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Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation.
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Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical manifestations. Our patient was a 64-year-old woman with bilateral ptosis as the chief complaint. She had bilateral miosis, and the pupil was only slightly dilated 60 min after 1% phenylephrine administration, suggesting autonomic dysfunction secondary to preganglionic sympathetic impairment. A head-up tilt test revealed asymptomatic orthostatic hypotension. She was diagnosed with NIID based on a skin biopsy and genetic testing. This study suggests that blepharoptosis is an early manifestation of NIID. Furthermore, patients with suspected NIID should be examined carefully for autonomic dysfunction.
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Enfermedades del Sistema Nervioso Autónomo , Blefaroptosis , Enfermedades Neurodegenerativas , Femenino , Humanos , Persona de Mediana Edad , Blefaroptosis/diagnóstico , Blefaroptosis/etiología , Biopsia , Pruebas Genéticas , Cuerpos de Inclusión IntranuclearesRESUMEN
In this study, a murine sepsis model was developed using the cecum ligation and puncture (CLP) technique. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) in the brain increased 6 h after CLP but decreased 24 h later when elevated endogenous dopamine levels in the brain were sustained. Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride reduced dopamine levels in the striatum and increased mortality in septic mice. Dopamine D1-like receptors were significantly expressed in the brain, but not in the lungs. Intraperitoneally administered SKF-81297 (SKF), a blood-brain barrier-permeable D1-like receptor agonist, prevented CLP-induced death of septic mice with ameliorated acute lung injury and cognitive dysfunction and suppressed TNF-α and IL-1ß expression. The D1-like receptor antagonist SCH-23390 abolished the anti-inflammatory effects of SKF. These data suggest that D1-like receptor-mediated signals in the brain prevent CLP-induced inflammation in both the brain and the periphery.
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Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).
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Anticuerpos Monoclonales Humanizados , Virus Linfotrópico T Tipo 1 Humano , Neopterin , Paraparesia Espástica Tropical , Humanos , Método Doble Ciego , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/líquido cefalorraquídeo , Adulto , Anciano , Neopterin/líquido cefalorraquídeo , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Quimiocina CXCL10/líquido cefalorraquídeo , Carga Viral/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) treatment markedly reduces motor fluctuations in patients with Parkinson's disease; however, some patients undergoing LCIG treatment may demonstrate clinical deterioration in the afternoon. Entacapone, a catechol-O-methyltransferase inhibitor, may be a promising adjunctive option for LCIG-treated patients; however, the optimal timing of oral entacapone administration to ameliorate clinical symptoms in the afternoon remains unexplored. This study aimed to investigate the optimal timing of oral entacapone administration in patients with Parkinson's disease undergoing LCIG treatment. METHODS: Pharmacokinetic analysis and symptom assessment were performed on three days: a day without entacapone administration, day with oral entacapone administration at 13:00, and day with oral entacapone administration at 15:00. RESULTS: Eight LCIG-treated patients were enrolled, of whom seven completed this study. The relative plasma concentrations of levodopa with entacapone administration at 13:00 were gradually increased, especially at 18:00 and were significantly higher than those without entacapone administration (127.10 ± 25.06% vs. 97.51 ± 22.20%). The relative plasma concentrations of 3-O-methyldopa were gradually increased without entacapone administration, whereas those with entacapone administration at 13:00 were lower than those without entacapone administration, especially at 17:00 (97.47 ± 3.70% vs. 110.71 ± 9.84%). Administering oral entacapone at 15:00 increased and decreased the relative plasma concentrations of levodopa and 3-O-methyldopa, respectively, but without significant difference. The "Off" time was shorter with entacapone administration at 13:00 (0.43 ± 0.79 h) and at 15:00 (0.57 ± 0.79 h) than that without entacapone administration (1.14 ± 1.46 h). CONCLUSIONS: The concomitant use of oral entacapone in the early afternoon may be effective in improving afternoon symptoms in patients undergoing LCIG treatment.
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Catecoles , Levodopa , Nitrilos , Enfermedad de Parkinson , Humanos , Levodopa/efectos adversos , Carbidopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/efectos adversos , Catecol O-Metiltransferasa/uso terapéutico , Combinación de MedicamentosRESUMEN
Introduction: Constipation is one of the most frequent non-motor symptoms of Parkinson's disease (PD), and magnesium oxide (MgO) is a frequently used laxative. This study aimed to investigate the effect of concomitant use of MgO on the pharmacokinetics of levodopa preparations in patients with PD. Methods: We prospectively enrolled 35 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and motor symptoms with and without MgO. The impact of alterations in pH and the addition of MgO on the solubility of levodopa formulations were also evaluated under in vitro conditions. Results: Concomitant use of MgO significantly reduced the maximum plasma concentration of levodopa (Cmax) (from 7.66 ± 3.74 µmol/L to 5.82 ± 3.69 µmol/L; p = 0.006) and area under the plasma concentration-time curve 3 h after drug administration (AUC3h, from 9.64 ± 3.23 µmol·h/L to 7.39 ± 3.15 µmol·h/L; p < 0.001), and further decreased carbidopa Cmax (from 64.02 ± 27.02 ng/mL to 38.83 ± 21.94 µmol/L; p < 0.001) and AUC3h (from 130.58 ± 65.64 ng/mL to 76.48 ± 52.24 ng·h/mL; p < 0.001). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III score also deteriorated significantly (from 30.71 ± 11.34 to 32.06 ± 11.22; p = 0.007). MgO significantly affected the pharmacokinetics of levodopa and carbidopa. This also applied when the findings were analyzed by sex and age. In vitro dissolution experiments revealed a decrease in the relative concentrations of levodopa, carbidopa, and benserazide as the pH increased and in the presence of MgO suspension, with the most prominent impact on benserazide. Conclusions: Concomitant use of MgO and levodopa should be discouraged to improve levodopa absorption.
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Serum growth differentiation factor 15 (GDF-15) levels are elevated in patients with Parkinson's disease (PD) and may help differentiate these patients from healthy individuals. We aimed to clarify whether serum GDF-15 levels can help differentiate PD from atypical parkinsonian syndromes and determine the association between serum GDF-15 levels and clinical parameters. We prospectively enrolled 46, 15, and 12 patients with PD, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA), respectively. The serum GDF-15 level in patients with PD (1394.67 ± 558.46 pg/mL) did not differ significantly from that in patients with PSP (1491.27 ± 620.78 pg/mL; p = 0.573) but was significantly higher than that in patients with MSA (978.42 ± 334.66 pg/mL; p = 0.017). Serum GDF-15 levels were positively correlated with age in patients with PD (r = 0.458; p = 0.001); PSP (r = 0.565; p = 0.028); and MSA (r = 0.708; p = 0.010). After accounting for age differences, serum GDF-15 levels did not differ significantly between patients with PD and MSA (p = 0.114). Thus, age has a strong influence on serum GDF-15 levels, which may not differ significantly between patients with PD and atypical parkinsonian syndromes such as PSP and MSA.
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The treatment of diseases can be broadly classified into causal and symptomatic therapies. All the drugs currently on the market for Parkinson's disease are symptomatic treatments. Levodopa, a dopamine precursor, is the mainstay of treatment for Parkinson's disease to correct the malfunction of basal ganglia circuits caused by dopamine deficiency in the brain. In addition, dopamine agonists, anticholinergics, NMDA receptor antagonists, adenosine A2A receptor antagonists, COMT inhibitors, and MAO-B inhibitors have been marketed. With regard to the causal therapies, 57 out of 145 clinical trials for Parkinson's disease registered on ClinicalTrials.gov in January 2020 were related to disease-modifying drugs. Anti-α-synuclein antibodies, GLP-1 agonists, and kinase inhibitors have been examined in clinical trials as disease-modifying drugs, but no drug has been obviously demonstrated to inhibit the progression of Parkinson's disease to date. It is not easy to prove the beneficial results obtained from basic research in clinical trials. Especially for neurodegenerative disorders such as Parkinson's disease, it is more difficult to demonstrate clinical efficacy of disease-modifying drugs because there is no useful biomarker to quantify the degree of neuronal degeneration in clinical practice. In addition, the difficulty of using placebos for long periods in a clinical trial also makes proper assessment difficult.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Dopamina , Levodopa/uso terapéutico , Agonistas de Dopamina/uso terapéuticoRESUMEN
Microglia play a central role in neuroinflammatory processes by releasing proinflammatory mediators. This process is tightly regulated along with neuronal activities, and neurotransmitters may link neuronal activities to the microglia. In this study, we showed that primary cultured rat microglia express the dopamine (DA) D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia exhibited increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of interleukin-1ß (IL-1ß) and tumor necrosis α (TNFα) in cultured microglia. Microglia in the normal mature rat prefrontal cortex (PFC) were sorted and significant expression of D1R, D2R, and D4R was observed. A delirium model was established by administering LPS intraperitoneally to mature male Wistar rats. The model also displayed sleep-wake disturbances as revealed by electroencephalogram and electromyogram recordings as well as increased expression of IL-1ß and TNFα in the PFC. DA levels were increased in the PFC 21 h after LPS administration. Increased cytokine expression was observed in sorted microglia from the PFC of the delirium model; however, TNFα, but not IL-1ß expression, was abruptly decreased 21 h after LPS administration in the delirium model, whereas DA levels were increased. A D1R antagonist SCH23390 partially abolished the TNFα expression change. This suggests that endogenous DA may play a role in suppressing neuroinflammation. Administration of the DA precursor L-DOPA or SKF to the delirium model rats inhibited the expression of IL-1ß and TNFα. The simultaneous administration of clozapine, a D4R antagonist, strengthened the suppressive effects of L-DOPA. These results suggest that D1R mediates the suppressive effects of LPS-induced neuroinflammation, in which microglia may play an important role. Agonists for D1R may be effective for treating delirium.
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Delirio , Dopamina , Animales , Masculino , Ratas , Antiinflamatorios/farmacología , Encéfalo , Dopamina/farmacología , Levodopa/farmacología , Lipopolisacáridos/toxicidad , Microglía , Enfermedades Neuroinflamatorias , Ratas Wistar , Factor de Necrosis Tumoral alfa/farmacología , Receptores de Dopamina D1/metabolismoRESUMEN
BACKGROUND: There is some phenotypic overlap between MS, AQP4-IgG positive NMOSD, and MOG-IgG associated disease (MOGAD), and distinguishing a true relapse and a pseudorelapse can be difficult. CSF neopterin, a marker of inflammation-immune-mediated processes in the CNS, may be a useful marker in a wide range of CNS infectious and inflammatory diseases. We compared CSF neopterin levels and other CSF parameters in patients with MS, AQP4-IgG-positive NMOSD, and MOGAD and also investigated whether CSF neopterin levels can distinguish between active and inactive phases of the diseases. METHODS: We retrospectively reviewed the medical records of 22 patients with MS, 18 with AQP4-IgG-positive NMOSD, and five with MOGAD. CSF neopterin concentrations were measured by HPLC with fluorometric detection. RESULTS: CSF neopterin levels at diagnosis were significantly higher in patients with AQP4-IgG-positive NMOSD (52.77 ± 34.56 pmol/mL) than patients with MS (16.92 ± 5.03 pmol/mL, p < 0.001), and tended to be higher in patients with MOGAD (28.87 ± 9.66 pmol/mL) than patients with MS (p = 0.092). ROC analysis revealed that CSF neopterin most accurately discriminated between MS and AQP4-IgG-positive NMOSD (AUC, 0.912; sensitivity, 75.0%; specificity, 100.0%). At diagnosis/relapse and during remission, CSF neopterin most accurately discriminated between the disease phases in patients with MS (AUC, 0.779; sensitivity, 58.1%; specificity, 94.7%) and patients with AQP4-IgG-positive NMOSD (AUC, 0.934; sensitivity, 83.3%; specificity, 94.1%). CONCLUSION: Measurement of CSF neopterin may be useful for differential diagnosis and assessment of disease activity in CNS demyelinating diseases. Further studies with larger cohorts, including comparisons with other biomarkers, are needed to validate the utility of CSF neopterin.
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Neopterin , Neuromielitis Óptica , Acuaporina 4 , Autoanticuerpos , Biomarcadores , Humanos , Inmunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica/diagnóstico , Recurrencia , Estudios RetrospectivosRESUMEN
The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.
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INTRODUCTION: Levodopa and carbidopa are reported to be degraded by magnesium oxide (MgO), which is often used as a laxative for patients with Parkinson's disease (PD). Ascorbic acid (AsA) can stabilize levodopa and carbidopa solutions; however, the effect of AsA on the degradation of levodopa and carbidopa induced by MgO has not been fully investigated. METHODS: The effect of AsA was evaluated using in vitro examinations, compared with lemon juice, and by measuring the plasma concentration of levodopa in a patient with PD. RESULTS: In vitro experiments showed that the relative concentrations of levodopa remained almost constant, and the relative concentrations of carbidopa decreased with time with addition of MgO. AsA mitigated this effect in a concentration-dependent manner, whereas the addition of lemon juice caused little change, although the pH decreased to the same extent. The results of levodopa pharmacokinetics of the patient showed that the area under the plasma concentration-time curve values from hour 0 to 8 were 53.00 µmol·h/L with regular administration and 67.27 µmol·h/L with co-administration of AsA. CONCLUSIONS: AsA can mitigate the degradation of carbidopa induced by MgO and may contribute to improving the bioavailability of levodopa in patients with PD.
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Carbidopa , Enfermedad de Parkinson , Antiparkinsonianos/farmacocinética , Ácido Ascórbico/farmacología , Carbidopa/farmacocinética , Humanos , Levodopa/farmacocinética , Óxido de Magnesio , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismoRESUMEN
Background: Levodopa-carbidopa intestinal gel (LCIG) therapy is used in advanced Parkinson's disease (PD) and consists of continuous administration of levodopa directly into the jejunum through a percutaneous endoscopic gastro-jejunal (PEG-J) tube. Recently, the metabolism of levodopa by Enterococcus faecalis (E. faecalis) has been reported. Intestinal bacteria can also affect this therapy. Objectives: To investigate intestinal bacteria and examine its impact on levodopa blood concentration in patients with PD receiving LCIG therapy. Methods: We enrolled 6 patients receiving LCIG therapy in our department. After PEG-J tube replacement, intestinal bacteria were collected from the tip of the tube and were identified using culture and polymerase chain reaction (PCR) tests. Moreover, the presence of tyrosine decarboxylase, which metabolizes levodopa, was also confirmed by PCR test. The ability of these bacteria to metabolize levodopa was confirmed in vitro. Levodopa blood concentrations were also examined before PEG-J tube replacement. Results: Bacteria were detected in all 6 patients. E. faecalis was present in 4 patients. Moreover, tyrosine decarboxylase was detected in 2 patients. The identified bacteria displayed in vitro metabolization to dopamine in the 4 E. faecalis positive samples. The addition of carbidopa did not inhibit the metabolism of levodopa. However, there was no difference in the mean blood concentration of levodopa, regardless of the presence of E. faecalis. Conclusions: We found bacteria, including E. faecalis in the PEG-J tube. We observed levodopa metabolism in vitro, but there was no association with levodopa blood concentration. The effect of intestinal bacteria may be limited in patients receiving LCIG therapy.
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BACKGROUND: Amyotrophic lateral sclerosis (ALS) causes deterioration of respiratory function. Muscle weakness of the orbicularis oris interferes with the accurate assessment of respiratory function using spirometry. Reduced forced vital capacity (FVC) is an indicator that helps determine the appropriate timing to provide noninvasive ventilation (NIV) for the survival of ALS patients. We employed ultrasonography to evaluate changes in respiratory function by measuring the thickness of the rectus abdominis (RA) muscle as a possible alternative to spirometry. METHODS: Sixteen subjects with ALS were included in this study. The thickness of RA muscles was measured using ultrasonography, and respiratory fluctuations, such as vital capacity (VC), FVC, FEV1, percentage of predicted VC (%VC), percentage of predicted FVC (%FVC), percentage of predicted FEV1 (%FEV1), and FEV1/FVC, were evaluated using spirometry. RESULTS: Sixteen subjects underwent assessment by ultrasonography. A positive correlation was observed between the percent change in RA muscle thickness evaluated from maximal expiration to maximal inspiration and %VC (P = .001), %FVC (P = .001), FEV1 (P = .009), and %FEV1 (P = .02). CONCLUSIONS: RA ultrasonography was useful for predicting a reduction in VC in subjects with ALS and may help determine the best timing for introducing NIV.
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Esclerosis Amiotrófica Lateral , Ventilación no Invasiva , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Humanos , Recto del Abdomen/diagnóstico por imagen , Pruebas de Función Respiratoria , Ultrasonografía , Capacidad VitalRESUMEN
Mitochondrial dysfunction and exacerbated neuroinflammation are critical factors in the pathogenesis of both familial and non-familial forms of Parkinson's disease (PD). This study aims to understand the possible ameliorative effects of zonisamide on microglial mitochondrial dysfunction in PD. We prepared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and lipopolysaccharide (LPS) co-treated mouse models of PD to investigate the effects of zonisamide on mitochondrial reactive oxygen species generation in microglial cells. Consequently, we utilised a mouse BV2 cell line that is commonly used for microglial studies to determine whether zonisamide could ameliorate LPS-treated mitochondrial dysfunction in microglia. Flow cytometry assay indicated that zonisamide abolished microglial reactive oxygen species (ROS) generation in PD models. Extracellular flux assays showed that LPS exposure to BV2 cells at 1 µg/mL drastically reduced the mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Zonisamide overcame the inhibitory effects of LPS on mitochondrial OCR. Our present data provide novel evidence on the ameliorative effect of zonisamide against microglial mitochondrial dysfunction and support its clinical use as an antiparkinsonian drug.
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BACKGROUND: Identifying the factors that influence health-related quality of life (HRQoL) is of great scientific interest, but a potential causal relationship between treatment and HRQoL has yet to be fully elucidated. Japanese patients reported better HRQoL outcomes on the Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain, a 6-question subset of the PDQ-39 which is considered to reflect the emotional aspects of the disease-specific HRQoL, when treated with rasagiline, than placebo, in both a monotherapy clinical trial (NCT02337725) and an adjunctive therapy clinical trial in patients with wearing-off phenomena (NCT02337738). OBJECTIVE: To investigate how rasagiline exerts its effect on the PDQ-39 emotional well-being domain in Japanese patients with Parkinson's disease. METHODS: A path analysis was performed to assess the direct treatment effects of rasagiline on the PDQ-39 emotional well-being domain and the effects mediated indirectly through the influence on items related to motor symptoms by a post-hoc analysis of two clinical trials in Japan. RESULTS: In the monotherapy trial, the PDQ-39 emotional well-being domain was mainly affected indirectly through items related to motor symptoms (80.7%) composed of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II (67.2%) and Part III (13.5%). In the adjunctive therapy trial, the PDQ-39 emotional well-being domain was also mainly influenced indirectly through effects on items related to motor symptoms (1 mg/day: 54.7%, 0.5 mg/day: 57.6%) composed of MDS-UPDRS Part II (1 mg/day: 35.6%, 0.5 mg/day: 40.9%), Part III (1 mg/day: 8.0%, 0.5 mg/day: 8.3%) and mean daily OFF-time (1 mg/day: 11.1%, 0.5 mg/day: 8.4%). CONCLUSIONS: The effects of rasagiline on the PDQ-39 emotional well-being domain were mediated primarily by influence on the subjective aspects of motor experiences of daily living.
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Antiparkinsonianos/uso terapéutico , Indanos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de Vida , Anciano , Emociones , Femenino , Humanos , Japón , Masculino , Enfermedad de Parkinson/psicología , Calidad de Vida/psicología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Myeloid differentiation primary response gene 88 (MyD88) is essential for microglial activation. Despite the significant role of microglia in regulating sleep homeostasis, the contribution of MyD88 to sleep is yet to be determined. To address this, we performed electroencephalographic and electromyographic recordings on MyD88-KO mice and wild-type mice to investigate their sleep/wake cycles. In the daytime, MyD88-KO mice exhibited prolonged wakefulness and shorter non-rapid eye movement sleep duration. Tail suspension and sucrose preference tests revealed that MyD88-KO mice displayed a depressive-like phenotype. We determined monoamines in the prefrontal cortex (PFC) using high-performance liquid chromatography and observed a decreased content of serotonin in the PFC of MyD88-KO mice. Flow cytometry revealed that CD11b, CD45, and F4/80 expressions were elevated at Zeitgeber time (ZT) 1 compared to at ZT13 only in wild-type mice. Furthermore, MFG-E8 and C1qB-tagged synapses were enhanced at ZT1 in the PFC of wild-type mice but not in MyD88-KO mice. Primary cultured microglia from MyD88-KO mice revealed decreased phagocytic ability. These findings indicate that genetic deletion of MyD88 induces insomnia and depressive behavior, at least in part, by affecting microglial homeostasis functions and lowering the serotonergic neuronal output.