Language：English   Publishing type：Research paper (scientific journal)  

Treatment with dopaminergic agents result excessive daytime sleepiness (EDS) and some studies have shown the benefit of using modafinil for treating excessive daytime sleepiness of Parkinson's disease (PD) patient. We investigated whether modafinil have ameliorative properties against levodopa induced excessive nighttime sleepiness (ENS) in MPTP-treated murine nocturnal PD model. Our EEG analyses of whole day recordings revealed that modafinil reduce ENS of this nocturnal PD models with levodopa medications. Therefore, we investigated whether, modafinil post-treatment followed by MPTP shows any effect on monoamine contents of brain and found to robustly increased noradrenaline (NA) concentration of MPTP treated mice. Modafinil post-treatment, in neurorestorative context (5 days post-lesion) led to increased striatal dopamine (DA) concentrations of MPTP-treated mice. Here, we first confirmed that modafinil ameliorates levodopa induced excessive sleepiness and restores monoaminergic systems. The arousal and anti-parkinsonian effects displayed by modafinil indicate that in combination with dopaminergic agents, modafinil co-administration may be worthwhile in trying to suppress the excessive daytime sleepiness and progressive dopaminergic neuron loss in PD.

DOI： 10.1016/j.jphs.2018.03.005

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Other Link： http://orcid.org/0000-0003-1056-5948

Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Introduction: Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia.
Methods: I-123-metaiodobenzyl guanidine (I-123-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using I-123-iofiupane (I-123-FP-CIT) were performed for the six patients from three SCA2 families.
Results: I-123-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinson's disease, most of the patients had minimal reduction uptake in the putamen.
Conclusion: DAT SPECT is expected to be useful in differentiating SCA2 from Parkinson's disease, making an early diagnosis, and allowing early therapeutic intervention. (C) 2017 Published by Elsevier Ltd.

DOI： 10.1016/j.parkreldis.2017.08.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.

DOI： 10.1002/glia.23199

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Other Link： http://orcid.org/0000-0003-1056-5948

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.106.1461

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I028386206

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Objectives The objective of this study was to assess the safety of administration of mucuna sheets which contains L-dopa, by conducting the pharmacokinetics (PK) and the open-label trial in healthy elderly subjects. Methods Twenty-one Japanese healthy subjects, who were older than 60 years old, were enrolled in the study. The pharmacokinetics parameter of L-dopa which is the content of mucuna sheets were examined in two groups following the administration of two or four sheets of mucuna. Mucuna sheets were made of roasting and powdering the mucuna by Kisyu Hoso- kawa corporation. After performing the PK trial, all participants ingested 6 sheets of mucuna per day for 12 weeks. The safety of ingestion of mucuna was evaluated through physical examination, interview, blood chemistry analysis, electrocardiogram (ECG), and questionnaires on sleep and fatigue at baseline and every 4 weeks of treatment. Results The maximum plasma concentration (Cmax) of L-dopa of the groups which received two sheets and four sheets of mucuna were 137.4±96.8 nM and 483.0±409.7 nM, respectively. The individual variability of plasma concentration is around eight fold. Subjects showed no adverse reactions except slight sleepiness. Although there were significant differences in renal function and blood glucose level during 12 weeks of mucuna treatment, they do not impose any clinically important meaning and they are also considered not to be related with ingestion of mucuna sheet. Conclusion According to our findings, we conclude that continuous long-Term administration of mucuna sheets at evaluated dose in elderly people is safe.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

We report a patient of 68-year-old woman who developed numbness of feet in 2008. Ataxic gait disturbance, truncal ataxia, muscle weakness of lower limbs have gradually appeared and she couldn't walk without assistance in 2013. Her cognitive function declined subacutely in 2014. When she was admitted to our hospital, it was difficult to fully evaluate her neurological symptoms and cognitive function. The tendon reflex were absent and Babinski reflex showed positive in both sides of the lower limbs. Diffusion weighted image of MRI showed high intensity in cerebrocortical area, and variation P102L prion protein gene mutation was detected. We diagnosed her with Gerstmann-Sträussler-Scheinker (GSS) disease. Cerebellar symptom such as ataxic gait occurs as the initial manifestation in 90% of patients with GSS disease. Her initial symptom was numbness of lower limbs and cerebellar symptom gradually appeared during the course of disease. In addition, her cognitive function declined six years after the onset. This case presented atypical clinical course as described above. Consequently, it led to diagnostic delay in GSS disease.

DOI： 10.5692/clinicalneurol.cn-000747

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Pregabalin, a novel agent for treating partial epilepsy and peripheral neuropathic and central pain, was studied for its effect on driving performance in healthy volunteers. Sixteen healthy male volunteers who drove regularly were enrolled in a double-blind, parallel-group, placebo-controlled study assessing the effect of pregabalin on driving performance. Subjects received an oral dose of pregabalin 75 mg or placebo, and a second dose 12 hours later. A driving simulator was used to test simple and complicated braking reaction time, and simple and complicated steering-wheel techniques before the first dose, and 1 hour and 3 hours after the second dose of pregabalin or placebo. The effect of training during the driving test on the driving performance of each group was also evaluated. There were no statistically significant differences in driving performance between the pregabalin and the placebo groups. However, the pregabalin group showed no significant improvement in steering-wheel skills with training, whereas the placebo group showed a significant (P<0.05) improvement with training. In this study using a driving simulator, pregabalin did not impair driving performance but mildly reduced the training effects of driving experiments. Although pregabalin caused sleepiness, it had no severe effect on driving ability after a second dose of 75 mg after the initial introduction of pregabalin. © 2014 Tujii et al.

DOI： 10.2147/IJGM.S57392

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Objectives: Some patients with Parkinson disease improved their symptoms on treatment with nicotine patch or gum. Nicotine has also been studied for its antidyskinetic effect on levodopa-induced dyskinesia. We determined the effects of nicotine on levodopa pharmacokinetics and gastric emptying in healthy subjects and on levodopa transport in Caco-2 monolayers in vitro. MethodS: Healthy subjects received transdermal nicotine patch application followed by oral levodopa/benserazide, 100/25 mg, in a fasting state and with enteral nutrition. Levodopa pharmacokinetics was determined, and gastric emptying was evaluated by carbon 13 (C)-labeled acetic acid breath testing. In vitro studies using intestinal Caco-2 cell monolayers evaluated whether the intestinal transport of levodopa was affected by nicotine and its metabolite, cotinine. RESULT: Nicotine did not increase mean plasma concentration significantly during fasting or with enteral nutrition, although the extent of levodopa absorption was reduced by 34% to 60% in some individuals and the mean plasma concentration of levodopa was statistically decreased by nicotine in subjects who received enteral nutrition. However, gastric parameters were not significantly affected by nicotine. Nicotine and cotinine at 0.1 μmol/L significantly reduced levodopa uptake by Caco-2 cells (P < 0.01). Conclusions: We found that nicotine reduced plasma levodopa concentration in some healthy subjects but with no alteration of gastric emptying rate. In vitro, nicotine inhibited levodopa transport by Caco-2 cell monolayers in an α-methyl amino isobutyric acid-independent, 2-amino-norbornanecarboxylic acid-dependent manner. These Results suggest that nicotine may inhibit the transport of levodopa by the system L-amino acid transporter. © 2013 by Lippincott Williams & Wilkins.

DOI： 10.1097/WNF.0b013e31827fd9cd

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Objective For patients with Parkinson's disease (PD), driving is challenging due to an impaired motor function and decreased attention capabilities. This study assessed the driving capacity in PD patients by comparing neurological signs. Methods The driving ability of PD patients was evaluated using a driving simulator (Safety Master NT-932) that tested the reaction time in response to traffic signals and steering wheel errors. We studied the correlations between the total Unified Parkinson's Disease Rating Scale (UPDRS) score, the UPDRS part III score, the subscores of the UPDRS part III score, age, PD disease duration, braking reaction time, steering wheel errors and total scores for driving safety test results. 'On' state regular PD licensed drivers (n=42; mean age: 63 years) in Hoehn and Yahr stages II-III participated after their cognitive status was confirmed using mini-mental state examinations. Results The UPDRS scores, the UPDRS part III scores and the postural instability subscores exhibited significant (p<0.05) correlations with the number of steering wheel errors but not with the braking reaction time or the total safety scores of the test results. Conclusion The UPDRS is an established evaluation method used to estimate PD signs, although it is not sufficient alone for deciding whether PD patients should be allowed to drive. Our findings suggest that determining the driving ability using a driving simulator might be a useful adjunct to UPDRS scores in the assessment of PD patients who are active drivers. Estimating the driving ability requires complex measurements, including motor performance with perception of stimuli and attention. © 2013 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.52.9292

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Language：Japanese   Publishing type：Research paper (scientific journal)  

In the last 30 years, a lot of drugs to treat neurological disorders have been developed. Now neurology is one of the fields where the medication is the most important factor deciding the prognosis of the treated patients. Neurologists are now required to have precise knowledge of drug metabolisms and interactions on the medication to treat neurological disorders. Insert Packages contain most useful and important information for medications, however, information for the drugs are not enough to prescribe some drugs, and even though in the same drugs, information offered is different especially on drug interactions. Pharmacists and physicians should choose the drugs which offer proper and useful drug information to treat patients. Developments of drugs to treat patients are important as a physician in Japan. It can also contribute to treat patients in the all of the world. The role of neurologists is especially big because the drugs of the brain are rapidly developed than any other fields in medicine.

DOI： 10.5692/clinicalneurol.53.907

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Pharmacological Society  

Randomized clinical trials have shown that pramipexole has an antidepressant effect in patients with Parkinson's disease. We investigated the comparative efficacy of pramipexole toward dopamine receptor D2 and D3 expression in rat brain. Groups of rats were treated subacutely with pramipexole (1 mg/kg), imipramine (10 mg/kg), or bromocriptine (5 mg/kg), with appropriate controls. Using real-time RT-PCR and immunoblotting, dopamine receptor D 2 and D3 expression was up-regulated in the striatum following pramipexole treatment, while imipramine and bromocriptine had no significant effects. These findings support that pramipexole exerts additional therapeutic benefits such as decreasing depression by increasing dopamine receptor D3 expression in the striatum. © 2012 The Japanese Pharmacological Society.

DOI： 10.1254/jphs.12096SC

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Spinocerebellar ataxia type 2 (SCA2) represents a family of dominant neurodegenerative disorders that results from CAG expansion repeat mutations. The phenotype consists of some common features, most notably progressive ataxia. We describe three siblings with SCA2, manifesting parkinsonism and ataxia in the first sibling, juvenile parkinsonism in the second and motor neuronopathy in the third. Genetic examination revealed expansion to 42, 43, and 42 CAG repeats. There was no relationship between the number of repeats and phenotype. The SCA2 gene should be studied in families with heterogeneous neurodegenerative disorders, including motor neuron disease.

DOI： 10.2169/internalmedicine.50.5262

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The effect of zonisamide, an antiepileptic agent with anti-parkinsonian effects, was studied on dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 mice and common marmosets. Groups of mice (n = 8 - 9) were treated with: MPTP (15 mg/kg every 2 h x4); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); zonisamide (40 mg/kg x4); and saline controls. Groups of common marmosets (n = 4 - 6) were treated with: MPTP (2.5 mg/kg every 24 h x3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); and saline controls. Brain dopamine and its metabolites were determined by HPLC. Dopamine content decreased in the striatum of MPTP-treated mice and monkeys. Co-administration of selegiline inhibited the effect of MPTP and dopamine contents were similar to those of the controls. Co-administration of zonisamide did not inhibit the effect of MPTP on dopamine content, but increased striatal dopamine turnover of animals treated with MPTP plus zonisamide more than in those treated with MPTP alone. MPTP treatment caused a compensatory increase of dopamine turnover in the striatum by remaining neurons. Zonisamide may help dopaminergic neurons by increasing striatal dopamine turnover following MPTP treatment.

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Language：Japanese   Publisher：一般社団法人 日本臨床薬理学会  

DOI： 10.3999/jscpt.35.231S

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

パーキンソン病は神経変性疾患で厚生労働省の特定疾患に指定されているが,研究が進み,現在では最も治療薬の豊富な疾患となっている.その結果,適切な薬物治療により正常な日常生活が送れるようになっている.さらに,神経の変性を防ぐ治療薬の臨床研究も開始された. Levodopaは最も重要な治療薬であるが,長期使用により不随意運動やwearing-off現象などが誘発される症例が多い.これを解決するために種々の治療薬が臨床応用され,また研究中である.

DOI： 10.2169/naika.92.1419

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Other Link： https://jlc.jst.go.jp/DN/JALC/00230706925?from=CiNii

Language：Japanese   Publisher：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.34.2_307S

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Other Link： http://search.jamas.or.jp/link/ui/2003251262

Language：English   Publisher：ELSEVIER SCIENCE BV  

Zonisamide is an antiepileptic drug that also improves the cardinal symptoms of Parkinson's disease. This study investigated the effects of zonisamide on dopaminergic neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Six groups of mice were treated as follows: 1) normal saline; 2) MPTP, 15 mg/kg x 4 every 2 h; 3) MPTP and zonisamide, 40 mg/kg x 1, 1 h after the last MPTP dose; 4) MPTP and zonisamide, 1 day after the last dose of MPTP; 5) MPTP and zonisamide, 1 h before the first MPTP dose; and 6) zonisamide, 40 mg/kg. MPTP-treatment decreased the contents of dopamine as well as the number and area of tyrosine hydroxylase (TH)-positive neurons. Concurrent treatment of mice with zonisamide and MPTP did not show any inhibition of the toxic effect of MPTP towards dopamine contents at 1 week after treatment but it increased the number and area of TH-positive neurons compared to the MPTP-treated group. Surviving TH-positive neurons had recovery of dopamine production after several weeks. Moreover, zonisamide increased the number of S100 beta-positive and glial fibrillary acidic protein (GFAP)-positive astrocytes and dopamine turnover. These results suggest that zonisamide acts as a neuro-protectant against MPTP-induced dopaminergic neuronal degeneration as shown by an increase of TH-positive neurons and this may be mediated by increased S100 beta secretion. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2011.02.017

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1016/j.parkreldis.2010.08.019

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Language：Japanese   Publisher：(公社)日本看護科学学会  

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Language：English   Publisher：JAPANESE PHARMACOLOGICAL SOC  

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in humans and animals. The effects of zonisamide on dopamine neurons were studied in MPTP-treated common marmosets (Callithrix jacchus). Groups of animals (n = 3) were treated with MPTP (2.5 mg/kg, every 24 h x 3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (a known MAO-B inhibitor) (2 mg/kg administered 1 h before each MPTP dose); and saline controls. An immunohistochemical study of the substantia nigra was performed 14 days after MPTP treatment in each group. MPTP reduced the mean number of tyrosine hydroxylase (TH)-positive neurons to 10% of the normal control group and mean cell size was significantly (P &lt; 0.001) reduced from 424 to 159 mu m(2). In the group pre-treated with zonisamide, the mean number of TH-positive neurons was reduced to 26% of that in the normal control group and the mean neuron size was significantly (P &lt; 0.05) increased from 159 to 273 mu m(2) compared with the group treated with MPTP alone. Moreover, in the group pre-treated with selegiline, the mean number of TH-positive neurons was 47% of that in the normal control group and the mean neuron size was increased significantly (P &lt; 0.01) from 159 to 319 mu m(2) compared to the group treated with MPTP alone. This observation suggests that zonisamide reduces MPTP toxicity.

DOI： 10.1254/jphs.10120FP

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Language：Japanese   Publisher：(公社)日本心理学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(公社)日本看護科学学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：Japanese   Publisher：日本ストレス学会  

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Language：Japanese   Publisher：(一社)日本看護研究学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MOSBY, INC  

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Language：Japanese   Presentation type：Oral presentation (general)  

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