Influence of fluctuations of plasma large neutral amino acids with normal diets on the clinical response to levodopa.

Plasma large neutral amino acids (LNAAs) compete with levodopa for entry into the brain. Fluctuations in plasma LNAA concentrations could therefore contribute to variability in clinical response to levodopa. The hourly plasma levodopa, plasma LNAAs and clinical response were investigated in 11 fluctuating Parkinsonian patients on a regular hospital diet. The fluctuations in plasma levodopa were 2 to 3 times greater than the fluctuations of plasma LNAAs. The correlation between clinical response and plasma levodopa was substantially improved in only one patient by considering plasma LNAAs and calculating relative levodopa flux into brain. Although plasma LNAAs significantly increased during the day, the patients' clinical status did not uniformly deteriorate and mean afternoon clinical scores correlated better with mean plasma levodopa and levodopa flux than with mean plasma LNAAs. Minimum effective concentrations of levodopa for clinical response did not correlate with 9 am LNAA concentrations. It is concluded that in most patients, the relatively small variation in plasma LNAAs in comparison with the large variations in plasma levodopa indicates that fluctuations in LNAA are not an important contributor to the fluctuating response to levodopa.     

Plasma levels of amino acids correlate with motor fluctuations in parkinsonism

Seven patients with Parkinson's disease who experienced severe motor fluctuations in response to levodopa were studied in detail with relation to the effect of dietary protein on their motor function. The levodopa dose for each patient was not changed during the period of study, and no other antiparkinsonian drugs were used. Regular and high-protein diets resulted in a marked elevation in the plasma concentrations of large neutral amino acids (LNAAs) that are known to compete with levodopa for transport across the blood-brain barrier. Despite elevated plasma levodopa levels, all patients with elevated LNAA levels experienced parkinsonian symptoms. When the amino acid level dropped while plasma levodopa levels were elevated, patients experienced relief of these symptoms. On a low-protein diet, LNAA levels remained low and all patients were consistently dyskinetic throughout the day, even though the mean plasma levodopa levels were somewhat lower than when the patients consumed a high-protein diet. A redistribution diet that is virtually protein free until supper and then unrestricted until bedtime is tolerated by patients because this simple manipulation permits near-normal daytime motor function.     

Diurnal rhythm in absolute and relative concentrations of large neutral amino acids in human plasma

In order to obtain detailed information on the diurnal plasma rhythmicity in those large neutral amino acids (LNAA) which compete with each other for carrier-mediated transport from plasma into the brain, blood samples were collected every hour for 24h from six healthy men, aged 25–50 yr. The well-known diurnal rhythm in the concentration of plasma amino acids was confirmed and is described in greater detail in this paper. These data might be helpful in clinical situations where LNAAs (e.g. L-dopa, -methyldopa and tryptophan) are used as therapeutic agents, since these amino acids compete with endogenous LNAAs for carrier-mediated transport from plasma into the brain. Furthermore, it was found that the amplitude of variation differed between the individual LNAAs. In addition the relationships between them, expressed as ratios of the concentrations of each single LNAA to total LNAA concentration also possess diurnal rhythms, different from those observed in absolute LNAA concentrations. This rhythmicity in relative LNAA concentrations might be of importance for brain function, since altered relationships between LNAAs in plasma might bring about altered concentrations of LNAAs in the brain and consequently, in monoamine synthesis.     

Protein intake in Parkinsonian patients using the EPIC food frequency questionnaire.

The dietary habits of 45 Italian patients with Parkinson's disease (PD) and their spouses were investigated using the EPIC food frequency questionnaire. Average daily energy intake was similar, but PD patients consumed significantly more vegetable proteins and carbohydrates (both +18%; P = 0.01 and P = 0.001, respectively). Daily protein intake, which interferes with levodopa absorption, was 50% higher than the recommended daily allowance (1.2 vs. 0.8 g/kg) in both PD patients and spouses and was significantly higher in patients with moderate/severe symptoms (1.27 +/- 0.29 vs. 1.07 +/- 0.28 g/kg; P < 0.001). In patients taking levodopa, there was a correlation between daily levodopa dosage and protein intake (P = 0.027). Dietary habits of patients with advanced and/or fluctuating PD should always be checked, with particular reference to protein intake.     

Transcranial imaging of audiogenic epileptic foci in the cortex of DBA/2J mice

Exposure to intense sound stimuli induces audiogenic seizures in DBA/2J mice. We investigated cortical activities during sound stimulation using flavoprotein fluorescence imaging. Most DBA/2J mice had seizures during intense sound stimulation, with more than half surviving after seizures. Surviving mice were anesthetized with urethane (1.6 g/kg, intraperitoneal), and the skull was exposed and then covered with clear resin. More than 3 days after surgery, the mice were lightly anesthetized with urethane (0.8 g/kg) and cortical activities during intense sound stimulation were visualized. Focal responses appeared near the somatosensory cortex together with spike activities localized in the response area. These findings indicate that epileptic foci of audiogenic seizure are formed in the cortex of DBA/2J mice.     

关节软骨及骨破坏模型大鼠经盐酸氨基葡萄糖干预的最佳剂量

背景：研究表明盐酸氨基葡萄糖可减轻骨关节炎的症状并能保护关节软骨,但该药的最佳剂量至今尚无共识。 目的：观察盐酸氨基葡萄糖对由白陶土与鹿角菜胶诱发大鼠关节炎的治疗最低有效剂量。 方法：将SD大鼠分别用蒸馏水,盐酸氨基葡萄糖溶液0.4,0.8及1.6 g/kg灌胃,采用白陶土与鹿角菜胶诱发大鼠单发关节炎模型。建模后1,3,5 d,用容积测量法测定各组大鼠的左右后肢足跖体积,计算足跖肿胀度。用游标卡尺测定其胫跗骨关节最大径;测定足跖伊文思蓝含量,右足跖制备组织切片,染色后镜下观察其病变程度并进行评分。 结果与结论：给予大鼠盐酸氨基葡萄糖1,3和5 d后,盐酸氨基葡萄糖0.8及1.6 g/kg组大鼠右后足跖肿胀度及胫跗骨关节径明显小于模型组(P < 0.05或P < 0.01),足跖肿胀度及胫跗骨关节径均有随给药剂量增大而减小。给药5 d后,盐酸氨基葡萄糖0.8及1.6 g/kg组大鼠右后足跖伊文思蓝含量及组织病理学评分明显小于模型组(P < 0.05或P < 0.01)。结果提示,盐酸氨基葡萄糖能够有效地预防骨关节炎关节软骨和骨的破坏,并可预防关节周围组织炎症,其最低有效剂量为0.8 g/kg。     

A prospective study of the modified Atkins diet for intractable epilepsy in adults

PURPOSE: The ketogenic diet is not typically offered to adults with epilepsy due to the significant lifestyle alterations needed for its use. The modified Atkins diet has been recently demonstrated to be therapeutic for children without the need for an admission, fasting period, weighing of foods, or fluid, calorie, and protein restriction. METHODS: A prospective, open-label study was performed of adults over 18 years of age, having at least weekly seizures and prior use of at least two anticonvulsants. Carbohydrates were initially restricted to 15 g/day, fats were encouraged, and fluids, protein, and calories were allowed ad lib. RESULTS: Thirty patients, with age ranging from 18 to 53 years, were enrolled. Using an intent-to-treat analysis, 47% had a >50% seizure reduction after 1 and 3 months on the diet; 33% after 6 months. In those with seizure reduction, the median time to improvement was 2 weeks (range: 1-8 weeks). The mean weight loss was 6.8 kg, p < 0.001. Body-mass index (BMI) decrease correlated with efficacy at 3 months, p = 0.03. Ten subjects (30%) discontinued the diet prior to 3 months. Side effects included increased cholesterol (mean 187 to 201 mg/dL), blood urea nitrogen (BUN; 13 to 16 mg/dL), and urine calcium to creatinine ratio (0.14 to 0.19). CONCLUSIONS: A modified Atkins diet appears to demonstrate preliminary efficacy for adults with intractable epilepsy, especially in those who lost weight. Considering the rapid response in those who improved, but somewhat high discontinuation rate, a 2-month trial period may be adequate to assess for efficacy.     

Is rat brain content of large neutral amino acids (LNAAs) a reflection of plasma LNAA concentrations?

Summary Competition between the large neutral amino acids (LNAAs), including the monoamine precursors tyrosine and tryptophan, for the carrier-mediated transport from plasma into the brain is considered the major regulator of brain LNAA content. The plasma ratio of each LNAA to the sum of all LNAAs, previously, in standardized experiments, has proved an excellent predictor of brain LNAA content. To investigate how diurnal variations in plasma LNAAs are reflected in the brain, we have killed rats, in groups of six, every l h throughout one 24 h period.The concentration of each LNAA in both plasma and brain varied with time-of-day. Also the total concentration of LNAAs in brain was shown to vary diurnally. Obviously, variations in total brain LNAA concentration cannot be explained by changes in plasma LNAA ratios. Consequently, other factors, contributing to the regulation of the diurnal rhythm in brain LNAA content, must be considered.     

Feeding and drinking in rats maintained on a low protein diet

Male and female rats born of protein malnourished mothers were fed a low-protein diet (8% casein) for 150 days after weaning and daily food and water intakes and body weights were monitored. Although daily intakes of diet throughout the study were significantly lower than those of rats maintained on a normal protein diet (25% casein) or stock diet, intakes/100 g body weight were significantly greater. Daily increments in body weight, as percent of previous day's weight, were consistently higher in rats fed the low-protein diet in comparison to rats fed the normal protein diet. Marked retardation of body growth was evident throughout the study although feeding efficiency ratios (daily body wt. increment per g daily food intake) were comparable among the various dietary groups. Compensation for reduction of the protein component of the diet by increased daily food intake/100 g body weight did not alleviate growth retardation.     

Low‐protein and protein‐redistribution diets for Parkinson's disease patients with motor fluctuations: A systematic review

The American Academy of Neurology suggests advising the redistribution of daily protein meal content to every Parkinson's disease (PD) patient with motor fluctuations during levodopa treatment. However, no comprehensive evaluation of this complementary therapy has been performed. A systematic review of intervention studies investigating the neurologic outcome of low‐protein (<0.8 g/kg of ideal weight/day) and protein‐redistribution diets in patients with PD experiencing motor fluctuations during levodopa treatment. All studies (uncontrolled or randomized) investigating a low‐protein and/or a protein‐redistribution diet (LPD and PRD) and involving patients with PD with motor fluctuations were included, provided that sufficient information on dietary protein content and neurologic outcome measures was available. We identified 16 eligible studies, but they were markedly heterogeneous. There was not enough evidence to support the use of LPD. Response to PRD seemed very good. Acceptability appeared high upon introduction, but it seemed to progressively decrease over time. On average, PRD resulted in improved motor function, but also complications occurred. At the beginning, drop‐outs were due to levodopa side effects rather than unsatisfactory benefits. Long‐term adherence was more affected by changes in dietary habits than by diet‐related side effects. Efficacy and benefits appeared to be higher when the intervention was proposed to subjects in the early stages of PD. PRD can be safely advised to fluctuating patients with PD, but those in whom benefits override the possible inconveniences still need to be identified. The long‐term effects of PRD on nutritional status should be evaluated and true effectiveness in clinical practice should be reassessed, given the changes in levodopa formulations and the introduction of several adjuvants (levodopa degradation inhibitors and/or dopamine agonists). © 2010 Movement Disorder Society.     

Dietary practices and use of the ketogenic diet in the UK.

With the introduction of Internet communications, parental interest has increased in the use of the ketogenic diet for epilepsy. It was decided to audit current practice in the use of the ketogenic diet in the UK. All paediatric dietitians who were members of the Paediatric Group of the British Dietetic Association were surveyed by a postal questionnaire. There was a 51% response rate. Twenty-two hospitals (17%) used the ketogenic diet with 101 patients being treated. Fifty-nine percent used the traditional 4:1 (four parts fat : one part carbohydrate, one part protein) classical ketogenic diet and 41% used the medium chain triglyceride diet (60% MCT fat). The age of patients ranged from 1 to over 11 years. There were wide variations in its application, with 66% of hospitals initiating the diet in hospital and 33% at home. The dietary energy administered varied from 60 to 90 kcal/kg/day, and there was no consistent policy on vitamin and mineral supplementation. Twenty-five patients continued to follow the diet after 12 months. Therefore, the ketogenic diet is commonly used for the treatment of intractable epilepsy in the UK. Further research work is needed on its nutritional safety and application.     

Influence of diet composition on food intake and hypothalamic neuropeptide Y (NPY) in the rat

Ingestion of a high carbohydrate (HC) or high fat (HF) diet induces obesity in association or not with modifications of the feeding behaviour. Effects of diet composition on NPY, a powerful stimulant of weight gain and food intake (particularly carbohydrates), are not known. That is why we measured NPY in 10 microdissected brain nuclei of rats fed either a HC diet (69% of energy from carbohydrates), a HF diet (68% of energy from fat) or a control well-balanced diet (54% of energy from carbohydrates; 30% of energy from fat) during a 14-day period. Total caloric intake was significantly greater (+12%) in rats fed on the HF diet than in the control and HC rats. HF rats also gained more weight than the two other groups (47.5 +/- 2.4 g vs 37.6 +/- 2.6 g (control) and 29.1 +/- 1.4 g (HC); p less than 0.001). NPY variations were restricted to two hypothalamic areas. In the parvocellular part of the paraventricular nucleus, NPY was smaller with the HC diet than with the HF diet (42.1 +/- 2.3 vs 49.5 +/- 2.7 ng/mg protein; p less than 0.05). A decrease was observed in the lateral hypothalamus with the HF diet when compared with the control diet (11.3 +/- 0.7 vs 14.6 +/- 1.1 ng/mg protein; p less than 0.05). No variations were observed either in other hypothalamic nuclei such as arcuate, dorsomedian, ventromedian or suprachiasmatic nuclei or in extra-hypothalamic areas such as the ventral tegmental area or submamillary bodies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study

BACKGROUND: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). METHODS: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. RESULTS: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. CONCLUSIONS: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.     

A balanced carbohydrate: protein diet in the management of Parkinson's disease

Although restricting dietary protein is a proposed adjunct to treating Parkinson's disease (PD), the effect of carbohydrate consumption is unknown. We measured plasma levodopa and large neutral amino acid (LNAA) levels in nine PD patients treated with carbidopa/levodopa and different isocaloric meals containing high protein-low carbohydrate, low protein-high carbohydrate, and balanced 5:1 carbohydrate:protein mixtures. We found that levodopa levels increased significantly regardless of the type of diet, but that plasma LNAA levels varied less and motor performance was superior after the balanced diet than after the other two meals. We conclude that PD patients can consume nutritionally adequate meals and still maintain a stable plasma levodopa:LNAA ratio.     

Microtubule-associated protein 2 (MAP2) in Purkinje cell dendrites: evidence that factors other than binding to microtubules are involved in determining its cytoplasmic distribution

We have studied the distribution of microtubule-associated protein 2 (MAP2) in the Purkinje cell dendrites of rats whose cerebella were exposed to X-irradiation during the second postnatal week. The Purkinje cells of such animals have abnormally elongated apical primary processes that branch in the other molecular layer rather than close to the cell body as in normal tissue. The results show that in these distorted dendrites the MAP2 distribution is "shifted" distally relative to the normal pattern, in which MAP2 is distributed evenly throughout the dendritic tree. Tubulin and other microtubule-associated proteins, such as MAP1, are not affected and remain evenly distributed throughout the dendritic tree despite the anatomical distortion. We conclude that the distribution of MAP2 in Purkinje cells is not determined solely by its binding to tubulin. Other factors must be involved and these appear to be related to dendritic morphology and possibly to branching.     

The effects of long-term diet and omega-3 fatty acid supplementation on coagulation factor VII and serum phospholipids with special emphasis on the R353Q polymorphism of the FVII gene

The aim of the present study was to investigate the effect of long-term diet and very long chain n-3 fatty acids (VLC n-3) intervention on plasma coagulation factor VII (FVII), choline-containing phospholipids (PC) and triglycerides (TG), especially related to the R353Q polymorphism of the FVII gene. The present investigation included 219 subjects from the Diet and Omega-3 Intervention Trial on atherosclerosis (DOIT), a 2x2 factorial designed study in elderly men with long-standing hypercholesterolemia. The subjects were randomly allocated to receive placebo capsules (corn oil) (control), placebo capsules and dietary advice ("Mediterranean type" diet), VLC n-3 capsules, or VLC n-3 capsules and dietary advice combined. The R353Q genotype and the levels of FVIIc, FVIIag, FVIIa, PC, and TG at baseline and after 6 months were determined. Diet intervention was followed by a significant reduction of 5.1% in the levels of FVIIag and 2.4 mU/ml in FVIIa (95% CI -7.4, -2.9, and -3.8, -1.1, respectively) (both p<0.001) compared to the no diet group, independent of genotype. No effects of diet intervention on FVIIc, PC or TG were observed. After VLC n-3 supplementation the TG levels were significantly reduced compared to placebo (p=0.01), whereas all FVII levels and PC remained unchanged. Dietary advice towards a "Mediterranean type" diet, but not VLC n-3 supplementation, was shown to reduce the levels of FVIIag and FVIIa after 6 months, independent of genotype. The results indicate the dietary advice to be more favourable in reducing this risk factor for CVD as compared to specific VLC n-3 supplementation.     

Effect of NIK-242 inj. (20% erythritol) on intracranial pressure in dogs with acute obstructive hydrocephalus

The effects of NIK-242 inj. (20% erythritol) on intracranial pressure (ICP) and serum osmotic pressure (Osm. P) were investigated in dogs with acute obstructive hydrocephalus, and they were compared with those of 20% mannitol or 10% glycerol in 5% fructose and 0.9% saline. Animals were divided into 5 groups (n = 6 in each group) and treated with either NIK-242 inj. (0.5 g/kg, 1.0 g/kg, 2.0 g/kg), mannitol (1.0 g/kg) or glycerol (0.5 g/kg). These drugs were administrated intravenously for 10 min. NIK-242 inj. rapidly reduced ICP and increased Osm. P. There was correlation between changes of ICP and Osm. P. The regression equation was Y = -6.489 X + 726.206 (n = 104, p less than 0.00001, R = -0.655). The effects were dose-dependent, but there were no significant differences between the effects of NIK-242 inj. 1.0 g/kg infusion and 2.0 g/kg infusion. The most appropriate dose of NIK-242 inj. was 1.0 g/kg, in which group ICP was significantly lower than the initial pressure until 120 minutes after administration (p less than 0.05). The maximum reduction rate of ICP [(initial ICP-minimum ICP)/initial ICP X 100] was 83.6 +/- 10.6% at 22.7 +/- 3.0 min. after administration. It was 61.6 +/- 6.9% at 19.3 +/- 1.6 min. in mannitol group and 77.1 +/- 7.4% at 15.0 +/- 0.8 min. in glycerol group. There was no rebound phenomenon on ICP during 150 min., but there was one in mannitol group and five in glycerol group. NIK-242 inj.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional distribution of calcium- and cyclic adenosine 3':5'-monophosphate-regulated protein phosphorylation systems in mammalian brain. II. Soluble systems

The regional distribution of phosphoproteins whose phosphorylation is regulated either by cyclic AMP or by calcium in combination with calmodulin or phospholipid has been investigated in soluble preparations from rat CNS. About 40 distinct phosphoproteins were observed. These cytosolic phosphoproteins exhibited widely different patterns of regional distribution. Based upon distribution patterns, we have divided these phosphoproteins into three categories: category A, phosphoproteins found in all parts of the CNS in approximately equal amounts; category B, phosphoproteins which are widely distributed within the CNS, but which show large regional variations; and category C, phosphoproteins which show a highly restricted regional distribution. We have tentatively interpreted the results on cytosolic phosphoproteins in the following way: some are present in all or nearly all brain cells, others are present only in certain classes of brain cells, and still others have an even more limited distribution, being present in only a single type of brain cell. The regional distribution of soluble protein kinase activity was also studied. Calcium/phospholipid-dependent protein kinase and calcium/calmodulin-dependent protein kinase had marked regional distributions. Cyclic AMP-dependent protein kinase was more evenly distributed throughout the CNS. This investigation thus demonstrates striking differences in the regional distribution of cytosolic protein phosphorylation systems in mammalian brain. These regional differences may reflect highly specific functional roles for certain of these protein phosphorylation systems. Similar conclusions concerning particulate protein phosphorylation systems are described in the preceding paper.     

Glucose effects on a continuous performance test of attention in adults

Increases in plasma blood glucose levels modulate memory, mood, and, to some extent, attention in adults. Participants in the present study were administered glucose (10, 100, and 500 mg/kg, or 50 g) or placebo (23.7 mg saccharin) shortly prior to completing the test of variables of attention (TOVA), a continuous performance test (CPT) commonly used to assess attention for diagnostic purposes. There were significant increases in blood glucose levels for the 500 mg/kg and 50 g groups, but only the 100 mg/kg group showed significant changes in behavior in comparison to the saccharin group. Specifically, the 100 mg/kg group performed worse on measures of commission errors, post-commission responses, and post-commission response time variability. There were no differences among the groups on other major variables of attention, including omission errors, response time, and response time variability. The results of this study demonstrate that large doses of glucose which increase blood glucose levels do not influence attention, but that a moderate dose (100 mg/kg) selectively impairs measures of impulsivity or disinhibition. Practitioners and researchers should maintain an awareness of dietary effects on attention and continue to examine micronutrients as potential confounds on diagnostic tests of cognition and behavior.     

Alcohol-induced memory impairment in trace fear conditioning: a hippocampus-specific effect

It has been hypothesized that the amnesic effects of alcohol are through selective disruption of hippocampal function. Delay and trace fear conditioning are useful paradigms to investigate hippocampal-dependent and independent forms of memory. With delay fear conditioning, learning of explicit cues does not depend on normal hippocampal function, whereas learning explicit cues in trace fear conditioning does. In both delay and trace fear conditioning, the hippocampus is involved in learning to contextual cues, but it may not be entirely necessary. The present study investigates the effects of alcohol on the acquisition of delay and trace fear conditioning in mice, using freezing as a measure of learning. Male C57BL/6J mice were injected with 0.8 or 1.6 g/kg of 20% v/v alcohol and were immediately exposed to eight tone-footshock pairings in which the conditional stimulus (CS) either coterminated with a footshock unconditional stimulus (US) (delay conditioning) or was separated from the footshock by a 30-s trace interval (trace conditioning). During trace, but not delay fear conditioning, 0.8 g/kg alcohol impaired learning to a tone CS. This dose also impaired context-dependent learning in both procedures (although only slightly for trace fear conditioning). The 1.6 g/kg alcohol exerted a nonselective impairment on learning. The impairment by alcohol of learning to a tone CS when it is hippocampus-dependent, but not when it is hippocampus-independent provides further support for the hypothesis that alcohol exerts a selective effect on hippocampus-dependent learning.