parkinson Disease; Pyruvate Dehydrogenase Complex; Rats; Rats, Sprague-Dawley; Substantia Nigra; Superoxide Dismutase; Thiazines

6-Hydroxydopamine (6-OHDA) is a dopaminergic neurotoxin putatively involved in the pathogenesis of Parkinson's disease (PD). Its neurotoxicity has been related to the production of reactive oxygen species. In this study we examine the effects of the antioxidants ascorbic acid (AA), glutathione (GSH), cysteine (CySH), and N-acetyl-CySH (NAC) on the autoxidation and neurotoxicity of 6-OHDA. In vitro, the autoxidation of 6-OHDA proceeds rapidly with the formation of H2O2 and with the participation of the H2O2 produced in the reaction. The presence of AA induced a reduction in the consumption of O2 during the autoxidation of 6-OHDA and a negligible presence of the p-quinone, which demonstrates the efficiency of AA to act as a redox cycling agent. The presence of GSH, CySH, and NAC produced a significant reduction in the autoxidation of 6-OHDA. In vivo, the presence of sulfhydryl antioxidants protected against neuronal degeneration in the striatum, which was particularly remarkable in the case of CySH and was attributed to its capacity to remove the H2O2 produced in the autoxidation of 6-OHDA. These results corroborate the involvement of oxidative stress as the major mechanism in the neurotoxicity of 6-OHDA and the putative role of CySH as a scavenger in relation to PD.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Cysteine; Female; Free Radical Scavengers; Glutathione; Hydrogen Peroxide; Neurons; Oxidation-Reduction; Oxidopamine; Oxygen Consumption; Parkinson Disease; Rats; Rats, Sprague-Dawley; Sympatholytics

We have previously shown that manganese enhances L-dihydroxyphenylanine (L-DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing effect [an increase in L-DOPA and dopamine (DA) auto-oxidation] was studied using microdialysis in the striatum of freely moving rats. Systemic L-DOPA [25 mg kg(-1) intraperitoneally (i.p.) twice in a 12 h interval] significantly increased baseline dialysate concentrations of L-DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were significantly decreased. A L-DOPA oxidation product, presumptively identified as L-DOPA semiquinone, was detected in the dialysate. The L-DOPA semiquinone was detected also following intrastriatal infusion of L-DOPA. In rats given L-DOPA i.p. , intrastriatal infusion of N-acetylcysteine (NAC) significantly increased DA and L-DOPA dialysate concentrations and lowered those of L-DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations. In rats given L-DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L-DOPA dialysate concentrations and greatly increased those of L-DOPA semiquinone. These changes were inhibited by NAC infusion. These findings demonstrate that auto-oxidation of exogenous L-DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L-DOPA auto-oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L-DOPA long-term therapy of Parkinson's disease.

Topics: 3,4-Dihydroxyphenylacetic Acid; Acetylcysteine; Animals; Ascorbic Acid; Chlorides; Chromatography, High Pressure Liquid; Corpus Striatum; Dialysis Solutions; Dopamine; Homovanillic Acid; Infusion Pumps; Levodopa; Male; Manganese; Manganese Compounds; Microdialysis; Movement; Oxidation-Reduction; Parkinson Disease; Rats; Rats, Wistar; Time Factors; Uric Acid

The role of ascorbic acid on dopamine (DA) oxidation-mediated cytotoxicity was studied using the PC12 cell line. DA cytotoxicity was slightly attenuated by ascorbic acid, whereas the cytotoxicity of 6-hydroxydopamine (6-OHDA), a DA oxidation product, was markedly potentiated. To elucidate the relationship between the ascorbic acid effect and the degree of DA oxidation, ascorbic acid was added in a time-dependent fashion after DA treatment. We found greater cell death the later ascorbic acid was applied. Treatment of cells with glutathione alleviated DA- and 6-OHDA-induced cell death, while L-buthionine sulfoximine potentiated DA and 6-OHDA cytotoxicity. Ascorbic acid combined with glutathione eliminated the toxicity of DA and 6-OHDA. These results suggest that the interaction between DA and ascorbic acid is dependent upon the degree of DA oxidation and glutathione availability.

Topics: Animals; Ascorbic Acid; Buthionine Sulfoximine; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Glutathione; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Oxidopamine; Parkinson Disease; PC12 Cells; Pharmacokinetics; Rats

In this study, we evaluated the ability of submandibular gland scintigraphy to predict the prognosis of peripheral facial nerve paralysis.. Submandibular gland scintigraphy was performed in 78 patients with acute peripheral facial nerve paralysis. After injection of 180-370 MBq [99mTc]pertechnetate, serial 1-min images were acquired for 25 min. At 15 min after injection of radionuclide, ascorbic acid was administered intraorally to stimulate salivary secretion. Regions of interest were set manually on both submandibular glands, and time-activity curves were generated. The ratios of peak count density (PCR) and washout (WR) of the affected side to the normal side were calculated. Parameters of > or = 0.8 suggested normal affected submandibular function and indicated a good prognosis.. Complete recovery of facial nerve paralysis was observed in 52 of 78 patients. The sensitivity, specificity and accuracy of PCR for a good prognosis were 79%, 50% and 69%, and those of WR were 85%, 77% and 82%, respectively. Positive and negative predictive values for a good prognosis were 76% and 54% in PCR and 88% and 71% in WR, respectively. When WR obtained within 14 days of the onset was used, positive and negative predictive values for a good prognosis were 94% and 73%, respectively. None of the eight patients who had values of <0.8 for both parameters within 14 days of the onset recovered completely.. Submandibular gland scintigraphy can serve as a reliable indicator to predict the prognosis of acute peripheral facial nerve paralysis in its early symptomatic period.

Topics: Acute Disease; Adolescent; Adult; Aged; Ascorbic Acid; Child; Child, Preschool; Facial Paralysis; Female; Humans; Male; Middle Aged; Parkinson Disease; Predictive Value of Tests; Prognosis; Radionuclide Imaging; Radiopharmaceuticals; Sensitivity and Specificity; Sodium Pertechnetate Tc 99m; Submandibular Gland

The interaction between sodium ascorbate and dopamine was investigated by three different parameters: radical intensity, prooxidant action, and cytotoxicity induction. Sodium ascorbate and dopamine produced the doublet and quartet ESR signals under alkaline conditions (pH 8.0-9.5), respectively. Addition of increasing concentrations of sodium ascorbate completely scavenged the dopamine radical and replaced the latter with its own radical. Similarly, dopamine slightly, but significantly reduced the radical intensity of sodium ascorbate. These two compounds stimulated the methionine oxidation and hydrogen peroxide generation in culture medium, but in combination, their stimulation activities were weakened. Both of these two compounds dose-dependently reduced the viable cell number of human oral squamous carcinoma HSC-4 cells, and their cytotoxic activity was significantly reduced by catalase. When these two compounds were mixed together before adding to HSC-4 cells, both of their cytotoxic activities were diminished. The present study demonstrates the interaction between sodium ascorbate and dopamine, which might modify their biological activities and generation of nerve disorders such as Parkinson's disease.

Topics: Amino Acids; Ascorbic Acid; Catalase; Cell Survival; Dopamine; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Free Radicals; Humans; Hydrogen Peroxide; Methionine; Oxidation-Reduction; Parkinson Disease; Tumor Cells, Cultured

It has been suggested that dietary antioxidants reduce Parkinson's disease (PD) risk by neutralizing free radicals, thus preventing injury to neurons in the substantia nigra. This case-control study examined the possible role of long-term dietary antioxidant intake in PD etiology. Cases (n = 57) were males 45-79 years old with at least two cardinal signs of PD and no evidence of other forms of parkinsonism or dementia. Age-matched friend controls (n = 50) were chosen from lists provided by the cases. Usual dietary intake 20 years ago, including vitamins E and C and carotenoids, was assessed by a 102-item food frequency questionnaire. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression. Antioxidant intake, adjusted for age, education, smoking, rural living, and total energy intake, was not associated with reduced PD risk. Trends toward greater PD risk were associated with higher intakes of vitamin C and carotenoids, especially xanthophylls, reflecting higher intakes by PD cases of fruit and certain vegetables. Intakes of sweet foods, including fruit, were associated with higher PD risk, suggesting that the observed trends may be due to a preference for sweet foods. This study does not provide support for a protective effect of long-term dietary antioxidant intake on PD risk.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Carotenoids; Case-Control Studies; Feeding Behavior; Free Radicals; Humans; Male; Mental Status Schedule; Middle Aged; Neurologic Examination; Nutritional Requirements; Parkinson Disease; Risk Factors; Vitamin E

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD). In a population-based, case-control study we examined whether dietary intake of antioxidants and other oxidative compounds was associated with PD. Dietary intake was assessed by a semiquantitative food-frequency questionnaire in 110 PD case patients and 287 control subjects. A higher caloric intake was observed in patients with PD and did not vary with increasing duration of symptoms. Energy-adjusted fat intake was significantly higher among patients with PD than control subjects (p for trend = 0.007). Intake of protein (p for trend = 0.17) and carbohydrates (p for trend = 0.46) did not differ in patients and control subjects. Analyses of the primary sources of fat indicated that increasing intake of animal fats were strongly related to PD (odds ratio, 5.3; 95% confidence interval, 1.8-15.5; p for trend = 0.001). No significant differences were observed for intake of vitamins with antioxidant activity. An increase in the consumption of animal fats among patients with PD is consistent with the hypothesis that oxidative stress and lipid peroxidation are important in the pathogenesis of this disease. No effect of vitamins with antioxidant activity, either from food or supplements, was observed.

Topics: Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Case-Control Studies; Diet Surveys; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Female; Humans; Lipid Peroxidation; Male; Odds Ratio; Parkinson Disease; Vitamin A; Vitamin E; Vitamins

We defined the temporal stability characteristics of levodopa/carbidopa (LD/CD) solution, and determined the effects of temperature, ascorbate, and light on LD stability over 7 days. At room temperature and without ascorbate, LD levels significantly declined by 48 h. Ascorbate prolonged stability to 72 h. Refrigeration and freezing prevented a significant decline in LD levels for the full 7 days. Light or darkness had no effect on stability. LD/CD solution, if made daily, requires no special handling and longer stability is maintained with ascorbate, refrigeration, or freezing.

Topics: Antiparkinson Agents; Ascorbic Acid; Carbidopa; Drug Combinations; Drug Stability; Drug Storage; Humans; Levodopa; Light; Parkinson Disease; Temperature; Time Factors

Topics: Ascorbic Acid; Brain; Glutamates; Humans; Parkinson Disease; Schizophrenia

We previously reported that mesencephalic dopaminergic neurons are resistant to cytotoxicity induced by nitric oxide (NO). This study investigated the intracellular mechanism that protects dopaminergic neurons against NO toxicity in rat mesencephalic cultures. Peroxynitrite anion, an active metabolite of NO, caused significant cytotoxic effects against dopaminergic and nondopaminergic neurons, but NO caused cytotoxic effects restricted to nondopaminergic neurons. In addition, we studied the effects of ascorbate, an anti-oxidant, on NO-induced neurotoxicity against dopaminergic neurons and found that coadministration of ascorbate failed to affect resistance against NO-induced neurotoxicity. These findings suggest that the protecting mechanism from NO neurotoxicity in dopaminergic neurons is based on inhibition of conversion of NO to peroxynitrite anion, is independent of the NO redox state, and is possibly due to suppression of superoxide anion production. Furthermore, we investigated NO-induced neurotoxicity with or without pretreatment with sublethal doses of methylphenylpyridium ion (MPP+). Following pretreatment with 1 microM MPP+, which did not show significant cytotoxic effects against dopaminergic neurons, NO demonstrated significant cytotoxicity. Therefore, MPP+ may inhibit the protecting systems from NO neurotoxicity in dopaminergic neurons.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Antioxidants; Ascorbic Acid; Cell Survival; Cells, Cultured; Dopamine; Drug Resistance; Mesencephalon; Nerve Tissue Proteins; Neurons; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Oxidation-Reduction; Parkinson Disease; Rats; Tyrosine 3-Monooxygenase

Recently, (R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl-(R)salsolinol, NM(R)Sal] and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion [DiMeDHIQ+] were found to cause a syndrome similar to parkinsonism in rodents. NM(R)Sal is produced in the brain by N-methylation of a naturally occurring catechol isoquinoline, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)salsolinol, (R)Sal], which is formed from dopamine. The mechanism of NM(R)Sal cytotoxicity to dopamine neurons was examined using in vitro experiments. NM(R)Sal was found to be nonenzymatically oxidized into DiMeDHIQ+, with concomitant formation of hydroxyl radicals. The oxidation and the radical production were completely inhibited by the antioxidants, ascorbic acid and reduced glutathione, and the radical formation was enhanced by Fe(II) and, to a less extent, by Fe(III). The oxidation of NM(R)Sal into DiMeDHIQ+ and the production of hydroxyl radicals may be essential for neurotoxicity to develop in dopamine neurons. The possible involvement of this catechol isoquinoline in the pathogenesis of Parkinson's disease is discussed.

Topics: Animals; Ascorbic Acid; Catalase; Chromatography, High Pressure Liquid; Dopamine; Ferric Compounds; Ferrous Compounds; Free Radicals; Glutathione; Humans; Hydroxyl Radical; Isoquinolines; Methylation; Neurons; Oxidation-Reduction; Parkinson Disease; Salsoline Alkaloids; Superoxide Dismutase; Tetrahydroisoquinolines

The influence of R(-) apomorphine, S(+) apomorphine and dopamine on the oxidation kinetics of two polyunsaturated fatty acids (PUFA) (cholesteryl linoleate (CL) and Trilinolein (TL)) was investigated. The oxidation was initiated by free radicals generated through thermal decomposition of 2.2'-Azobis(2-methyl-propionitrile) (AMPN) in phosphate buffer (pH 7.4) thermostated at 50 degrees C. The hydroperoxides formed were determined by iodine titration using a diode array spectrophotometer at 290nm. Both enantiomers of apomorphine as well as dopamine exerted an inhibitory effect. Tocopherol (alpha-tocopherol) and ascorbic acid were used as controls. The former inhibited while ascorbic acid facilitated the oxidation reaction. These results are discussed in relation with the possible role of oxidative injury in parkinsonism and the usefulness of apomorphine in elevating "on-off" episodes. On this basis, the non-dopaminergic enantiomer of apomorphine (S(+)-isomer) is put foward to test the importance of its radical scavenging properties in parkinsonism which could eventually lead to a therapeutic alternative with less side effects.

Topics: Apomorphine; Ascorbic Acid; Corpus Striatum; Dopamine; Free Radicals; Oxidative Stress; Parkinson Disease; Peroxides; Spectrophotometry

Postmortem caudate and substantia nigra tissue samples from human parkinsonian patients (PD) and age-matched controls (NC) were analyzed for uric acid (UA), dopamine (DA), and ascorbic acid (AA) by HPLC/UV/ED. Uric acid and DA levels were significantly lower in the substantia nigra of PD by 54% and 85%, respectively. In the caudate, DA levels were significantly lower while UA levels were nonsignificantly reduced (0.10 < p < 0.05). Ascorbic acid levels were not significantly different from the controls in either brain region. Conditions favorable for oxidative stress were evaluated by measuring the oxidation of DA in individual brain homogenates. The rate constant for DA oxidation in control caudate was 0.34 x 10(-2) min-1 and in parkinsonian caudate was 4.20 x 10(-2) min-1. In control and parkinsonian substantia nigra DA oxidation rate constants were 2.82 x 10(-2) min-1 and 4.57 x 10(-2) min-1, respectively. Addition of UA or catalase to parkinsonian homogenate decreased the rate of DA oxidation, while addition of uricase to control homogenate increased the rate of DA oxidation. The data support the hypothesis that UA is decreased in nigrostriatal dopamine neurons in parkinsonian patients which contributes to an environment susceptible to oxidative stress, particularly through dopamine oxidation reactions.

Topics: Aged; Ascorbic Acid; Brain Chemistry; Dopamine; Female; Humans; Male; Nerve Degeneration; Neural Pathways; Oxidation-Reduction; Parkinson Disease; Substantia Nigra; Tissue Extracts; Uric Acid

To elucidate the possible role of vitamin C in the risk for developing Parkinson's disease (PD), we compared serum levels of ascorbic acid (vitamin C), measured by a fluorometric method, of 63 PD patients using their spouses as the control group. The serum levels of vitamin C did not differ significantly between the groups (47.13 +/- 0.89 micrograms/ml for PD and 47.60 +/- 0.60 micrograms/ml for controls). There was no influence of antiparkinsonian therapy on vitamin C. Serum levels of vitamin C did not correlate with age, age at onset and duration of the disease, scores of the Unified PD Rating Scale or the Hoehn and Yahr staging in the PD group. These results suggest that serum vitamin C concentrations are apparently unrelated to the risk of developing PD.

Topics: Age Factors; Age of Onset; Aged; Ascorbic Acid; Female; Humans; Male; Middle Aged; Parkinson Disease; Risk Factors; Spectrometry, Fluorescence

Levodopa, at concentrations of 0.25 x 10(-4) M or larger, is toxic for the human neuroblastoma cell NB69. Toxicity is associated with high levels of quinones, increased activity of complex II-III, and lack of changes of complex I of the mitochondrial respiratory chain. Deprenyl, which does not alter the production of quinones, has a partial protective effect. Tocopherol, 23 or 115 x 10(-6) M, lacks significant preventive effect on levodopa toxicity, but ascorbic acid, 10(-3) M, prevents levodopa toxicity and quinone formation. Deprenyl, 10(-4) M, provides additional protection in cultures treated with levodopa and ascorbic acid. Our results indicate that ascorbic acid and deprenyl prevent levodopa neurotoxicity by unrelated mechanisms. Both compounds should be considered as complementary drugs to test for slowing the progression of Parkinson's disease.

Topics: Ascorbic Acid; Brain; Brain Neoplasms; Catecholamines; Cell Line; Drug Interactions; Female; Humans; Levodopa; Male; Neuroblastoma; Parkinson Disease; Quinones; Selegiline

Oxidation of catecholamines may lead to the formation of o-semiquinones and o-quinones in catecholaminergic brain tissues, and these reactive molecules may form DNA or protein adducts. In this study, cultured cells were treated with dopamine (DA) for 24 h and 32P-postlabelling was used to detect DA-DNA adducts. In HL-60 cells, 250 microM DA induced 8.5 DNA adducts/10(8) nucleotides; adduct formation was dose-dependent up to 500 microM DA. Addition of H2O2 increased the relative adduct levels 7- to 13-fold, but no adducts were detected when DA and ascorbic acid were added simultaneously. In human glioblastoma cell lines U87, U251, SF-763 and SF-767, 1000 microM DA produced 0.98-2.31 adducts/10(8) nucleotides. These results suggest that the formation of DNA adducts by DA may contribute to the development of certain neurodegenerative diseases such as Parkinson's disease.

Topics: Ascorbic Acid; Brain; Cells, Cultured; DNA; Dopamine; Humans; Hydrogen Peroxide; Parkinson Disease; Tumor Cells, Cultured

Concentrations of the naturally occurring antioxidant vitamins A, C and E were measured in 27 patients with Parkinson's disease and 16 age-matched control subjects, from a similarly disabled patient group. There was no significant difference in the serum concentrations of vitamins A and E in the two groups. Vitamin C was significantly higher (P < 0.05) in the Parkinson's disease group, however, the mean leucocyte vitamin C concentration in the control group was low (101 nmol/10(8) WBCS) compared to established data in healthy young individuals (119-301 nmol/10(8) WBCS). There was no correlation between the severity or duration of Parkinson's disease and concentrations of vitamins A, C and E. There is therefore no evidence from this study that a deficiency of these antioxidants contributes to the onset or progress of Parkinson's disease.

Topics: Aged; Aged, 80 and over; Ascorbic Acid; Cholesterol; Female; Humans; Leukocytes; Male; Middle Aged; Parkinson Disease; Vitamin A; Vitamin E

High dosages of a combination of alpha-tocopherol and ascorbate were administered to patients with early Parkinson's disease as an open-labeled trial and pilot study to test the endogenous toxic hypothesis of the etiology of Parkinson's disease. Patients receiving concomitant amantadine and anticholinergics were allowed to participate, but those receiving levodopa or dopamine agonists were not. The study was begun prior to the availability of deprenyl. The primary end point of the trial was progression of the disease until patients needed treatment with levodopa or a dopamine agonist. The time when levodopa became necessary in the treated patients was compared to another group of patients followed elsewhere who did not receive antioxidants. The time when levodopa became necessary was extended by 2.5 years in the group receiving alpha-tocopherol and ascorbate. Results of this pilot study suggest that the progression of Parkinson's disease may be slowed by administration of these antioxidants. Controlled clinical trials using double-blind randomization techniques are required to confirm these results.

Topics: Adult; Aged; Ascorbic Acid; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects; Research Design; Vitamin E

Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinson's disease and age-matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Topics: Aged; Animals; Ascorbic Acid; Brain; Fatty Acids, Unsaturated; Female; Ferrous Compounds; Free Radicals; Humans; Hydrogen Peroxide; Lipid Peroxidation; Male; Malondialdehyde; Parkinson Disease; Postmortem Changes; Rats; Rats, Inbred Strains; Substantia Nigra; Thiobarbiturates

The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinson's disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)-binding, protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.

Topics: Aged; Ascorbic Acid; Brain; Calcium; Copper; Female; Ferritins; Glutathione; Humans; Iron; Magnesium; Male; Metals; Parkinson Disease; Substantia Nigra; Tissue Distribution; Zinc

Topics: Ascorbic Acid; Drug Therapy, Combination; Humans; Levodopa; Parkinson Disease

Topics: Ascorbic Acid; Drug Interactions; Drug Therapy, Combination; Humans; Levodopa; Male; Middle Aged; Parkinson Disease