Does the Operation of Mitochondrial ATP-Dependent Potassium Channels Affect the Structural Component of Mitochondrial and Endothelial Dysfunctions in Experimental Parkinsonism?

We have previously demonstrated that the development of oxidative stress in some pathologies can be prevented by activation of the mitochondrial ATP-dependent potassium channel (mitoKATP). Here we studied the effect of modulation of mitoKATP on the development of mitochondrial and endothelial dysfunction in the medulla oblongata and myocardium of rats with experimental parkinsonism. It is known that uridine-5'-diphosphate, activator of mitoKATP, does not penetrate the plasma membrane, but it can be synthesized in cells from exogenous uridine that is delivered into cells by special transport systems. Our results suggest that mitoKATP is involved in the development of mitochondrial and endothelial dysfunction in experimental parkinsonism and prove the cardio- and neuroprotective effects of uridine.

[The study of telomere length in patients with Parkinson's disease].

OBJECTIVE: Telomeres which are formed by double-strand breaks and DNA under replication, cause cell cycle arrest resulting in cellular senescence and apoptosis. The erosion of telomeres is an important mechanism for regulating the aging process by limiting cell proliferation. Over the last decade, many investigations in the field of telomeric biology showed that telomeric DNA and telomeric proteins are involved in the pathogenesis of some human diseases. The aim of the study was to compare telomere length in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Telomere length was measured in buccal epithelial cells and leukocytes in PD patients and controls. RESULTS AND CONCLUSION: The length of telomeres in cells of buccal epithelium was shorter in patients with PD than in the control group. In blood cells, telomere length did not differ. It is suggested that shortening of telomeres in buccal epithelial cells may be due to oxidative stress and, hence, it can be used as a marker for the early stages of disease.

Reduction of the postexcitatory cortical inhibition upon paired-click auditory stimulation in patients with Parkinson's disease.

OBJECTIVES: The aims of this study were: to investigate the postexcitatory inhibition of cortical evoked potentials on auditory paired-click stimulation in patients with Parkinson's disease (PD), to analyze the correlation of N1-P2 amplitude ratios (A2/A1) with latency of the P300 auditory event-related potential and to determine the influence of Levodopa intake on postexcitatory inhibition and P300 latency. METHODS: The central (Cz) auditory evoked potentials were recorded in 61 patients with PD and 21 age-matched healthy subjects. RESULTS: Postexcitatory inhibition in auditory cortex in PD was significantly reduced for interstimulus intervals 500, 700 and 900ms compared to control group. The degree of this reduction correlated positively with the potential P300 latency and negatively with the summary score of the Mini Mental State Examination (MMSE) which was used to study general cognitive status of the PD patients. Increase of the postexcitatory inhibition towards normal values and decrease of the P300 latency were observed (P<0.001) following the administration of Levodopa. CONCLUSIONS: The findings of this study testify that inhibitory processes in auditory cortex are deficient in PD patients. The positive effect of Levodopa administration indicates an important role of dopamine-dependent neural mechanisms in modulation of inhibitory processes in the auditory sensory system. SIGNIFICANCE: The results show that inability of the brain to provide normal inhibition in PD is accompanied by the decline of cognitive indices, including parameters of evoked potential P300 that is related to fundamental aspects of cognitive functions, such as attention and memory.

Two phases of the contingent negative variation in humans: association with motor and mental functions.

The question of the relationship between contingent negative variation and the mechanisms controlling motor and mental functions has received inadequate study. The aims of the present work were to investigate the relationship between the early and late phases of contingent negative variation and the state of motor and mental functions in patients with Parkinson's disease and to study the effects of levodopa on contingent negative variation. Patients with Parkinson's disease showed significant decreases in the amplitudes and areas of both phases of contingent negative variation as compared with subjects of similar age. Correlation analysis demonstrated a negative relationship between the extent of impairment of coordinatory muscle interactions and the amplitudes of both phases of this variation (p < 0.01). There was a positive relationship between the magnitudes of both phases and the state of mental functions, particularly memory (p < 0.05). Treatment of patients with Parkinson's disease with levodopa was followed by a significant increase in the late phase (p < 0.05). The results obtained here provide evidence for the important role of structures supporting both direct motor control and mental functions in forming both phases of contingent negative variation. The greater effect of levodopa on the late phase of contingent negative variation suggests that the efferent system of the basal ganglia has a greater role in generating the late phase than in organizing the early phase of the variation.

[Two phases of the contingent negative variation in humans: connection with motor and mental functions].

The question of dependence of the contingent negative variation (CNV) on the regulating mechanisms of motor and mental functions is not sufficiently studied. The tasks of the present work were: to investigate the dependence of the CNV early and late phases on the state of motor and mental functions in patients with Parkinson's disease (PD), and to elucidate the levodopa influence on the CNV parameters. 18 healthy subjects and 56 patients with PD were studied. In PD patients, significant reductions of amplitudes and squares of two CNV phases were observed. A negative correlation of the degree of coordinating muscle relationships disturbance with amplitudes of two CNV phases was found (p < 0.01). A positive interdependence between values of the both CNV phases and the state of mental functions was established, memory in particular (p < 0.05). After levodopa administration in PD patients, the early CNV phase did not significantly change, whereas the late CNV phase significantly increased (p < 0.05). Results of the investigation suggest an important role of the structures ensuring both direct motor control and mental functions in two CNV phases formation. A more obvious levodopa influence on the late CNV phase suggest participation of the basal ganglia efferent system in generation of the late CNV phase rather than in organization of the early CNV phase.

[Effect of cerebrolysin on the electroencephalographic indices of brain activity in Parkinson's disease]. / Elektroéntsefalograficheskie pokazateli deiatel'nosti mozga pri lechenii tserebrolizinom bolezni Parkinsona.

Cerebrolysin is a brain-derived peptide drug that increases the BBB-GLUT1 and MAP2 genes expression, thus exerting a neuroprotective effect. The present study aimed at investigating in patients with Parkinson's disease (PD) influence of Cerebrolysin infusions (intravenously, 10 ml during 10 days) combined with levodopa treatment on the electroencephalographic (EEG) indices of brain activity: P300 potential, contingent negative variation (CNV) and recovery functions of the cortical auditory evoked potentials, which reflect the postexcitatory inhibition at the paired stimulation. Nineteen PD patients, mean age 61.4 +/- 1.7 years; disease stage according to M.M. Hoehn and M.D. Yahr, 1967-2.2 +/- 0.1) and 18 age-matched healthy controls were studied. In the patients with essential differences of the EEG indices, comparing to the normal values, statistically significant changes were revealed: a decrease of P300 latency from 419.4 +/- 23.5 to 356.3 +/- 18.4 ms (8 patients, 42%); an increase of CNV duration from 423.1 +/- 93.3 to 600.6 +/- 38.5 ms; 2-fold increase of CNV mean amplitude and 3-fold increase of CNV square (8 patients, 42%) and strengthening of postexcitatory inhibition in auditory system at the paired stimulation (13 patients, 68%). In conclusion, Cerebrolysin may be recommended as an additional neuroprotective drug for brain functions improvement in the complex pathogenetic therapy of earlier PD stages.

[The use of amantadine sulfate in combined therapy of Parkinson's disease]. / Primenenie amantadina sul'fata v kompleksnoi terapii bolezni Parkinsona.

The efficacy of PK-Merz medication has been studied in 17 patients with Parkinson's disease (PD), who have developed a resistance to levodopa as a result of a long-term treatment. The efficacy was evaluated according to clinical symptoms (UPDRS) and electromyography (EMG) indices. The summary motor score measured by UPDRS estimated as 49-79 (58.1 +/- 3.2) one hour after a single levodopa/carbidopa intake, decreased to 36-65 (45.2 +/- 2.9, p < 0.05) after levodopa/carbidopa combination with i.v. PK-Merz infusion. The biceps and triceps resting EMG amplitude and values of its variance also decreased significantly (p < 0.01). The percentage of the registered burst muscle discharges of 4-7 Hz frequency reduced from 32 to 13%. Under functional stress, the reflex antagonist muscle co-activation decreased in the majority of the patients. Selective correlations were found between the EMG indices and some UPDRS PD symptom scores. PK-Merz improves both motor functions and muscle coordination in PD.

Geriatric men at altitude: hypoxic ventilatory sensitivity and blood dopamine changes.

BACKGROUND: Short-term exposure to high-altitude hypoxia increases hypoxic ventilatory sensitivity (HVS) in healthy humans. Dopamine (DA) is the implicated neurotransmitter in carotid body (CB) chemoreceptor response, and the microenvironmental conditions in CB tissue are comparable to blood. Continuous DA infusion affected ventilation in animals and humans. Age-related oscillations in blood DA levels may influence peripheral chemoreflexes. OBJECTIVE: Hypoxic ventilatory responses (HVR) relative to blood DA concentration and its precursor, dihydroxyphenylalanine (DOPA) was measured in young and elderly men during short-term altitude adaptation. METHODS: Nine elderly climbers (group 1:61+/-1.4 years) and 7 young healthy subjects (group 2: 23+/-2 years) were tested at sea level on day 0, on day 3 after passive transport to 2,200 m, and on day 14 after climbing to 4,200 and 5,642 m. RESULTS: Sea level HVR in group 1 was 47% lower than in group 2, accompanied by higher blood DOPA (300%) and DA (37%) content. Initial DA and DOPA concentrations showed a negative correlation with initial HVR but a positive correlation with age. Passive transport to middle altitude (2,200 m) increased HVS, doubling HVR slopes in groups 1 and 2 and producing increased maximum expired minute ventilation during isocapnic rebreathing (29 and 28%, respectively). Day 3 2,200-meter blood DOPA content decreased by 22% in group 1 and increased by 300% in group 2. DA increased in both groups. CONCLUSION: The relationship between HVR and the reciprocal DA and DOPA values seen in both groups is associated with age, producing decreased DA receptor sensitivity and enhanced DA reuptake during adaptation to high altitude.

Human hypoxic ventilatory response with blood dopamine content under intermittent hypoxic training.

Adaptation to intermittent hypoxia can enhance a hypoxic ventilatory response (HVR) in healthy humans. Naturally occurring oscillations in blood dopamine (DA) level may modulate these responses. We have measured ventilatory response to hypoxia relative to blood DA concentration and its precursor DOPA before and after a 2-week course of intermittent hypoxic training (IHT). Eighteen healthy male subjects (mean 22.8+/-2.1 years old) participated in the study. HVRs to isocapnic, progressive, hypoxic rebreathing were recorded and analyzed using piecewise linear approximation. Rebreathing lasted for 5-6 min until inspired O2 reached 8 to 7%. IHT consisted of three identical daily rebreathing sessions separated by 5-min breaks for 14 consecutive days. Before and after the 2-week course of IHT, blood was sampled from the antecubital vein to measure DA and DOPA content. The investigation associated pretraining high blood DA and DOPA values with low HVR (r = -0.66 and -0.75, respectively), elevated tidal volume (r = 0.58 and 0.37) and vital capacity (r = 0.69 and 0.58), and reduced respiratory frequency (r = -0.89 and -0.82). IHT produced no significant change in ventilatory responses to mild hypoxic challenge (Peto2 from 110 to 70-80 mm Hg; 1 mm Hg = 133.3 Pa) but elicited a 96% increase in ventilatory response to severe hypoxia (from 70-80 to 45 mm Hg). Changes in HVRs were not accompanied by statistically significant shifts in blood DA content (24% change), although a twofold increase in DOPA concentration was observed. Individual subject's changes in DA and DOPA content were not correlated with HVR changes when these two parameters were evaluated in relation to the IHT. We hypothesize that DA flowing to the carotid body through the blood may provoke DA autoreceptor-mediated inhibition of endogenous DA synthesis-release, as shown in our baseline data.

Intermittent hypoxia alters hypoxic ventilatory responses.

Intermittent hypoxic training (IHT) shows promise for prevention and treatment of some diseases and efficiently produces great advancement in athletic training. We studied (1) hypoxic ventilatory responses (HVR) in supine and sitting positions during normobaric, isocapnic, progressive hypoxia (rebreathing technique) and (2) lung ventilation and gas exchange while breathing ambient air at rest and during 5 min of breathing 11% O2. Duel measurements were made pre- and post-15-day IHT regimen on 12 (experimental) healthy males (24.6 y.o. +/- 1.9 y.o.) and on 6 (control) healthy males (24.2 y.o. +/- 2.3 y.o.) given pseudo-IHT (p-IHT) without decreasing PiO2. IHT involved rebreathing eucapnic (chemically absorbed) air as P(ET)O2 decreased to 35 mmHg, three 6-7 min sessions, three times a day, with 10 min breaks between each session over a 15 day training period. Without IHT, HVRs were the same in sitting and supine positions at low levels of hypoxic challenge (slope one--S1: P(ET)O2 from 110-60 mm Hg) and significantly higher (by 45%) during severe hypoxia (slope two--S2: P(ET)O2 from 60-35 mm Hg). IHT caused an increase in HVR in both sitting and supine positions: S1 by 70 and 100%, S2 by 158 and 200%, maximal lung ventilation by 35 and 78%, respectively. There were no significant changes in the p-IHT group. IHT also caused enhanced respiratory reactions during sustained hypoxia (lung and alveolar ventilation increased by 36 and 22%, respectively). A striking hypoxic ventilatory sensitivity was noted in subjects with hyper-reactive breathing patterns.

[Regional distribution of the brain steady potential level in patients with Parkinson's disease]. / Regional'noe raspredelenie urovnia postoiannogo potentsiala golovnogo mozga u bol'nykh Parkinsonizmom.

Regional distribution of the brain steady potential level (SPL) was shown to depend on the predominant clinical symptom in parkinsonian patients. Those with prevailing bradykinesia revealed a statistically significant decrease in the SPL in the frontal area as compared with the healthy subjects or the patients with prevailing tremor.

[Serotonin antibodies and their possible role in parkinsonism]. / Antitela k serotoninu i ikh vozmozhnaia rol' pri parkinsonizme.

Serotonin antibodies (SAb) were found in the blood sera of middle-aged and elderly parkinsonian patients. The incidence of Sab in young and middle-aged healthy subjects was less, but increasing with age. Injected into the rabbit caudate nuclei, Sab suppressed the main pathogenetic mechanism of parkinsonian syndrome, the generator of pathologically enhanced excitation (GPEE) and parkinsonian symptoms induced by the MPP injection into substantia nigra. The intracaudate injection of serotonin enhanced GPEE activity and parkinsonian syndrome. The role of serotoninergic system and Sab in parkinsonism is discussed.

[Dopamine antibodies in parkinsonism patients and their possible role in the pathogenesis of the parkinsonian syndrome]. / Antitela k dofaminu u bol'nykh parkinsonizmom i ikh vozmozhnaia rol' v patogeneze parkinsonicheskogo sindroma.

Dopamine antibodies (DAb) were found in the blood serum of parkinsonian patients, middle-aged and elderly, but not young. There was a correlation between the DAb incidence and dominant symptom in the middle-aged and elderly patients and between DAb and anginal parkinsonism in the elderly patients. DAb-binding serum gamma-globulins of parkinsonian patients injected into rat caudate nuclei induced the pathogenetic mechanism of Parkinson's syndrome (the generator of pathologically enhanced excitation-GPEE) in this brain part and evoked main parkinsonian symptoms (oligokinesia, rigidity and tremor). This effect was more expressed in the elderly rats compared with the young animals. The DAb role in the Parkinson's syndrome pathogenesis and in L-DOPA therapeutic tolerance formation is discussed.

[Dopamine antibodies in the pathogenesis of parkinsonism]. / Antitela k dopaminu v patogeneze parkinsonizma.

L-DOPA and dopamine (DA) binding antibodies were found in the blood serum of Parkinsonian patients and middle-aged and elderly normal persons. DA-binding serum gamma-globulins of parkinsonian patients injected into rat caudate nuclei induced the pathogenetic mechanism of Parkinson's syndrome (generator of pathologically enhanced excitation) in these brain part and evoked main parkinsonian symptoms (oligokinesia, rigidity, tremor). The serum gamma-globulins of Parkinsonian patients without Da-antibodies caused less pronounced EEG disturbances. Parkinsonian symptoms developed rarely and were shorter and less pronounced compared with the DA-antibody effect. The DA binding antibodies role in Parkinson's syndrome pathogenesis and is L-DOPA therapeutic tolerance formation was discussed.

[The dynamics of the cerebral circulation and of brain functional activity in patients with initial atherosclerotic encephalopathy under the influence of a single intravenous administration of sermion]. / Dinamika mozgovogo krovoobrashcheniia i funktsional'noi aktivnosti mozhga u bol'nykh s nachal'noi ateroskleroticheskoi éntsefalopatiei pod vliianiem odnokratnogo vnutrivennogo vvedeniia sermiona.

The efficacy of sermion was studied in 41 patients of the middle and elderly ages. The reactive changes in the parameters of the cerebral circulation (the frontomastoidal RhEG), total hemodynamics, frequency-integration characteristics of EEG and visual evoked potentials at the administration of 2 mg and 4 mg of sermion were shown. There are given recommendations for the differential approach to the choice of the drug doses in the elderly persons taking into consideration the parameters of the background reactivity of the CNS and the state of vascular regulation.

[Central mechanisms of the development of motor disorders during human aging]. / Tsentral'nye mekhanizmy razvitiia dvigatel'nykh narushenii pri starenii cheloveka.

This paper deals with the functional state of the brain and its descending regulatory influences on the brain stem-spinal formations in the elderly. The role of changes revealed in the formation of the clinical syndrome of age-related extrapyramidal insufficiency (EPI) as a risk factor of Parkinson's disease, has been shown. 274 apparently healthy subjects aged from 20 to 102 and 136 patients with early stages of Parkinson's disease were examined. The program of the neurophysiological investigation included: frequency-integrative analysis of EEG, visual and somatosensory potentials, simple motor reaction time and stimulating electroneuromyography (H reflex). It has been found that in aging and in Parkinson's disease one-directional changes in the CNS function that form age-related and pathologic EPI occur. The complex of neurophysiological indices is a reflection of the CNS influence on the underlying spinal formations, and it can be used for early diagnostics of the motor disorders in aging.

[Catecholamines in the blood of parkinsonism patients]. / Katekholaminy v krovi bol'nykh parkinsonizmom.

Data are reported on age aspects of blood catecholamine metabolism in parkinsonism patients of middle and elderly age. The content of adrenalin, noradrenalin, dopamine was determined in the blood plasma of 95 patients with parkinsonism and in 75 practically healthy persons of similar age (control). Changes were shown of metabolism biogenic amines depending on the level of drug correction of parkinsonism and stage of the clinical course of the disease.

[Age-related features of the functional state of the brain in patients with circulatory encephalopathy]. / Vozrastnye osobennosti funktsional'nogo sostoianiia golovnogo mozga u bol'nykh distsirkuliatornoi éntsefalopatiei.

Complex clinico-physiological examinations was performed in 300 patients of middle and old ages with early and pronounced dyscirculatory encephalopathy of atherosclerotic and, in most cases, hypertensive etiologies. The cerebral hemodynamics was found to be relatively independent of the central one in patients with early atherosclerotic encephalopathy; the level of the systemic circulation and that of the median regional cerebral flow were found to correlate in early and advanced hypertensive encephalopathy cases. The cerebral function was shown to be more associated with the cerebral flow in the early encephalopathy in elderly patients than in middle-aged ones. The individual and personal traits of the patients were largely related to the disease stage rather than to the predominant etiological factor.

[Initial dyscirculatory encephalopathy in middle-aged and elderly patients (problems of early diagnosis and therapy)]. / Nachal'naia distsirkuliatornaia éntsefalopatiia u bol'nykh srednego i pozhilnogo vozrasta (voprosy rannei diagnostiki i terapii).

Combined clinicophysiological investigation was performed in IDE (195 patients) in order to assess the degree of cerebral circulation disorders and their impact on the levels of brain functional activity. The informative values of several quantitative indices of brain hemodynamics and neurodynamics were assessed with respect to the patients' age. Single administration and full course of cavinton and sermion (nicergoline) were effective as judged by cerebral circulation studies (133Xe clearance), brain bioelectric activity (EEG frequency integration analysis, visual evoked potentials). In senile patients, the effect of i.v. sermion administration was dose-dependent.