RESUMEN
The role of inflammation and dysfunction of the cholinergic system in obstructive sleep apnea (OSA) has not exhaustively clarified. Thus, in this study, we explore the non-neuronal cholinergic system and the balance of T helper (Th) 17- and T regulatory (Treg)-related cytokines in OSA patients. The study includes 33 subjects with obstructive sleep apnea and 10 healthy controls (HC). The expression levels of cholinergic system component, RAR-related orphan receptor (RORc), transcription factor forkhead box protein 3 (Foxp3) and cytokines were evaluated. Th17- and Treg-related cytokines, choline levels and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activity were quantified in OSA and control subjects. AChE and nicotinic receptor α 7 subunit (α7nAChR) gene expression and serum levels of choline, AChE and BuChE were lower in OSA patients than in the HC group. Compared with the HC group, OSA patients exhibited an increased expression, secretion and serum levels of pro-inflammatory cytokines, a reduced expression, secretion and serum levels of transforming growth factor (TGF)ß and reduced Foxp3 mRNA levels. The Th17/Treg-related cytokine ratio was higher in the OSA group. Our results confirm and reinforce the hypothesis that OSA may be considered a systemic inflammatory disease, and that an imbalance of non-neuronal cholinergic and pro/anti-inflammatory cytokines may contribute to development and progression of comorbidities in OSA subjects. The evaluation of Th17/Treg-related cytokine may provide an additional explanation for OSA pathogenesis and clinical features, opening new directions for the OSA management.
Asunto(s)
Colina/metabolismo , Citocinas/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Adulto , Biomarcadores , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/etiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Acetylcholine (ACh) and its receptors of muscarinic and nicotinic types are involved in the modulation of immune and inflammatory responses. In present work we have characterized the nicotinic receptors expression in PBMC of RR-MS patients and healthy donors (HD) and their ability to modulate pro-inflammatory cytokines. Here we report that the IL-1ß e IL-17 levels are significantly increased in serum of RR-MS patients in respect to HD and that the PBMC stimulation with PHA caused a significant increase in pro-inflammatory cytokine levels both in RR-MS and HD subjects, with higher increase of protein release in RR-MS patients than in HD. The PBMC treatment with PHA plus nicotine produced a significant decrease of IL-1ß e IL-17 both as transcript and as protein, confirming that the PBMC of the patients respond to the cholinergic stimulation more than PBMC of HD. By real time PCR and western blot analysis we have also demonstrated that in particular α7 receptor subtype appeared expressed at comparable levels both in RR-MS patients and HD. The PHA stimulation results to inhibit the α7 subunit expression while the nicotine causes a significant increase in α7 transcripts but only in MS patients. The data obtained highlight the role of α7 receptor subtype in the modulation of anti-inflammatory cytokines also in MS. Moreover the ability of nicotine to up-regulate the expression of α7 receptor subtype in RR-MS patients, indicates that nicotinic receptor stimulation may contribute to down-modulate the inflammation occurred in MS by a positive feedback control of its expression.
Asunto(s)
Citocinas/metabolismo , Inflamación/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Receptores Nicotínicos/metabolismo , Células Cultivadas , Citocinas/genética , Regulación de la Expresión Génica/fisiología , Humanos , Leucocitos Mononucleares/metabolismo , Fitohemaglutininas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Nicotínicos/genéticaRESUMEN
A novel system for the neuro-motor rehabilitation of upper limbs was validated in three sub-acute post-stroke patients. The system permits synchronized cortical and kinematic measures by integrating high-resolution EEG, passive robotic device and Virtual Reality. The brain functional re-organization was monitored in association with motor patterns replicating activities of daily living (ADL). Patients underwent 13 rehabilitation sessions. At sessions 1, 7 and 13, clinical tests were administered to assess the level of motor impairment, and EEG was recorded during rehabilitation task execution. For each session and rehabilitation task, four kinematic indices of motor performance were calculated and compared with the outcome of clinical tests. Functional source maps were obtained from EEG data and projected on the real patients' anatomy (MRI data). Laterality indices were calculated for hemispheric dominance assessment. All patients showed increased participation in the rehabilitation process. Cortical activation changes during recovery were detected in relation to different motor patterns, hence verifying the system's suitability to add quantitative measures of motor performance and neural recovery to classical tests. We conclude that this system seems a promising tool for novel robot-based rehabilitation paradigms tailored to individual needs and neuro-motor responses of the patients.
Asunto(s)
Electroencefalografía/métodos , Recuperación de la Función , Robótica/métodos , Rehabilitación de Accidente Cerebrovascular , Interfaz Usuario-Computador , Actividades Cotidianas , Anciano , Fenómenos Biomecánicos , Encéfalo/fisiopatología , Corteza Cerebral/fisiopatología , Femenino , Lateralidad Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Trastornos del Movimiento/etiología , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/rehabilitación , Medicina de Precisión , Desempeño Psicomotor , Accidente Cerebrovascular/fisiopatología , Resultado del TratamientoRESUMEN
One post-stroke patient underwent neuro-motor rehabilitation of one upper limb with a novel system combining a passive robotic device, Virtual Reality training applications and high resolution electroencephalography (HR-EEG). The outcome of the clinical tests and the evaluation of the kinematic parameters recorded with the robotic device concurred to highlight an improved motor recovery of the impaired limb despite the age of the patient, his compromised motor function, and the start of rehabilitation at the 3rd week post stroke. The time frequency and functional source analysis of the HR-EEG signals permitted to quantify the functional changes occurring in the brain in association with the rehabilitation motor tasks, and to highlight the recovery of the neuro-motor function.
Asunto(s)
Electroencefalografía , Actividad Motora/fisiología , Rehabilitación Neurológica , Recuperación de la Función , Robótica , Accidente Cerebrovascular/fisiopatología , Terapia de Exposición Mediante Realidad Virtual , Anciano , Fenómenos Biomecánicos , Encéfalo/fisiopatología , Humanos , Masculino , Accidente Cerebrovascular/terapia , Rehabilitación de Accidente Cerebrovascular , SobrevivientesRESUMEN
Acetylcholine (ACh) has been the first molecule to be identified as neurotransmitter. The cholinergic and cholinoceptive areas, both in central and peripheral nervous system, have been well documented. Acetylcholine has been described to control, during embryogenesis, cell proliferation as well as neuron and glial cell survival and differentiation. In the adult, acetylcholine and its receptors are distributed in many tissues other than in the nervous system. More recently, new physiological roles in neuronal and non-neuronal tissues have been proposed for ACh as well as its possible involvement in different pathologies. Altered levels of ACh or modified receptors expression and function, in selected areas of the nervous system, have been described in several neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington as well as in psychiatric disorders such as schizophrenia. Frequently own cognitive, behavioral and motor disabilities that characterize these pathologies are correlated to cholinergic circuit dysfunction. Moreover the involvement of ACh as modulator of the inflammation, in and out of the nervous system, has suggested that its altered functions might represent an additional pathogenetic mechanism negatively influencing the disease outcome as recently suggested in multiple sclerosis. The present review will focus on identifying the cause/effect relationship that may explain the cholinergic dysfunction in several nervous system disorders. Moreover the possible therapeutic novelties including cholinesterase inhibitors, muscarinic agonists and antagonists, and genetic therapy will be discussed.
Asunto(s)
Acetilcolina/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Animales , Sistema Nervioso Central/fisiología , Sistema Nervioso Central/fisiopatología , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Neuroinmunomodulación/fisiologíaRESUMEN
Increasing evidence suggests that elevated production and/or reduced clearance of amyloid-ß peptide (Aß) drives the early pathogenesis of Alzheimer's disease (AD). Aß soluble oligomers trigger a neurotoxic cascade that leads to neuronal dysfunction, neurodegeneration and, ultimately, clinical dementia. Inflammation, both within brain and systemically, together with a deficiency in the neurotransmitter acetylcholine (ACh) that underpinned the development of anticholinesterases for AD symptomatic treatment, are invariable hallmarks of the disease. The inter-relation between Aß, inflammation and cholinergic signaling is complex, with each feeding back onto the others to drive disease progression. To elucidate these interactions plasma samples and peripheral blood mononuclear cells (PBMCs) were evaluated from healthy controls (HC) and AD patients. Plasma levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and Aß were significantly elevated in AD vs. HC subjects, and ACh showed a trend towards reduced levels. Aß challenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1ß (IL-1ß), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) from AD vs. HC subjects, with IL-10 being similarly affected. THP-1 monocytic cells, a cell culture counterpart of PBMCs and brain microglial cells, responded similarly to Aß as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning Aß-induced changes in cytokine expression. As amyloid-ß precursor protein expression, and hence Aß, has been reported regulated by particular cytokines and anticholinesterases, the latter were evaluated on Aß- and PHA-induced chemocytokine expression. Co-incubation with selective AChE/BuChE inhibitors, (-)-phenserine (AChE) and (-)-cymserine analogues (BuChE), mitigated the rise in cytokine levels and suggest that augmentation of the cholinergic anti-inflammatory pathway may prove valuable in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/metabolismo , Quimiocinas/metabolismo , Inhibidores de la Colinesterasa/farmacología , Citocinas/metabolismo , Acetilcolinesterasa/metabolismo , Anciano , Butirilcolinesterasa/metabolismo , Células Cultivadas , Quimiocina CCL2/metabolismo , Femenino , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/fisiología , Masculino , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The protein kinase C (PKC) family of enzymes is a regulator of transmembrane signal transduction, and involvement of some PKC isoforms in T-cell activation has been demonstrated. Nevertheless, very little is known about their involvement in the Amyloid beta (Abeta)-dependent molecular signals in the T lymphocytes of Alzheimer disease (AD) patients. Therefore, the aim of this study was to investigate the involvement of PKC-alpha, PKC-delta and PKC-zeta expression and activity in the signaling machinery activated in Abeta-reactive T cells, in adult healthy individuals, elderly healthy subjects, and from patients with AD. The results show that in peripheral T-cells from early AD patients, Abeta(1-42) produced a distinct subpopulation highly expressing P-PKC-delta, while in severe AD patients the same treatment induced two distinct P-PKC-delta and P-PKC-zeta T-cell subpopulations. Such subpopulations were not noticeable following CD3/CD28 treatment of the same samples or after treatment of peripheral T cells from healthy adult or elderly subjects with Abeta(1-42) or with CD3/CD28. We believe that these findings may be of help in possible attempts to develop further diagnostic strategies useful for the characterization of AD.