The effect of antioxidants on in vivo and in vitro methemoglobin formation in erythrocytes of patients with Parkinson’s disease

Methemoglobin formation was examined in erythrocytes of 16 patients with Parkinson’s disease (PD) (stage 3–4 by the Hoehn and Yahr scale). The patients receiving levodopa-containing drugs (madopar, nakom) were also treated with intramuscular injections of mexidol (daily dose 100 mg/day) for 14 days. Control group included 12 clinically healthy persons. The erythrocyte methemoglobin content was determined by electronic paramagnetic resonance (EPR) using the EPR signal intensity with the g-factor 6.0. The methemoglobin content was significantly higher in erythrocytes of PD patients than in healthy donors. The complex therapy with mexidol normalized the methemoglobin content in erythrocytes of PD patients. Incubation in vitro of erythrocytes of donors and PD patients with acrolein increased the methemoglobin content, while incubation with carnosine normalized the methemoglobin content in erythrocytes of PD patients. Prophylactic (i.e. before acrolein addition) and therapeutic administration of carnosine to the incubation system with acrolein decreased the methemoglobin content to its initial level. Results of this study suggest that inclusion of the antioxidants mexidol and carnosine in the scheme of basic therapy of PD may reduce side effects associated with methemoglobinemia.     

The effects of pergolide on memory and oxidative stress in a rat model of Parkinson’s disease

One of the most widely used animal models of Parkinson’s disease (PD) involves injecting 6-hydroxydopamine (6-OHDA) directly into the substantia nigra (SN). Some recent reports speculated that dopaminergic drugs may exert brain antioxidant activity, which could explain some of their protective actions. In this way, the aim of the present study was to examine the effects of low-dose pergolide on memory deficits and brain oxidative stress in a 6-OHDA-induced rat model of PD. Right-unilateral lesions of the SN were produced with 6-OHDA. Two weeks after neurosurgery, pergolide (0.3 mg/kg/day) was injected intraperitoneally in the 6-OHDA + pergolide and sham-operated + pergolide groups, while sham-operated and 6-OHDA alone groups received saline. Radial-8-arm maze and Y-maze were used for memory assessment. We also determined some enzymatic antioxidant defenses like superoxide dismutase or glutathione peroxidase and a lipid peroxidation marker [malondialdehyde (MDA)], from the temporal lobe. A reduced number of working/reference memory errors was observed in 6-OHDA + pergolide group, compared to sham-operated rats. Additionally, post hoc analysis showed significant differences between 6-OHDA and 6-OHDA + pergolide groups in both Y-maze and radial-arm-maze tasks. We also noted a significant decrease of MDA level in the 6-OHDA + pergolide group, compared to sham-operated rats. Significant correlations were also found between behavioral parameters and MDA levels. Our data suggest that pergolide facilitates spatial memory and improves brain oxidative balance, after a 6-OHDA-induced model of PD. This could be useful for further investigations and clinical applications of pergolide.     

Investigation of muscle tone in patients with Parkinson’s disease in unloading conditions

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, the main symptoms of which are hypertonicity and difficulties emerging during performance of stepping movements due to increased muscle stiffness. Biomechanical (stiffness) and electrophysiological (shortening reaction, SR) characteristics of hip and shank muscles were examined in 25 patients with mild and moderate stages of PD (1 to 3 of Hoehn and Yahr Rating Scale, 61 ± 9 years) and 22 age-matched healthy controls in unloading leg conditions during passive flexion/extension of hip, knee, and ankle joints, as well as the changes in the tonic state of muscles under the influence of levodopa. The data obtained were compared with similar findings in healthy subjects. Essentially greater stiffness in all leg muscle groups (except foot extensors) was observed in patients with PD as compared to the healthy subjects. In patients with PD, SR values in hip and shank extensors as well as in foot flexors and extensors were essentially greater then in the healthy subjects. The medicine essentially reduced the stiffness of hip flexors and knee flexors and extensors. The SR persisted, although the frequency of its occurrence decreased in half of studied muscles, and a significant decrease in the SR value was observed in foot extensors. The medicine had no marked effect on the SR in the proximal muscles. Thus, the increased muscle stiffness in patients with PD manifests itself as distorted reactions to external disturbances and increased reflectory reactions of muscles.     

The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson’s disease

The etiology of sporadic Parkinson’s disease (PD) is unknown, although mitochondrial dysfunction and oxidative stress have been implicated in the mechanisms associated with PD pathogenesis. Dopamine (DA) neurons of the substantia nigra pars compacta have been shown to degenerate to a greater extent in PD than other neurons suggesting the possibility that DA itself may be contributing to the neurodegenerative process. This review discusses our work on the effects of DA oxidation and reactive DA quinones on mitochondrial function and protein modification and the potential for exacerbating toxicity associated with mitochondrial dysfunction in PD.     

Chronic exposure of homocysteine in mice contributes to dopamine loss by enhancing oxidative stress in nigrostriatum and produces behavioral phenotypes of Parkinson’s disease

Increased homocysteine (Hcy) level has been implicated as an independent risk factor for various neurological disorders, including Parkinson’s disease (PD). Hcy has been reported to cause dopaminergic neuronal loss in rodents and causes the behavioral abnormalities. This study is an attempt to investigate molecular mechanisms underlying Hcy-induced dopaminergic neurotoxicity after its chronic systemic administration. Male Swiss albino mice were injected with different doses of Hcy (100 and 250 mg/kg; intraperitoneal) for 60 days. Animals subjected to higher doses of Hcy, but not the lower dose, produces motor behavioral abnormalities with significant dopamine depletion in the striatum. Significant inhibition of mitochondrial complex-I activity in nigra with enhanced activity of antioxidant enzymes in the nigrostriatum have highlighted the involvement of Hcy-induced oxidative stress. While, chronic exposure to Hcy neither significantly alters the nigrostriatal glutathione level nor it causes any visible change in tyrosine hydroxylase-immunoreactivity of dopaminergic neurons. The finding set us to hypothesize that the mild oxidative stress due to prolonged Hcy exposure to mice is conducive to striatal dopamine depletion leading to behavioral abnormalities similar to that observed in PD.     

The marked decrease in cardiac MIBG-uptake correlates with the severity of sleep disturbance in patients with Parkinson’s disease

Sleep and Biological Rhythms - We investigated the relationship between sleep disturbances and 123I-meta-iodobenzylguanidine (MIBG)-uptake during myocardial scintigraphy in patients with...     

Selenium speciation analysis in the cerebrospinal fluid of patients with Parkinson’s disease

BackgroundThe aim of the study was to investigate if speciation analysis by liquid chromatography coupled to mass spectrometry could be used to detect organic and inorganic binding forms of selenium in the cerebrospinal fluid (CSF) of patients with Parkinson’s disease (PD) and age-matched control subjects (AMC).MethodsPD patients and control subjects were enrolled from three different neurological departments. CSF samples were collected according to standardized biomarker protocols and subjected to inductively coupled plasma mass spectrometry (ICP-MS) for total selenium determination and ion exchange chromatography (IEC) hyphenated to ICP-MS for selenium speciation analysis.Results75 PD patients and 68 age-matched controls were enrolled for speciation analysis. 8 different species could be detected, but only selenoprotein P (SELENOP), human serum albumin-bound Se (Se-HSA), selenomethionine (Se-Met) and an unidentified Se-compound (U2) presented with more than 50% values above the limit of quantification, without showing significant differences between both groups (p > 0.05). The Se-HSA / Se-Met ratio yielded a significant difference between PD and AMC (p = 0.045). The inorganic species Se-IV and Se-VI were only detectable in a minor part of PD and AMC samples. A highly significant correlation between total selenium levels and SELENOP (PD p < 0.0001; AMC p < 0.0001) and Se-HSA (PD p < 0.0001; AMC p < 0.0001) could be demonstrated, respectively.ConclusionsSpeciation analysis yielded new insight into selenium homeostasis in PD but cannot be used to establish a diagnostic biomarker. The small number of detectable values for Se-IV and Se-VI suggests an inferior role of these potentially neurotoxic binding forms in PD pathology in contrast to other neurodegenerative disorders.     

Complexity of resting-state EEG activity in the patients with early-stage Parkinson’s disease

To investigate the abnormal brain activities in the early stage of Parkinson’s disease (PD), the electroencephalogram (EEG) signals were recorded with 20 channels from non-dementia PD patients (18 patients, 8 females) and age matched healthy controls (18 subjects, 8 females) during the resting state. Two methods based on the ordinal patterns of the recorded series, i.e., permutation entropy (PE) and order index (OI), were introduced to characterize the complexity of the cortical activities for two groups. It was observed that the resting-state EEG of PD patients showed lower PE and higher OI than healthy controls, which indicated that the early-stage PD caused the reduced complexity of EEG. We further applied two methods to determine the complexity of EEG rhythms in five sub-bands. The results showed that the gamma, beta and alpha rhythms of PD patients were characterized by lower PE and higher OI, i.e., reduced complexity, than healthy subjects. No significant differences were observed in theta or delta rhythms between two groups. The findings suggested that PE and OI were promising methods to detect the abnormal changes in the dynamics of EEG signals associated with early-stage PD. Further, such changes in EEG complexity may be the early markers of the cortical or subcortical dysfunction caused by PD.     

PARK2 gene variants in Korean patients with Parkinson’s disease

Mutations in PARK2 are considered a common cause of Parkinson’s disease (PD). To assess the frequency of PARK2 mutations in the Korean population, we screened the PARK2 gene in 83 Korean PD patients: two young onset (YO, ≤ 49), 32 middle onset (MO, 50–69) and 49 late onset (LO, ≥ 70). Detection of the point mutations was performed by direct sequencing of the PARK2 exons, and exonic rearrangements were analyzed using multiplex ligation-dependent probe amplification. Five known PARK2 variants were identified in 53 (63.9 %) of the Korean PD patients: two missense mutations (Y267H and M458L) and three polymorphisms (S167N, L272I and V380L). We also found an increased frequency of PARK2 variants in PD patients and a lowered PD age at onset (AAO) in those having two variants, suggesting that the genetic variation in PARK2 gene might be a genetic risk factor of PD in Korean population.     

Are interlimb interactions disturbed in patients with Parkinson’s disease? A study under unloading conditions

During natural human locomotion, neural connections are activated that are typical of regulation of the quadrupedal walking. The interaction between the neural networks generating rhythmic movements of the upper and lower limbs depends on tonic state of each of these networks regulated by motor signals from the brain. Distortion of these signals in patients with Parkinson’s disease (PD) may lead to disruption of the interlimb interactions. We examined the effect of movements of the limbs of one girdle on the parameters of the motor activity of another limb girdle at their joint cyclic movements under the conditions of arm and leg unloading in 17 patients with PD and 16 healthy subjects. We have shown that, in patients, the effect of voluntary and passive movements of arms, as well as the active movement of the distal parts of arms, on the voluntary movement of legs is weak, while in healthy subjects, the effect of arm movements on the parameters of voluntary stepping is significant. The effect of arm movements on the activation of the involuntary stepping by vibrational stimulation of-legs in patients was absent, while in healthy subjects, the motor activity of arms increased the possibility of involuntary rhythmic movements activation. Differences in the effect of leg movements on the rhythmic movements of arms were found in both patients and healthy subjects. The interlimb interaction appeared after drug administration. However, the effect of the drug was not sufficient for the recovery of normal state of the neural networks in patients. In PD patients, neural networks generating stepping rhythm have an increased tonic activity, which prevents the activation and appearance of involuntary rhythmic movements facilitating the effects of arms on legs.     

Circadian regulation and its disorders in Parkinson’s disease patients. Part 1: The role of dopamine in circadian dysfunction

Circadian disturbances related to Parkinson’s disease are reviewed, and possible pathogenetic mechanisms are discussed. The role of dopaminergic system degeneration in the development of circadian dysfunction is emphasized. The accumulation of α-synuclein in the suprachiasmatic nucleus is considered as a possible mechanism of circadian dysfunction unrelated to dopamine deficiency. Data on the disbalance of dopamine and melatonin levels in Parkinson’s disease patients and its role in disturbances of circadian rhythms of physiological processes are analyzed.     

The preventive effect of Se-methylselenocysteine on γ-radiation-induced oxidative stress in rat lungs

We investigated the preventive effect of Se-methylselenocysteine (MSC) administration on γ-radiation (whole body irradiation, single 10-Gy dose)-induced oxidative damage in rat lungs. Rats were pretreated with MSC (0.75 mg/rat/day) for 1 week before γ-irradiation. The MSC pretreatment prevented the irradiation-induced increase in lipid peroxidation and the concomitant decrease in cellular glutathione content. The prevention of irradiation-induced oxidative damage in MSC-pretreated rat lungs appeared to be associated with increased antioxidant capacity, particularly in the glutathione system. The 1-week MSC treatment resulted in an increase in glutathione peroxidase, glutathione reductase, and glucose 6-phosphate dehydrogenase activities, which are involved in glutathione redox cycling. An increase in catalase activity was also observed in the rat lungs. Additionally, a significantly increased level of nuclear factor erythroid 2-related factor 2 (Nrf2) was exhibited in the MSC-treated rat lungs. Heme oxygenase 1, glutathione S-transferase pi, and peroxiredoxin 1, which are known target proteins of Nrf2, were also increased in MSC-treated lungs. These results implicate Nrf2 signaling in the MSC-induced activation of the antioxidant system.     

Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease

Complex factors contribute to the appearance of Parkinson’s disease (PD), but with a constant mitochondrial involvement. There are two interdependent conditions in PD: brain mitochondrial dysfunction and brain mitochondrial oxidative damage. Mitochondrial dysfunction and reduced complex I activity are recognized in substantia nigra and in frontal cortex in PD patients. The molecular mechanism involved in the inactivation of complex I is likely accounted by the sum of ONOO⁻ mediated reactions, reactions with free radical intermediates of the lipid peroxidation process and amine-aldehyde adduction reactions. The inhibitory effects on complex I lead synergistically to denaturation of the protein structure and to further increases of O₂⁻ and ONOO⁻ production at the vicinity of complex I. An adaptive response in PD patients has been described with increases in mtNOS activity, mitochondrial mass and mitochondrial biogenesis. Mitochondrial dysfunction in the human frontal cortex is to be considered a factor contributing to impaired cognition in PD.     

Prevention of progression in Parkinson’s disease

Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson’s disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents.     

Mitochondrial dysfunction and oxidative damage in the molecular pathology of Parkinson’s disease

Parkinson’s disease is a complex disorder that is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Its development is determined by the interaction between the genetic constitution of a body and environmental factors. Analysis of the genes associated with monogenic forms of Parkinson’s disease implicated proteasomal degradation, differentiation of dopaminergic neurons, mitochondrial dysfunction, and oxidative damage in its pathogenesis. The review considers ample data that suggest a key role for mitochondrial dysfunction and oxidative stress.     

Dopaminergic modulation of multi-muscle synergies in postural tasks performed by patients with Parkinson’s disease

BackgroundPostural instability is one of most disabling motor symptoms in Parkinson’s disease. Indices of multi-muscle synergies are new measurements of postural stability.ObjectivesWe explored the effects of dopamine-replacement drugs on multi-muscle synergies stabilizing center of pressure coordinate and their adjustments prior to a self-triggered perturbation in patients with Parkinson’s disease. We hypothesized that both synergy indices and synergy adjustments would be improved on dopaminergic drugs.MethodsPatients at Hoehn-Yahr stages II and III performed whole-body tasks both off- and on-drugs while standing. Muscle modes were identified as factors in the muscle activation space. Synergy indices stabilizing center of pressure in the anterior-posterior direction were quantified in the muscle mode space during a load-release task.ResultsDopamine-replacement drugs led to more consistent organization of muscles in stable groups (muscle modes). On-drugs patients showed larger indices of synergies and anticipatory synergy adjustments. In contrast, no medication effects were seen on anticipatory postural adjustments or other performance indices.ConclusionsDopamine-replacement drugs lead to significant changes in characteristics of multi-muscle synergies in Parkinson’s disease. Studies of synergies may provide a biomarker sensitive to problems with postural stability and agility and to efficacy of dopamine-replacement therapy.     

Levodopa therapy reduces DNA damage in peripheral blood cells of patients with Parkinson’s disease

Oxidative stress seems to play a major role in the pathogenesis of neurodegeneration. In Parkinson’s disease (PD) patients, the dopaminergic neurons are subjected to oxidative stress resulting from reduced levels of antioxidant defenses such as glutathione and high amount of intracellular iron. Levodopa (LD) is widely used for the symptomatic treatment of PD, but its role in oxidative damage control is still unclear. The aim of this study was to analyze the presence of DNA damage in peripheral blood lymphocytes (PBL) of PD patients, during a washout and a controlled LD dosage and to evaluate the oxidative damage fluctuation after LD intake. The standard and the Fpg-modified version of Comet assay were applied in analyzing DNA damage in PBL from blood samples of nine PD patients and nine matched controls. Due to the limited number of patients we cannot reach definite conclusions even if our data confirm the accumulation of DNA lesions in PD patients; these lesions decrease after LD intake.