L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D₂ receptor (D₂R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D₂R⁺ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D₂R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D₂-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D₂R⁺ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D₂R⁺ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D₂R⁺ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D₂R⁺ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Rats ; Animals ; Levodopa/toxicity* ; Dopamine ; Parkinsonian Disorders/drug therapy* ; Oxidopamine ; Dyskinesia, Drug-Induced ; Corpus Striatum/metabolism* ; Neurons/metabolism* ; Receptors, Dopamine D2/metabolism* ; Antiparkinson Agents/toxicity*

Dopamine (DA), as a catecholamine neurotransmitter widely distributed in the central nervous system and the peripheral tissues, has attracted a lot of attention. Especially in recent years, DA has been found to regulate the function of the immune system, and the involvement of DA in the intestinal mucosal inflammation-related diseases has become a hot research topic. The digestive tract is an important source of peripheral DA, and DA is not only produced in the enteric nervous system and gastrointestinal epithelium, but also produced by intestinal microorganisms. In addition to the synthetases of DA, the DA contents in body tissues are also affected by the two kinds of metabolic enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). This article reviewed the sources, metabolism, and functions of DA in digestive tract, especially focusing on the distribution and function of MAO and COMT, the enzymes degrading DA.
Catechol O-Methyltransferase ; Catechol O-Methyltransferase Inhibitors ; Dopamine ; Gastrointestinal Tract ; Monoamine Oxidase ; Monoamine Oxidase Inhibitors

The traditionally used oriental herbal medicine Moutan Cortex Radicis [MCR; Paeonia Suffruticosa Andrews (Paeoniaceae)] exerts anti-inflammatory, anti-spasmodic, and analgesic effects. In the present study, we investigated the therapeutic effects of differently fractioned MCR extracts in a 6-hydroxydopamine (OHDA)-induced Parkinson's disease model and neuro-blastoma B65 cells. Ethanol-extracted MCR was fractionated by n-hexane, butanol, and distilled water. Adult Sprague-Dawley rats were treated first with 20 μg of 6-OHDA, followed by three MCR extract fractions (100 or 200 mg·kg) for 14 consecutive days. In the behavioral rotation experiment, the MCR extract-treated groups showed significantly decreased number of net turns compared with the 6-OHDA control group. The three fractions also significantly inhibited the reduction in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta following 6-OHDA neurotoxicity. Western blotting analysis revealed significantly reduced tyrosine hydroxylase expression in the substantia nigra pars compacta in the 6-OHDA-treated group, which was significantly inhibited by the n-hexane or distilled water fractions of MCR. B65 cells were exposed to the extract fractions for 24 h prior to addition of 6-OHDA for 30 min; treatment with n-hexane or distilled water fractions of MCR reduced apoptotic cell death induced by 6-OHDA neurotoxicity and inhibited nitric oxide production and neuronal nitric oxide synthase expression. These results showed that n-hexane- and distilled water-fractioned MCR extracts inhibited 6-OHDA-induced neurotoxicity by suppressing nitric oxide production and neuronal nitric oxide synthase activity, suggesting that MCR extracts could serve as a novel candidate treatment for the patients with Parkinson's disease.
Animals ; Anti-Inflammatory Agents ; pharmacology ; therapeutic use ; Antiparkinson Agents ; pharmacology ; therapeutic use ; Cell Death ; drug effects ; Cell Line ; Disease Models, Animal ; Drugs, Chinese Herbal ; chemistry ; Neurons ; pathology ; Nitric Oxide ; analysis ; Nitric Oxide Synthase Type I ; biosynthesis ; Oxidopamine ; toxicity ; Paeonia ; chemistry ; Parkinsonian Disorders ; chemically induced ; drug therapy ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Plants, Medicinal ; Rats ; Rats, Sprague-Dawley ; Substantia Nigra ; drug effects ; enzymology ; Tyrosine 3-Monooxygenase ; genetics ; metabolism

The dysfunction of subthalamic nucleus is the main cause of Parkinson's disease. Local field potentials in human subthalamic nucleus contain rich physiological information. The present study aimed to quantify the oscillatory and dynamic characteristics of local field potentials of subthalamic nucleus, and their modulation by the medication therapy for Parkinson's disease. The subthalamic nucleus local field potentials were recorded from patients with Parkinson's disease at the states of on and off medication. The oscillatory features were characterised with the power spectral analysis. Furthermore, the dynamic features were characterised with time-frequency analysis and the coefficient of variation measure of the time-variant power at each frequency. There was a dominant peak at low beta-band with medication off. The medication significantly suppressed the low beta component and increased the theta component. The amplitude fluctuation of neural oscillations was measured by the coefficient of variation. The coefficient of variation in 4-7 Hz and 60-66 Hz was increased by medication. These effects proved that medication had significant modulation to subthalamic nucleus neural oscillatory synchronization and dynamic features. The subthalamic nucleus neural activities tend towards stable state under medication. The findings would provide quantitative biomarkers for studying the mechanisms of Parkinson's disease and clinical treatments of medication or deep brain stimulation.
Antiparkinson Agents ; therapeutic use ; Beta Rhythm ; Electrodes ; Evoked Potentials ; Humans ; Oscillometry ; Parkinson Disease ; drug therapy ; physiopathology ; Subthalamic Nucleus ; physiopathology ; Theta Rhythm

In addition to classical triad such as gait disturbance, urinary incontinence and dementia, parkinsonian extrapyramidal motor signs and neuropsychiatric symptoms can be observed in patients with normal pressure hydrocephalus (NPH). In our case, a 46 year old female patient showed extrapyramidal symptoms such as bradykinesia, rigidity and neuropsychiatric symptoms such as agitation, anxiety, restlessness and regressed behavior beside two(gait disturbance & urinary incontinence) symptoms of three classical triad. It was difficult to diagnose this patient as NPH from the beginning because of her relatively young age and previous psychiatric mediation history for controlling advanced anxiety and affective disorder. Antiparkinsonian agents and discontinuation of psychiatric medications did not work for this patient. Patient's brain computed tomographic finding showed enlarged ventricles. We suspected NPH and did empirical drainage of 30mL CSF. Finally, patient's pyramidal and neuropsychiatric symptoms as well as two of three classical triad of NPH were improved dramatically within several days. It is important to consider NPH as one of the differential diagnosis in patient with parkinsonian symptoms and various neuropsychiatric symptoms who did not respond to usual clinical management especially in case of ventricular enlargement in neuroimaging because of its treatable property by CSF shunt operation.
Antiparkinson Agents ; Anxiety* ; Bipolar Disorder* ; Brain ; Dementia ; Diagnosis, Differential ; Dihydroergotamine ; Drainage ; Female ; Gait* ; Humans ; Hydrocephalus, Normal Pressure* ; Hypokinesia* ; Mood Disorders ; Negotiating ; Neuroimaging ; Psychomotor Agitation ; Urinary Incontinence

PURPOSE: To evaluate the effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on levodopa-induced peakdose dyskinesia in patients with Parkinson's disease (PD). MATERIALS AND METHODS: A retrospective review was conducted on patients who underwent STN DBS for PD from May 2000 to July 2012. Only patients with levodopa-induced dyskinesia prior to surgery and more than 1 year of available follow-up data after DBS were included. The outcome measures included the dyskinesia subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV (items 32 to 34 of UPDRS part IV) and the levodopa equivalent daily dose (LEDD). The patients were divided into two groups based on preoperative to postoperative LEDD change at 12 months after the surgery: Group 1, LEDD decrease >15%; Group 2, all other patients. Group 2 was further divided by the location of DBS leads. RESULTS: Of the 100 patients enrolled, 67 were in Group 1, while those remaining were in Group 2. Twelve months after STN DBS, Groups 1 and 2 showed improvements of 61.90% and 57.14%, respectively, in the dyskinesia subscore. Group 1 was more likely to experience dyskinesia suppression; however, the association between the groups and dyskinesia suppression was not statistically significant (p=0.619). In Group 2, dyskinesia was significantly decreased by stimulation of the area above the STN in 18 patients compared to stimulation of the STN in 15 patients (p=0.048). CONCLUSION: Levodopa-induced dyskinesia is attenuated by STN DBS without reducing the levodopa dosage.
Aged ; Aged, 80 and over ; Antiparkinson Agents/administration & dosage/*adverse effects ; *Deep Brain Stimulation ; Dyskinesia, Drug-Induced/*therapy ; Female ; Humans ; Levodopa/administration & dosage/*adverse effects ; Male ; Middle Aged ; Outcome Assessment (Health Care) ; Parkinson Disease/*drug therapy ; Postoperative Period ; Retrospective Studies ; Subthalamic Nucleus ; Treatment Outcome

OBJECTIVE: To explore the association of VEGFR2 gene polymorphisms (rs2305948 and rs1870377) with the effect of levodopa (L-dopa) and dyskinesia in Chinese population and to provide theoretical basis for clinical treatment.
 METHODS: By using Taqman MGB analysis and gene sequencing, the rs2305948 and rs1870377 polymorphisms of 69 enrolled Parkinson's disease (PD) patients were detected. Among them, 32 cases developed dyskinesia during 5 years and 37 cases did not develop dyskinesia during 8 years (as the control).
 RESULTS: There was no significant association between the occurrence of dyskinesia and VEGFR2 polymorphisms at rs2305948 and rs1870377. However, rs1870377 polymorphism of AA showed greater maximum L-dopa dose [(565.00±163.55) mg/d vs (396.88±200.39) mg/d, (300.00±80.18) mg/d, P=0.038] and higher value of Modified Abnormal Involuntary Movement Scale (mAIMS) compared with that with polymorphisms of AT and TT [17.00±5.24 vs 8.94±6.53, 7.86±4.45, P=0.026]. 
 CONCLUSION VEGFR2 genes polymorphism (rs1870377) is associated with maximum L-dopa dose and mAIMS value in PD patients.
Antiparkinson Agents ; pharmacology ; Humans ; Levodopa ; pharmacology ; Parkinson Disease ; drug therapy ; genetics ; Polymorphism, Genetic ; Vascular Endothelial Growth Factor Receptor-2 ; genetics

This study aimed to analyze the patterns of antipsychotic prescription to patients with schizophrenia in Korea. Using the Health Insurance Review & Assessment Service-National Patients Sample (HIRA-NPS), which was a stratified sampling from the entire population under the Korean national health security system (2009), descriptive statistics for the patterns of the monopharmacy and polypharmacy, neuropsychiatric co-medications, and prescribed individual antipsychotic for patients with schizophrenia were performed. Comparisons of socioeconomic and clinical factors were performed among patients prescribed only with first- and second-generation antipsychotics. Of 126,961 patients with schizophrenia (age 18-80 yr), 13,369 were prescribed with antipsychotic monopharmacy and the rest 113,592 with polypharmacy. Two or more antipsychotics were prescribed to 31.34% of the patients. Antiparkinson medications (66.60%), anxiolytics (65.42%), mood stabilizers (36.74%), and antidepressants (25.90%) were co-medicated. Patients who were prescribed only with first-generation antipsychotics (n=26,254) were characterized by significantly older age, greater proportion of male, higher proportion of medicaid, higher total medical cost, lower self-payment cost, and higher co-medication rates of antiparkinson agents and anxiolytics than those who were prescribed only with second-generation antipsychotics (n=67,361). In this study, it has been reported substantial prescription rates of first-generation antipsychotics and antipsychotic polypharmacy and relatively small prescription rate of clozapine to patients with schizophrenia. Since this study has firstly presented the patterns of antipsychotic prescription to schizophrenic patients in Korean national population, the findings of this study can be compared with those of later investigations about this theme.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Anxiety Agents/therapeutic use ; Antidepressive Agents/therapeutic use ; Antiparkinson Agents/therapeutic use ; Antipsychotic Agents/*therapeutic use ; Clozapine/therapeutic use ; Drug Therapy, Combination ; Female ; Humans ; Insurance, Health ; Male ; Middle Aged ; *Physician's Practice Patterns ; Polypharmacy ; Republic of Korea ; Schizophrenia/*drug therapy ; Young Adult

Diffuse esophageal spasm, an uncommon esophageal motility disorder, has recently been defined using high-resolution manometry. Patients with distal esophageal spasm usually complain of chest pain or dysphagia. The etiology and pathophysiology of this disorder are poorly known, and treatment options are limited. However, some options to improve symptoms are available, including endoscopic injection of botulinum toxin. Nevertheless, few reports have described the effects of endoscopic injection of botulinum toxin in patients with symptomatic diffuse esophageal spasm with clear endoscopic and high-resolution manometry images. Here, we report a case of diffuse esophageal spasm diagnosed with high-resolution manometry and treated by endoscopic injection of botulinum toxin with good results at the 7-month follow-up.
Aged ; Anti-Dyskinesia Agents/*therapeutic use ; Botulinum Toxins/*therapeutic use ; Endoscopy, Digestive System ; Esophageal Spasm, Diffuse/radiography/*therapy ; Female ; Humans ; Manometry ; Tomography, X-Ray Computed

BACKGROUND: The development of dyskinesia in patients with Parkinson's Disease (PD) has been associated with several risk factors, including the use of Levodopa.
OBJECTIVES: To determine the prevalence of dyskinesia among Filipino patients with Parkinson's Disease given Levodopa versus Dopamine Agonist. To determine the time to development of dyskinesia among Filipino PD patients given Levodopa versus Dopamine Agonists, and to determine the risk factors for the development of dyskinesia among patients on Levodopa.
METHODS: In this retrospective case-control study, the occurrence of dyskinesia was evaluated in 367 PD patiems given Levodopa or Dopamine Agonists.
RESULTS: The prevalence of dyskinesia was significand higher in patients on Levodopa compared to those on DopamineAgonist (36.11% vs 0.86%, p 0.005). Kaplan Meier survival curve showed that at 9 years of treatment, a greater proportion of patients in the dopamine agonist group remained free of dyskinesia compared to the levodopa group (87 vs 3-5%) Patients in the Dopamine agonist group had a longer time to dyskinesia at 7 years compared to those in the Levodopa group at 6.25 years (CI 2 - 20 years). Among patients on Levodopa younger at onset of PD (53.29 vs. 62.37, p < 0.05), female sex (60.44 vs. 39.56%, p 0.006), and longer duration of treatment (6.25 vs. 3.73, p < 0.05) were significant risk factors for the occurrence of dyskinesia.
CONCLUSION: Among Filipino PD patients, the prevalence of dyskinesia is significantly higher in patients on Levodopa compared to those on Dopamine Agonists (36.11% vs 0.8%). At 9 years of treatment, a greater proportion of patients in the DA group remained free of dyskinesia compared to the L-dopa group (87% vs 37.5%). Patients on DAs also had a longer time to the onset dyskinesia at 7 years of treatment compared to those in the L-dopa group at 6.25 years (range at 2 - 20 years of treatment). Among patients on L-dopa, the significant risk factors that predispose patients to the development of dyskinesia are: younger age, female sex, and longer duration of treatment.

Human ; Female ; Antiparkinson Agents ; Disease Susceptibility ; Dopamine Agonists ; Dyskinesias ; Kaplan-meier Estimate ; Levodopa ; Parkinson Disease ; Prevalence