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BACKGROUND: Although unmet medical needs for better care of patients with chronic cough exist in Japan, epidemiological information about these patients and their treatments is very limited. OBJECTIVES: To describe patient characteristics, underlying cough-related diseases and drug utilisation patterns in patients with chronic cough, and their changes over time. METHODS: This large retrospective claims database study enrolled subjects with chronic cough, identified either by a specific diagnostic cough code for chronic cough (Population 1) or by multiple cough-related diagnostic codes spanning > 8 weeks (Population 2). Within Population 2, patients with each of the three most frequent diagnostic cough codes were analysed as subgroups. Patient characteristics, underlying cough-related diseases and utilisation patterns for drugs used for cough were documented at the index date, during the 6-month pre-index period and during the 12-month post-index period. RESULTS: 6,038 subjects were enrolled in the cohort (Population 1: N = 3,500; Population 2: N = 2,538). The mean age was 43.7 ± 12.2 years and 61.8% were women. The largest cough diagnosis subgroups in Population 2 were 'other coughs' (N = 1,444), 'cough-variant asthma' (N = 1,026) and 'atopic/allergic cough' (N = 105). At the index date, the most frequent underlying cough-related diseases were allergic rhinitis/nasal inflammation (N = 3,132; 51.9%), asthma (N = 2,517; 41.7%) and gastro-esophageal reflux disease (N = 829; 13.7%). At the index date, 4,860 participants (80.5%) were prescribed at least one cough-related treatment. 194 participants (4.0% of medication users) were prescribed central antitussives alone, principally in Population 1, and 2,331 (48.0%) were prescribed expectorants. Other frequently prescribed medications were antiallergic drugs (N = 2,588; 53.3%), antimicrobials (N = 1,627; 34.4%) and inhaled corticosteroids with long-acting beta-agonists (N = 1,404; 28.9%). Over time, cough diagnoses tended to be lost, with only 470 participants in Population 1 retaining a diagnostic code for chronic cough one year later. The frequency of underlying cough-related diseases was stable over time. CONCLUSIONS: Patients in this cohort with chronic cough are most frequently identified by a diagnostic cough code for chronic cough, followed by codes for other coughs, cough-variant asthma and atopic cough. Chronic cough frequently presents with an underlying cough-related disease, most frequently allergic rhinitis/nasal inflammation, asthma or GERD. Medication prescription for the underlying cough-related diseases was generally appropriate.
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Asma , Reflujo Gastroesofágico , Hipersensibilidad Inmediata , Rinitis Alérgica , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Tos/tratamiento farmacológico , Tos/epidemiología , Japón/epidemiología , Estudios Retrospectivos , Utilización de Medicamentos , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/epidemiología , Asma/complicaciones , Asma/tratamiento farmacológico , Asma/epidemiología , InflamaciónRESUMEN
BACKGROUND: Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese patients with refractory chronic cough (refractory to treatment of underlying relevant medical conditions) and unexplained chronic cough (symptoms of unexplained origin). METHODS: This non-interventional, cross-sectional study was conducted between February and March 2021 among patients (aged ≥ 20 years) with self-reported refractory or unexplained chronic cough. Subjects with a history of comorbid respiratory conditions were excluded. Eligible subjects participated in a 60-min online semi-structured interview. Verbatim terms from interviews were qualitatively transcribed and generated into word clouds, followed by a clustering analysis in which meaningful clusters were chosen, manually coded, and utterances and burdens categorized. RESULTS: A total of 21 participants (95.2% with refractory chronic cough, mean age 53.5 years, and 76.2% being males) with Leicester Cough Questionnaire mean ± standard deviation scores of physical 4.8 ± 1.1, psychological 4.4 ± 1.3, social 4.9 ± 1.4, and total 14.1 ± 3.5 were included. The word cloud identified the most frequently used word ('cough'); etiology ('asthma'); and words associated with change in states ('influence,' 'changing,' 'change') and expressions ('tough,' 'pain,' 'hard,' 'terrible,' 'unpleasant'). The patients experienced 'mental/social burden,' 'physical burden,' 'impact on sleep and meals,' 'impact on work and housework,' 'impact on communication,' 'impact on hobbies and leisure,' and 'economic burden.' By closed coding analysis, the situations or types of burden patients experienced from the cough were ordered sequentially as emotion, working style, acquaintanceship, hobbies and leisure, and sleeping pattern. CONCLUSIONS: The present study indicated that there were two types of participant clusters, in which one showed mainly the burdens in the social communications such as work-related communication and another one showed the burdens of relationships with others. Also, some participants highlighted 'mental burden,' on social life due to the current pandemic. To relieve these burdens, disease awareness and knowledge should be improved for patients with refractory and unexplained chronic cough. Trial registration The trial was registered under UMIN-CTR as UMIN000042772, on 17/12/2020. The study was approved by the Medical Corporation Toukeikai Kitamachi Clinic (IRB registration number: 11001110).
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Costo de Enfermedad , Tos , Enfermedad Crónica , Tos/psicología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Investigación CualitativaRESUMEN
BACKGROUND: Cough lasting 3-8 weeks and more than 8 weeks are defined as subacute/prolonged cough and chronic cough, respectively. Japanese chronic cough population has not been well studied. This study aimed to describe the prevalence and characteristics of chronic cough and subacute cough patients in Japan. This study also sought to compare between chronic cough patients who were not greatly satisfied with treatment effectiveness for resolving cough and other chronic cough patients. METHODS: Data from a cross-sectional online 2019 Japan National Health and Wellness Survey and a supplemental chronic cough survey were used to understand respondents' chronic cough status and their cough-specific characteristics and experience. The prevalence, patient characteristics and cough-specific characteristics were summarised descriptively. Patients who were not greatly satisfied with treatment effectiveness and other chronic cough patients were compared for their characteristics and cough severity. RESULTS: The point prevalence of chronic cough was 2.89% and 12-month period prevalence was 4.29%. Among all chronic cough patients analysed, the average age was 56 years old, 61.1% were males and 29.4% were current smokers. Patients were most frequently told by a physician that cough was related to allergic rhinitis, asthma and cough variant asthma. Only 44.2% of chronic cough patients had spoken with a physician about their cough, and half of chronic cough patients did not use any medications. Patients who were not greatly satisfied with treatment effectiveness had significantly greater cough severity during past 2 weeks compared with other chronic cough patients (Visual Analogue Scale 45.34 vs 39.63). CONCLUSIONS: This study described the prevalence and patient characteristics information of chronic cough patients in Japan. Furthermore, the study highlighted an unmet need for better diagnosis and treatments for chronic cough patients, especially among patients who were not greatly satisfied with treatment effectiveness and reported significantly worse cough severity.
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Tos , Internet , Tos/epidemiología , Estudios Transversales , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y CuestionariosRESUMEN
BACKGROUND: Cough lasting 3-8 and >8 weeks are defined as subacute/prolonged cough and chronic cough (CC), respectively. Studies have revealed that CC negatively impact patients' quality of life (QoL). In Japan, there is limited data on the impact of CC on health-related quality of life (HRQoL), work productivity and activity impairment (WPAI) and healthcare resource utilisation (HRU) using validated instruments. This study aimed to estimate the burden of CC and to compare the burden among patients with CC between subgroups. METHODS: Data from two cross-sectional online surveys conducted between September and November 2019 were combined for the analysis. Eligible patients with cough were propensity score matched to non-cough respondents. Comparisons of general HRQoL, WPAI, HRU and other symptoms experienced were conducted between matched non-cough respondents and patients with cough. Among patients with CC, subgroup comparisons were performed to understand general HRQoL, WPAI, HRU, cough-related QoL (Leicester Cough Questionnaire and Hull Airway Reflux Questionnaire) between patients with CC of different severities, patients with refractory CC and patients with non-refractory CC and patients with CC whose underlying diseases were unknown and others. RESULTS: Patients with CC (n=568) in Japan reported significantly poorer HRQoL, increased WPAI, more HRU and higher proportion of psychological and sleep problems, compared with matched non-cough respondents selected from 21 415 non-cough respondents. More patients with severe CC reported significantly poorer HRQoL, increased WPAI and worse cough-related QoL. Patients with refractory CC experienced significantly greater burden measured by cough-related QoL. No significant differences were observed between patients with CC whose underlying diseases were unknown and other patients with CC in terms of general HRQoL and cough-related QoL. CONCLUSIONS: This study showed that patients with CC in Japan experienced significant burden compared with non-cough respondents. Patients with more severe cough and refractory CC experienced worse cough-related QoL. These results highlighted the unmet need for better interventions and treatments to reduce the burden among patients with CC.
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Costo de Enfermedad , Calidad de Vida , Tos/epidemiología , Estudios Transversales , Encuestas Epidemiológicas , Humanos , Japón/epidemiologíaRESUMEN
To investigate medication adherence to oral antihyperglycemic agents and its associated factors in Japanese type 2 diabetic patients, a questionnaire survey was conducted in 983 adult patients receiving once-daily (QD) or twice-daily (BID) dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitor) or BID biguanides (BG) as monotherapy at 502 pharmacies in Japan. The percentage of patients with good adherence (the proportion of days in which patients took all pills as prescribed in the past 7 days ≥80%) was high (≥90%) in any dosing regimen with no significant difference among the groups. The following factors were identified as associating with good adherence: the longer duration of type 2 diabetes (≥1 year) (p=0.002), "Feeling your disease gets worse if you don't take medications" (p=0.031), "Not forgetting to bring along your medicine when you leave home" (p=0.007), "Feeling anxiety on taking medications for long period of time" (p=0.042), "Neither feeling nor not feeling anxiety on taking medications for a long period of time" (p=0.004), "Never run out of your medicine because you get a refill on time" (p=0.035), and the lower MMAS-4 score (p<0.001). Subgroup analyses revealed that adherence of younger patients (<65 years) with BG (BID) was lower than those with DPP-4 inhibitor (QD) (p=0.021). Additionally, around 60% of patients currently prescribed with QD preferred QD regimen, and ≥80% patients prescribed with BID equally preferred once-weekly or QD regimen, suggesting a large discrepancy exists between their preference and the actual regimen in patients on BID.
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Biguanidas/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Hipoglucemiantes/administración & dosificación , Cumplimiento de la Medicación , Administración Oral , Adulto , Anciano , Ansiedad , Femenino , Humanos , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is undertreated in Japan. We sought to understand the potential factors associated with reluctance to initiate/continue oral antihyperglycemic agents (OAHA) treatment in Japan. METHODS: A two-phase study was conducted which included cognitive interviews in the first phase (Nâ¯=â¯12) to ensure retrieval from memory of relevant information to respond to questions. The second phase included recruitment of respondents from an internet re-contact survey (Nâ¯=â¯560) using NHWS or other Lightspeed panels. Patients' self-reported measures were collected to identify the potential barriers to T2DM treatment initiation or continuation. All measured variables were summarized descriptively using means and standard deviations for continuous variables, and frequencies and percentages for categorical variables. RESULTS: A total of 560 respondents were assessed. Of those who were drug-naïve and ever been recommended prescription medication, only 17.3% were satisfied with how physicians presented the treatment options compared to current users or those who discontinued treatment (47.2% and 47.6% respectively). More than 50% of respondents did not realize neuropathic pain and end organ damage as potential consequences of untreated T2DM. 34.8% and 47.6% of drug-naïve and T2DM respondents who discontinued treatment were likely to start/restart treatment after realizing potential complications. Among those who discontinued treatment, 23.1% were extremely dissatisfied with their dosing frequency and less than 15% reported that their physicians discussed the importance of staying on medication long-term. CONCLUSION: The potential barriers addressed in this study should be considered when planning intervention strategies targeted at T2DM patients to promote their treatment in Japan.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Hipoglucemiantes/uso terapéutico , Cumplimiento de la Medicación/psicología , Cumplimiento de la Medicación/estadística & datos numéricos , Medición de Resultados Informados por el Paciente , Biomarcadores/análisis , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Investigación Cualitativa , Autoinforme , Encuestas y CuestionariosRESUMEN
BACKGROUND: Sleep disturbance in Alzheimer's disease (AD) patients may have a negative impact not only on patients themselves but also on the physical and mental health of their caregivers. Detailed analysis of these issues is lacking. OBJECTIVE: This study investigated the association between sleep disturbance in AD patients and the burden on, and health status of, their caregivers in Japan. METHODS: We conducted a cross-sectional web-based questionnaire survey among caregivers of AD patients with insomnia symptoms in Japan. Demographic data and Sleep Disorders Inventory (SDI) scores for patients, caregiver burden (Burden Index of Caregivers-11 [BIC-11]) and health status, including Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9, and 12-Item Short Form Health Survey v2, were collected. Multivariate analysis was used to examine the association between the burden and health status of caregivers and sleep disturbance in their care recipients with AD. RESULTS: A total of 496 caregivers of AD patients with insomnia symptoms were examined in this study. We found that the BIC-11 total score increased as the SDI score increased, indicating a significant positive association, even after adjusting for confounding factors. We also found an association between sleep disturbances of AD patients and health of caregivers (sleep quality, depression, and physical/mental quality of life). CONCLUSION: This study demonstrated that sleep disturbance in AD patients was associated with an increased burden and poorer health status of caregivers. Our findings highlight the importance of sleep management in AD patients.
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Enfermedad de Alzheimer/enfermería , Cuidadores , Costo de Enfermedad , Familia , Estado de Salud , Calidad de Vida , Trastornos del Inicio y del Mantenimiento del Sueño/enfermería , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Adulto JovenRESUMEN
AIMS/INTRODUCTION: The present study aimed to describe hospital utilization and examine actual medical costs for severe hypoglycemic events in patients with type 2 diabetes mellitus in Japan. MATERIALS AND METHODS: Medical resource utilization associated with severe hypoglycemia was evaluated using a receipt database of acute-care hospitals in Japan. Patients with type 2 diabetes treated with antihyperglycemic agents were included. Severe hypoglycemic events were identified and divided into two groups: with or without hospitalization. Total and attributable medical costs per event were calculated based on the actual medical treatment after severe hypoglycemic events. Attributable costs were estimated from the receipt codes directly associated with the treatment of severe hypoglycemia. RESULTS: In the hospitalized patients, the median length of hospital stay was 11 days, and the median total and attributable medical costs were ¥402,081 and ¥302,341, respectively. The majority of the hospitalized patients underwent a radiographic examination and general blood tests. Apart from the hospitalization costs, the costs associated with diagnosis accounted for 29.6% of the total medical costs. In the outpatients, 60.6% visited hospitals only once for the severe hypoglycemic event, whereas 11.4% visited hospitals daily for a week after the severe hypoglycemic event. The mean number of hospital visits of the outpatient after a severe hypoglycemic event was 2.7 ± 2.6 days. The median total and attributable medical costs were ¥265,432 and ¥4,628, respectively. CONCLUSIONS: Significant medical resources are used for the treatment of severe hypoglycemic events of patients with type 2 diabetes in Japan.
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Análisis Costo-Beneficio , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/economía , Recursos en Salud/economía , Hospitalización/economía , Hipoglucemia/economía , Insulina/efectos adversos , Anciano , Biomarcadores/análisis , Glucemia/análisis , Servicio de Urgencia en Hospital , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Costos de la Atención en Salud , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/diagnóstico , Hipoglucemia/terapia , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/economía , Insulina/economía , Japón , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
AIMS/INTRODUCTION: To evaluate the incidence rate of and identify factors associated with severe hypoglycemic episodes in patients with treated type 2 diabetes mellitus. MATERIALS AND METHODS: Using Diagnosis Procedure Combination hospital-based medical database, we carried out a retrospective cohort study to assess the incidence rate of severe hypoglycemia in treated type 2 diabetes mellitus patients. We evaluated the associations between severe hypoglycemia and age, sex, complications, and current use of insulin or sulfonylurea (SU) in a nested case-control study. RESULTS: Of 166,806 eligible patients, 1,242 had episodes of severe hypoglycemia during the observational period. The incidence rate of the first hypoglycemic events was 3.70/1,000 patient years. Based on the nested case-control analysis, age was associated with hypoglycemic events with adjusted odds ratios (ORs) of 1.64 or 65-74-year-old patients and 3.79 for ≥75-year-old patients in comparison with 20-64-year-old patients. Comorbidities, such as cognitive impairment, cancer, macrovascular disease and diabetic complications (retinopathy, nephropathy and neuropathy), were associated with severe hypoglycemia, with adjusted ORs ranging from 1.25 to 3.80. Severe hypoglycemic events also increased in patients with current use of both SU and insulin, either SU or insulin, with adjusted ORs of 18.36, 6.31 or 14.07, respectively, compared with patients with other antihyperglycemic agents. In patients with an SU glimepiride, adjusted ORs increased dose-dependently from 3.65 (≤1 mg) to 13.34 (>2 mg). CONCLUSIONS: The incidence rate of severe hypoglycemia in this cohort was 3.70/1,000 patient years. Age, cognitive impairment, cancer, diabetic complications, current use of insulin + SU and SU dosage were identified as risk factors for severe hypoglycemia.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemia/epidemiología , Adulto , Anciano , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/uso terapéutico , Incidencia , Insulina/uso terapéutico , Japón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Compuestos de Sulfonilurea/uso terapéutico , Adulto JovenRESUMEN
Drug development for neurodegenerative and neuroinflammatory diseases such as multiple sclerosis and traumatic brain injury is challenging. One promising strategy is to target a molecule with multiple biological actions affecting divergent pathophysiological disease phases simultaneously since these diseases arise from multiple pathological phases. In recent years, we pursued this strategy with a focus on multiple sclerosis and spinal cord injury and found that repulsive guidance molecule-a (RGMa) inhibits regeneration of injured CNS axons following spinal cord injury. We also found that RGMa enhances CD4(+) T cell activation facilitating CNS demyelination in an animal model of MS, mouse experimental autoimmune encephalomyelitis (EAE), which supports the idea that RGMa has distinct pathological actions. The multiple functions of RGMa in the CNS and the immune system would provide a therapeutic opportunity to concurrently block the autoimmune reactions and axon injury in neurodegenerative and neuroinflammatory diseases. In this article, we introduce the therapeutic potential of targeting RGMa as a novel intervention for MS and spinal cord injury.
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Enfermedades Desmielinizantes/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/fisiología , Animales , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Sistemas de Liberación de Medicamentos/métodos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/fisiología , Humanos , Factores Inmunológicos/administración & dosificación , Ratones , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Proteínas del Tejido Nervioso/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
BACKGROUND: The exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA. METHODS: Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7, 14, 21, and 28 days post injection. Dorsal root ganglia (DRG) were immunostained for three molecules after 7, 14, 21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant. RESULTS: Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn. CONCLUSIONS: Pain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.
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Artralgia/patología , Mediadores de Inflamación/toxicidad , Ácido Yodoacético/toxicidad , Osteoartritis de la Rodilla/patología , Células Receptoras Sensoriales/patología , Animales , Artralgia/etiología , Artralgia/fisiopatología , Enfermedad Crónica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Inflamación/inducido químicamente , Inflamación/patología , Inflamación/fisiopatología , Estudios Longitudinales , Degeneración Nerviosa/etiología , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/fisiopatología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Ratas Sprague-Dawley , Células Receptoras Sensoriales/metabolismoRESUMEN
In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.
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Encefalomielitis Autoinmune Experimental/inmunología , Proteínas del Tejido Nervioso/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos Neutralizantes/administración & dosificación , Secuencia de Bases , Linfocitos T CD4-Positivos/inmunología , Adhesión Celular/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Activación de Linfocitos , Macrófagos/inmunología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/inmunología , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Proteínas del Tejido Nervioso/antagonistas & inhibidores , ARN Interferente Pequeño/genéticaRESUMEN
Glial cells, including astrocytes and macrophages/microglia, are thought to modulate pathological states following spinal cord injury (SCI). In the present study, we evaluated the therapeutic effects of interferon-γ (IFN-γ), which is one of the cytokines regulating glial function, in a mouse contusive SCI model. We found that intraperitoneal injection of IFN-γ significantly facilitated locomotor improvement following SCI. Immunohistochemistry demonstrated that IFN-γ decreased the accumulation of chondroitin sulfate proteoglycans (CSPGs), which are critical axon outgrowth inhibitors produced by reactive astrocytes in the injured central nervous system (CNS). Quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting demonstrated that neurocan, one of several CSPGs, was reduced in the spinal cords of IFN-γ-treated mice compared to vehicle-treated mice. Consistently, IFN-γ inhibited the production of neurocan from activated astrocytes in vitro. In addition, IFN-γ treatment enhanced the number of serotonin-positive nerve fibers and myelinated nerve fibers around the lesion epicenter. We also found that glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor-1 (IGF-1) were upregulated post-SCI following IFN-γ treatment. Our results indicate that IFN-γ exhibits therapeutic effects in mouse contusive SCI, presumably by reducing CSPG expression from reactive astrocytes and increasing the expression of neurotrophic factors.
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Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Miembro Posterior/efectos de los fármacos , Interferón gamma/farmacología , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Análisis de Varianza , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Western Blotting , Células Cultivadas , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Miembro Posterior/fisiopatología , Inmunohistoquímica , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/patología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
The roles of T lymphocytes in the central nervous system (CNS) are diverse; their roles in the injured CNS have been reported to be both detrimental and advantageous. Hence, an investigation of the effects of specific subsets of T cells on neurons may provide an insight into the interaction between the nervous system and the immune system. In the present study, we demonstrate that a specific subset of T lymphocytes enhanced neurite outgrowth in vitro. When cultured T helper type 1 (Th1) cells were co-cultured with cortical neurons, neurite outgrowth from neurons was enhanced; however, the same was not observed when Th2 or naïve T cells were used. We observed that the promotion of neurite outgrowth by Th1 cells was completely inhibited by anti-interferon γ (IFN-γ) neutralizing antibody, but that IFN-γ did not directly promote neurite growth. Furthermore, experiments using knockout mice revealed that semaphorin 4A (Sema4A) but not Sema7A was required for the effect produced by Th1 cells. These results demonstrate that Sema4A and IFN-γ expressed in Th1 cells play a critical role in enhancing neurite outgrowth from cortical neurons.
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Corteza Cerebral/citología , Neuritas/fisiología , Neuronas/fisiología , Semaforinas/fisiología , Células TH1/fisiología , Animales , Antígenos CD/genética , Antígenos CD/fisiología , Técnicas de Cocultivo , Interferón gamma/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuritas/efectos de los fármacos , Neuronas/efectos de los fármacos , Semaforinas/genéticaRESUMEN
Clinical course and prognosis are variable among patients with chronic inflammatory demyelinating polyneuropathy (CIDP), whereas the extent of axonal degeneration is the major prognostic factor. We studied the effects of sera from CIDP patients on axonal growth in cultured mouse dorsal root ganglion neurons. Compared with control sera, CIDP sera prominently suppressed axonal outgrowth of dorsal root ganglion neurons and shortened axonal length. The inhibitory activity was abolished by adding Y27632, a Rho-kinase inhibitor. These findings suggest that CIDP sera inhibit axonal elongation by Rho-kinase activation, and some serum factors may be responsible for development of axonal degeneration in CIDP.
Asunto(s)
Axones/patología , Ganglios Espinales/patología , Inhibición Neural/fisiología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/patología , Suero , Quinasas Asociadas a rho/metabolismo , Adulto , Amidas/farmacología , Animales , Axones/efectos de los fármacos , Axones/enzimología , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/enzimología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Inhibición Neural/efectos de los fármacos , Neuritas/efectos de los fármacos , Neuritas/enzimología , Neuritas/patología , Piridinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/fisiologíaRESUMEN
Rho-kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho. The Rho-ROCK pathway is involved in many aspects of neuronal functions including neurite outgrowth and retraction. The Rho-ROCK pathway becomes an attractive target for the development of drugs for treating central nervous system (CNS) disorders, since it has been recently revealed that this pathway is closely related to the pathogenesis of several CNS disorders such as spinal cord injuries, stroke, and Alzheimer's disease (AD). In the adult CNS, injured axons regenerate poorly due to the presence of myelin-associated axonal growth inhibitors such as myelin-associated glycoprotein (MAG), Nogo, oligodendrocyte-myelin glycoprotein (OMgp), and the recently identified repulsive guidance molecule (RGM). The effects of these inhibitors are reversed by blockade of the Rho-ROCK pathway in vitro, and the inhibition of this pathway promotes axonal regeneration and functional recovery in the injured CNS in vivo. In addition, the therapeutic effects of the Rho-ROCK inhibitors have been demonstrated in animal models of stroke. In this review, we summarize the involvement of the Rho-ROCK pathway in CNS disorders such as spinal cord injuries, stroke, and AD and also discuss the potential of Rho-ROCK inhibitors in the treatment of human CNS disorders.
RESUMEN
During the early developmental stage, a neural circuit is established between the entorhinal cortex (EC) and the hippocampal dentate gyrus (DG) via the perforant pathway. However, the manner in which the perforant fibers are navigated has mostly remained a mystery. Here, we analyzed the functional role of a chemokine, namely, stromal cell-derived factor 1alpha (SDF-1alpha), in the navigation of the perforant fibers. SDF-1alpha was observed to promote neurite growth, which is dependent on mDia1, in cultured entorhinal cortical neurons obtained from rats at postnatal day 0. We then used entorhino-hippocampal cocultures comprising green fluorescence-labeled EC and DG slices to assess the projection of the perforant fibers from the EC. Although the specific laminar termination of the entorhinal axons was observed with this system, the number of appropriately terminating entorhinal axons decreased significantly when the SDF-1alpha signaling pathway was blocked by a neutralizing antibody against SDF-1alpha or by the specific SDF-1alpha receptor antagonist AMD3100 (1,1'-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetra-azacyclotetradecane octahydrochloride). Furthermore, inhibition of the SDF-1alpha signaling pathway resulted in a decrease in the immunoreactivity for PSD-95 (postsynaptic density protein-95) in the DG, possibly because of a reduction in the number of projecting perforant fibers. These results demonstrate that SDF-1alpha plays a critical role in promoting the growth of perforant fibers from the EC to the DG.
Asunto(s)
Axones/fisiología , Quimiocina CXCL12/fisiología , Giro Dentado/fisiología , Corteza Entorrinal/fisiología , Hipocampo/fisiología , Vía Perforante/fisiología , Animales , Animales Modificados Genéticamente , Células Cultivadas , Técnicas de Cultivo de Órganos , Vía Perforante/efectos de los fármacos , RatasRESUMEN
Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system. Functional studies in Xenopus and chick embryos revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos demonstrated its function in regulating cephalic neural tube closure. Moreover, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we demonstrate in vitro that RGMa, an RGM homolog, inhibits neurite growth and cortical neuron branching on mouse embryonic day 16. Further, exposure of cultured neurons to RGMa significantly reduced the number of colocalized immunoreactive clusters of synapsin 1 and PSD-95 in the spines. This RGMa-mediated inhibition of the assembly of presynaptic and postsynaptic components suggests a role of RGMa in inhibiting mature synapse formation. Thus, RGMa may negatively regulate neuronal network formation in cortical neurons.
Asunto(s)
Proteínas del Tejido Nervioso/fisiología , Neuritas/fisiología , Células Piramidales/fisiología , Tractos Piramidales/crecimiento & desarrollo , Animales , Células Cultivadas , Técnicas de Cocultivo , Homólogo 4 de la Proteína Discs Large , Proteínas Ligadas a GPI , Guanilato-Quinasas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos , Proteínas del Tejido Nervioso/farmacología , Neuritas/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Tractos Piramidales/citología , Tractos Piramidales/efectos de los fármacos , Sinapsinas/metabolismoRESUMEN
Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system [T. Yamashita, B.K. Mueller, K. Hata, Neogenin and RGM signaling in the central nervous system, Curr. Opin. Neurobiol. 17 (2007) 29-34]. Functional studies in Xenopus and chick embryos have revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos have demonstrated its function in regulating the cephalic neural tube closure. Importantly, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we identified two RGMa-derived peptides that functioned as antagonists against RGMa. The peptides studied in vitro dose-dependently suppressed the neurite growth inhibition and growth cone collapse induced by RGMa. Thus, these peptides are promising reagents to treat injuries of the central nervous system.
Asunto(s)
Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/química , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/química , Péptidos/química , Péptidos/farmacología , Secuencia de Aminoácidos , Animales , Células Cultivadas , Proteínas Ligadas a GPI , Conos de Crecimiento/efectos de los fármacos , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Neuritas/efectos de los fármacos , Péptidos/síntesis química , Ratas , Ratas EndogámicasRESUMEN
Although myelin-associated neurite outgrowth inhibitors express their effects through RhoA/Rho-kinase, the downstream targets of Rho-kinase remain unknown. We examined the involvement of myosin II, which is one of the downstream targets of Rho-kinase, by using blebbistatin - a specific myosin II inhibitor - and small interfering RNA targeting two myosin II isoforms, namely, MIIA and MIIB. We found that neurite outgrowth inhibition by repulsive guidance molecule (RGMa) was mediated via myosin II, particularly MIIA, in cerebellar granule neurons. RGMa induced myosin light chain (MLC) phosphorylation by a Rho-kinase-dependent mechanism. After spinal cord injury in rats, phosphorylated MLC in axons around the lesion site was up-regulated, and this effect depends on Rho-kinase activity. Further, RGMa-induced F-actin reduction in growth cones and growth cone collapse were mediated by MIIA. We conclude that Rho-kinase-dependent activation of MIIA via MLC phosphorylation induces F-actin reduction and growth cone collapse and the subsequent neurite retraction/outgrowth inhibition triggered by RGMa.