An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models.

Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (l-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other l-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of l-DOPA, were evaluated in two monkey models of PD (i) the gold-standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits. Behavioural analyses in l-DOPA-primed MPTP-treated macaques showed that istradefylline alone specifically alleviated postural deficits. When combined with an optimal l-DOPA treatment dose, istradefylline increased on-time, enhanced therapeutic effects on bradykinesia and locomotion, but exacerbated dyskinesia. Istradefylline treatment at specific doses with sub-optimal l-DOPA specifically alleviated bradykinesia. Cognitive assessments in CLD MPTP-treated macaques showed that the attentional and working memory deficits caused by l-DOPA were lowered after istradefylline administration. Taken together, these data support a broader clinical use of istradefylline as an adjunct treatment in PD, where specific treatment combinations can be utilised to manage various l-DOPA-induced complications, which importantly, maintain a desired anti-parkinsonian response.

Selenium reduces bradykinesia and DNA damage in a rat model of Parkinson's disease.

OBJECTIVE: The aim of this study was to explore the effects of selenium (Se) on locomotor activity and DNA damage in a rat model of Parkinson's disease (PD) induced by paraquat (PQ). METHODS: Forty-eight male Wistar rats were divided into four groups: control group (n = 12), Se group (n = 12), PQ group (n = 12), and Se + PQ group (n = 12). PQ was administered intraperitoneally (10 mg/kg). Se was offered in the drinking water at a concentration of 11.18 µg/L. Locomotor activity was evaluated weekly using the narrow beam test. The comet assay was performed to assess the level of DNA damage in leukocytes and in brain cells. RESULTS: As expected, increased DNA damage was found in the PQ group compared with the control and Se groups (P < 0.001). Interestingly, coadministration of Se and PQ effectively prevented the harmful effects of the toxin in locomotor activity and at the molecular level, reducing bradykinesia (P < 0.01) and DNA damage in leukocytes compared with the PQ-only group (P < 0.001), whereas the levels of DNA damage were comparable to those found in the control and Se groups (P > 0.05). Using the comet assay to analyze brain cells, no differences were found between the groups with regard to damage index (P = 0.774), damage frequency (P = 0.817), or non-detectable cell nuclei (P = 0.481). CONCLUSION: In this experimental model of PQ-induced PD, the use of Se could contribute to the maintenance of locomotor activity and the integrity of leukocytes DNA. No changes in the levels of DNA damage in brain cells were observed between the experimental groups.

Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study.

OBJECTIVE: The use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non-motor symptoms of PD. METHODS: Twenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. RESULTS: Mean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P < 0.001). Analysis of specific motor symptoms revealed significant improvement after treatment in tremor (P < 0.001), rigidity (P = 0.004), and bradykinesia (P < 0.001). CONCLUSIONS: There was also significant improvement of sleep and pain scores. No significant adverse effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.

[Effect of melatonin on activity of superoxide dismutase (CuZn-SOD) in erythrocytes of patients during short- and long-term hypokinesis]. / Wplyw melatoniny na aktywnosc dysmutazy ponadtlenkowej (CuZn-SOD) w krwinkach czerwonych chorych w okresie hipokinezji krótko- i dlugoterminowej.

INTRODUCTION: Short- or long-lasting hypokinesis is to a large degree the consequence of negative habits of human beings towards a comfortable and more sedentary lifestyle. The period of decreased physical activity can cause disturbance in the balance between systemic processes of the oxidation and reduction, which leads to an increase in reactive oxygen species (ROS) and oxidative stress generation. The aim of the study was to determine the effect of melatonin administration on the cellular superoxide dismutase (CuZn-SOD) activity in red blood cells of patients with short- and long-term hypokinesis as compared to the group of subjects with normal physical activity. MATERIAL AND METHODS: The study included 33 subjects with immobilization. The study group was divided into two subgroups (depending on hypokinesis duration): group A: 15 subjects classified for total hip alloplasty (a short-lasting decrease in physical activity); group B: 18 subjects suffering from multiple sclerosis or the stroke of brain (the long-term hypokinesis). The control group (group C) comprised 17 subjects with normal physical activity. Melatonin was applied at a dose of 5 mg daily, one hour before sleep. The CuZn-SOD activity in red blood cells was determined, according to the Misra and Fridovich method, in two periods: 1) on the first day, 2) on the 10th day (group A), and 30 days (group B) after melatonin administration. RESULTS: A slight increase in CuZn-SOD activity (+3.1%) was observed in group A 10 days after alloplasty and melatonin administration as compared to group B, where a considerable rise in the enzyme activity (+23.3%) was found 30 days after rehabilitation and melatonin supplementation. The average CuZn-SOD activity in both investigative groups was lower than that in the controls (group C). CONCLUSIONS: It was estimated that the short- and long-lasting hypokinesis leads to an increase in ROS generation, what is confirmed by the increase in CuZn-SOD activity. The results of the study on superoxide dismutase activity indicate that oral administration of melatonin for the period of 30 days has a more favorable influence on antioxidative processes than 10-day's melatonin intake.

Phosphate measurements during hypokinesia and phosphate supplements in disclosing phosphate changes in hypokinetic subjects.

BACKGROUND: Hypokinesia (diminished movement) induces significant phosphate (P) change, however, little is known about P retention and P depletion during hypokinesia (HK). Measuring P retention and P balance during HK and P supplementation, the objective of this work was to disclose whether HK could contribute to the decreased P retention and consequently to P depletion in normal subjects. METHODS: Studies were done during 30 days pre-HK period and 364 days HK period. Forty normal male individuals aged, 25.3+/-6.4 years were chosen as subjects. They were divided equally into 4 groups: unsupplemented active control subjects (UACS), unsupplemented hypokinetic subjects (UHKS), supplemented active control subjects (SACS) and supplemented hypokinetic subjects (SHKS). Hypokinetic subjects were limited to an average walking distance of 0.5 km day-l, while active control subjects were kept on an average running distance of 9.6 km day-l. Both, SHKS and SACS received daily 14 mmol dicalcium phosphate per kg body weight. RESULTS: Negative P balance, fecal P, urinary calcium (Ca) and P excretion, serum P and total (Cat) level increased significantly (p<0.05) while P retention, serum intact parathyroid hormone (iPTH), 1,25 dihydroxyvitamin D (1,25 (OH)2 D3) and thyrocalcitonin (TC) decreased significantly (p<0.05) in SHKS and UHKS compared with their pre-HK values and their respective active controls (SACS and UACS). However, negative P balance, P retention incapacity, serum, fecal and urinary P level increased significantly (p<0.05) more in SHKS compared with UHKS. Fecal P loss, urinary P and Ca loss, serum P and Cat level, iPTH, TC and 1,25 (OH)2 D3 level, P retention and P balance change insignificantly (p>0.05) in SACS and UACS compared with their pre-HK level. CONCLUSIONS: It was concluded that a significant P excretion in urine and feces in spite of negative P balance and P supplementation may demonstrate reduced P retention, while a significant increase of negative P balance may demonstrate P depletion. Clearly, P intake, regardless of its low or higher dose, was significantly wasted during HK probably due to the decreased ability of the body to retain P.

Effect of fluid and salt supplementation on body hydration of athletes during prolonged hypokinesia.

Body hydration decreases significantly during hypokinesia (HK) (diminished movement), but little is known about the effect of fluid and salt supplements (FSS) on body hydration during HK. The aim of this study was to measure the effect of FSS on body hydration during HK. Studies were done during 30 days pre HK period and 364 days HK period. Thirty male athletes aged 24.5 +/- 6.6 yr were chosen as subjects. They were equally divided into three groups: unsupplemented ambulatory control subjects (UACS), unsupplemented hypokinetic subjects (UHKS) and supplemented hypokinetic subjects (SHKS). Hypokinetic subjects were limited to an average walking distance of 0.7 km day-1. The SHKS group took daily 30 ml of water/kg body weight and 0.1 g of sodium chloride (NaCl)/kg body weight. Control subjects experienced no changes in their professional training and routine daily activities. Plasma volume (PV), urinary and plasma sodium (Na) and potassium (K), plasma osmolality, plasma protein, whole blood hemoglobin (Hb) and hematocrit (Hct), plasma renin activity (PRA) plasma aldosterone (PA) levels, physical characteristics, food and fluid intakes were measured. Plasma osmolality, plasma protein, urinary and plasma Na and K, whole blood Hct and Hb, PRA and PA levels decreased significantly (p < or = 0.01), while PV and body weight increased significantly (p < or = 0.01) in the SHKS group when compared with the UHKS group and did not change when compared with the UACS group. Plasma osmolality, plasma protein, urinary and plasma Na and K, PRA and PA, whole blood Hb and Hct levels increased significantly (p < or = 0.01), while PV body weight, food and fluid intakes decreased significantly (p < or = 0.01) in UHKS group when compared with the SHKS and UACS groups. The measured parameters did not change in the UACS group when compared with their baseline control values. It was shown that during HK body hydration decreased significantly, while during HK and FSS body hydration increased significantly. It was concluded that daily intake of FSS prevents the decrease of PV and blunts the increase of activity of the PRA and PA during prolonged HK.

Potassium supplements' effect on potassium balance in athletes during prolonged hypokinetic and ambulatory conditions.

Electrolyte supplements may be used to prevent changes in electrolyte balance during hypokinesia (diminished movement). The aim of this study was to measure the effect of potassium (K) supplements on K balance during prolonged hypokinesia (HK). Studies were done during 30 d of a pre-HK period and during 364 d of an HK period. Forty male athletes aged 25.1+/-4.4 yr were chosen as subjects. They were divided equally into four groups: unsupplemented ambulatory control subjects (UACS), unsupplemented hypokinetic subjects (UHKS), supplemented hypokinetic subjects (SHKS) and supplemented ambulatory control subjects (SACS). The SHKS and UHKS groups were kept under an average walking distance of 0.7 km/d. The SACS and SHKS groups were supplemented daily with 50.0 mg elemental potassium chloride (KCl) per kilogram body weight. The K balance, fecal K excretion, urinary K, sodium (Na), and chloride (Cl) excretion, plasma K, Na, and Cl concentration, plasma renin activity (PRA) and plasma aldosterone (PA) concentration, anthropometric characteristics and peak oxygen uptake were measured. Negative K balance, fecal K excretion, urinary K, Na, and Cl excretion, plasma K, Na, and Cl concentration, and PRA and PA concentration increased significantly (p < or = 0.01), whereas body weight and peak oxygen uptake decreased significantly in the SHKS and UHKS groups when compared with SACS and UACS groups. However, the measured parameters changed much faster and much more in SHKS group than UHKS group. By contrast, K balance, fecal, urinary, and plasma K, plasma hormones, body weight, and peak oxygen uptake did not change significantly in the SACS and UACS groups when compared with the baseline control values. It was concluded that prolonged HK induces a significant negative K balance associated with increased plasma K concentration and urinary and fecal K excretion. However, negative K balance appeared much faster and was much greater in the SHKS group than UHKS group. Thus, K supplementation was not effective in preventing negative K balance during prolonged HK.

[The effect of GABA-ergic agents on the electrolyte balance under hypokinesia]. / Vliianie GAMK-ergicheskikh sredstv na balans élektrolitov v usloviiakh gipokinezii.

The effect of hypokinesia on the blood electrolyte balance was studied. In restricted motor activity marked deviations of the type of hypokalemia and hypercalcemia were encountered, which could promote the development of various pathological processes, including disorder of central and regional hemodynamics. GABA and piracetam had no effect on the blood serum electrolyte content in the early periods of hypokinesia. In later periods of hypokinesia both drugs under examination corrected the disorders of blood electrolyte balance induced by prolonged restriction of motor activity.

[The effect of GABA and piracetam on the qualitative and quantitative composition of the brain phospholipids in rats under hypokinetic conditions]. / Vliianie GAMK i piratsetama na kachestvennyi i kolichestvennyi sostav fosfolipidov golovnogo mozga krys v usloviiakh gipokinezii.

The influence of hypokinesia on phospholipid composition of the brain tissue was investigated. Hypokinesia was found to cause significant disorders in the phospholipid composition. Changes exhibit a phase character and are more pronounced on the 15-th and 30-th days of hypokinesia. The use of GABA and pyracetam promotes the processes aimed at normalization of the phospholipid metabolism in the brain tissue.

Fluid-electrolyte changes in physically conditioned subjects after hypokinesia and chronic hyperhydration.

The aim of this study was to determine whether fluid-electrolyte changes, which are developed during prolonged hypokinesia (decreased number of km per day), can be prevented or minimized with the use of a daily intake of fluid and salt supplementation (FSS). The experiments on hypokinesia (HK) were performed for 364 days on 18 endurance-trained male volunteers in the age range of 21-23 years, with an average maximum oxygen uptake of 67 ml kg-1. All volunteers were divided into three equal groups: six volunteers were placed on a continuous regime of exercise of 14.0 km day-1 and served as control subjects. Six volunteers were subjected to continuous HK without FSS and were considered as the unsupplemented hypokinetic subjects (UHS). The remaining volunteers were under continuous HK and FSS and were considered as the supplemented hypokinetic subjects (SHS). For the simulation of the hypokinetic effect, the UHS and SHS groups were kept continuously under an average of 2.7 km day-1 for the duration of the experiment. Prior to exposure to HK, all volunteers were on the same exercise regime as the controls. During the pre-experimental period of 60 days and during the post-experimental period, urinary excretion of electrolytes and concentrations of sodium, potassium, calcium and magnesium in serum as well as serum osmolality were determined. An increased renal excretion of fluid and electrolytes and a decreased serum electrolyte concentration were observed in the SHS, while a decreased renal excretion of fluid and electrolytes and an increased serum electrolyte concentration were observed in the UHS, during the initial stages of the post-hypokinetic period. By day 30 of the post-hypokinetic period these changes were reverted back to the control levels. We concluded that chronic hyperhydration may be used to attenuate urinary and serum electrolyte changes in endurance-trained volunteers after exposure to prolonged HK.

Effect of potassium and calcium loading on healthy subjects under hypokinesia and physical exercise with fluid and salt supplements.

The objective of this investigation was to determine the acute responses to the electrolyte challenges under hypokinesia and physical exercise (PE) of different intensities with fluid and salt supplementation (FSS). The studies were performed on 12 physically healthy male volunteers aged 19-24 years under 364 days of hypokinesia (decreased number of steps per day) with a set of PE with FSS. The volunteers were divided into two equal groups. The first group was subjected to a set of intensive PE and the second group was submitted to a set of moderate PE. Both groups of subjects consumed daily water and salt supplements that aimed to increase the body hydration level. For simulation of the hypokinetic effect all subjects were kept under an average of 3000 steps per day. Functional tests with a potassium chloride (KCl) and calcium lactate (Cal) load were performed during the hypokinetic period of 364 days and the 60-day, prehypokinetic period that served as control, while both groups of subjects consumed daily calcium and potassium supplements. The concentration of electrolyte and hormone levels in the blood and their excretion rate in urine were determined. Renal excretion of calcium and potassium and the blood concentration thereof increased markedly in both groups of subjects. With the potassium chloride load tests the increased potassium excretion was accompanied by higher aldosterone and insulin blood levels, and with the calcium lactate load tests the increased calcium excretion was accompanied by a decreased parathyroid content in the blood. FSS and PE, regardless of intensity, failed to attenuate calcium and potassium losses. Additional intake of KCl and Cal also failed to normalize potassium and calcium abnormalities. It was concluded that during the KCl and Cal loading tests, the increased losses of potassium and calcium in the hypokinetic subjects were due to the inability of their bodies to retain these electrolytes, and that electrolyte abnormalities could not be reversed by PE or rehydration in individuals subjected to prolonged restriction of motor activity.

Chronic hyperhydration and hematological changes in trained subjects during prolonged restriction of motor activity.

The objective of this investigation was to evaluate the effect of a daily intake of fluid and salt supplementation (FSS) on the hemoglobin content of endurance trained athletes during hypokinesia (decreased number of steps from 10,000 to 3000 steps per day). The studies were performed on 30 long-distance runners who had a VO2max average of 66 ml kg-1 min-1 and were in the age range of 19-24 years. Prior to their exposure to hypokinesia (HK) of 364 days, all volunteers were on an average of 10,000 steps per day. All volunteers were divided into three equal groups: the first group underwent normal ambulatory life (control subjects), the second group was kept under continuous restriction of motor activity (hypokinetic subjects), and the third group was placed under continuous restriction of motor activity and consumed 26 ml water kg-1 body weight daily and 0.1 g sodium chloride kg-1 body weight in the form of supplementation (hyperhydrated subjects). For simulation of the hypokinetic effect, the number of steps taken per day by the second and third groups of volunteers was restricted to an average of 3000. During the hypokinetic period we determined reticulocytes (Rt), hemoglobin (Hb), hematocrit (Hct), plasma volume (PV), red blood cell (RBC) mass and VO2max. In hyperhydrated volunteers the content of Hb and Hct decreased significantly, while PV, RBC mass and Rt count increased significantly. In hypokinetic volunteers Hb and Hct increased, while PV, RBC and Rt decreased significantly. It was concluded that chronic hyperhydration may be used to attentuate an increase in the Hb content of physically conditioned subjects during prolonged restriction of motor activity.

Phosphate-loading test influences on endurance-trained volunteers during restriction of muscular activity and chronic hyperhydration.

The purpose of this investigation was to determine whether negative phosphate balance, which is developed during hypokinesia (a decreased number of walking steps/d) could be reversed with daily supplementation with phosphate, fluid, and salt (FSS). The studies on hypokinesia (HK) were performed for 364 d on 30 endurance-trained male volunteers in the age range of 23-26 yr, with an average maximum oxygen uptake, MOU, of 65 mL/kg min. All subjects were divided into three equal groups: Ten volunteers were placed on a continuous regime of exercise of 14.4 km/d at 10,000 steps/d and served as controls. Ten volunteers were subject to continuous HK without FSS and were considered as the hypokinetic subjects (HS). The remaining subjects were under continuous HK and FSS and were considered as the hypokinetic, hyperhydrated subjects (HHS). The three groups were on a diet that averaged 2620 cal/d and contained 1.7 g calcium, 1.6 g phosphate, and 5.6 g sodium chloride. For simulation of the hypokinetic effect, the HS and HHS groups were kept continuously under 2.9 km/d (3000 walking steps/d) for the duration of the study. Prior to exposure to HK, all volunteers were on the same exercise regime as the controls. During a 60-d pre-HK period and during the remainder of the study, phosphate-loading tests, urinary and plasma phosphate concentrations were performed in all subjects. In the HHS group, plasma phosphate concentration and urinary excretion of phosphate were decreased, while in the HS group these values increased after phosphate loading. Based on our results, we concluded that chronic hyperhydration and phosphate supplementation may be used to minimize phosphate losses in endurance-trained volunteers during prolonged restriction of muscular activity.

[The effect of mexidol on the rat periodontium during hypokinesia]. / Vliianie meksidola na parodont krys pri gipokinezii.

During 30-days-long hypokinesia changes in calcium-phosphoric metabolism, glycoprotein state, acid and alkaline phosphatase activity in bone tissue of the low jaw of rats proceed in some stages, that determines the nature of mexidol (3-oxipyridine derivative) effects. The remedy demonstrated the most expressed protective effect on parodontal tissues on the 15th day of animals' mobility limitation. The data obtained show that mexidol effecting hypokinesia develop in some stages and depend on the initial state of the organism. They also reflect indirectly the significance of the antioxidant status of the organism in mineralization of the parodontal bone tissue.