RESUMEN
The benefits of neuromodulatory procedures as a possible therapeutic application for cognitive rehabilitation have increased with the progress made in non-invasive modes of brain stimulation in aged-related disorders. Transcranial magnetic stimulation (TMS) is a non-invasive method used to examine multiple facets of the human brain and to ameliorate the impairment in cognition caused by Alzheimer's disease (AD). The present study was designed to evaluate how a chronic TMS treatment could improve learning and memory functions after sleep deprivation (SD) in old Octodon degus. SD was executed by gently handling to keep the animals awake throughout the night. Thirty young and twenty-four old O. degus females were divided in six groups (control, acute and chronic TMS treatment). Behavioral tests included; Radial Arm Maze (RAM), Barnes Maze (BM) and Novel Object Recognition (NOR). Although learning and memory functions improved in young animals with only one session of TMS treatment, a significant improvement in cognitive performance was seen in old animals after 4 and 7days of TMS, depending on the task that was performed. No side effects were observed following, which showed therapeutic potential for improving age-related cognitive performance.
Asunto(s)
Envejecimiento/fisiología , Encéfalo/fisiopatología , Cognición/fisiología , Memoria/fisiología , Privación de Sueño/fisiopatología , Aprendizaje Espacial/fisiología , Animales , Conducta Animal/fisiología , Femenino , Octodon , Estimulación Magnética TranscranealRESUMEN
AIMS: Mice and nonhuman primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. METHODS: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell-specific markers and analysed by confocal microscopy. RESULTS: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. CONCLUSIONS: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Neuronas Dopaminérgicas/patología , Neostriado/citología , Oligodendroglía/citología , Trastornos Parkinsonianos/patología , Sustancia Negra/citología , Animales , Modelos Animales de Enfermedad , Macaca , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Parkinsonianos/inducido químicamenteRESUMEN
Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA-induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3-4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment (p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PD patients.
Asunto(s)
Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Trastornos Parkinsonianos , Animales , Levodopa/efectos adversos , Antiparkinsonianos/efectos adversos , Calidad de Vida , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , Enfermedad de Parkinson/tratamiento farmacológico , PrimatesRESUMEN
Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson's disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1+; CD68+) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-α and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68+/ Iba-1+ cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions. Graphical Abstract MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxicant that, after crossing the Blood Brain Barrier, is metabolized by astrocytic MAO-B to MPDP+, a pyridinium intermediate, which undergoes further two-electron oxidation to yield the toxic metabolite MPP+ (methyl-phenyltetrahydropyridinium) that is then selectively transported into nigral neurons via the mesencephalic dopamine transporter. In this study, we demonstrated that MPTP induced death of dopaminergic neurons, microgliosis, increase of gliapses, motor impairment and neuroinflammation in mice, which were inhibited by combined 1-deoxynojirimycin and ibuprofen treatment.
Asunto(s)
1-Desoxinojirimicina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Ibuprofeno/farmacología , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/patología , Animales , Antiinflamatorios/farmacología , Conducta Animal/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Inhibidores Enzimáticos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/patología , Fagocitosis/efectos de los fármacosRESUMEN
OBJECTIVE: To estimate the influence of skin-to-skin care on the thermal regulation of the infant and the rate of breastfeeding at different points of time. We also aim to establish whether skin-to-skin contact reduces maternal pain during episiotomy repair and decreases the time to expel the placenta. METHODS: A randomized control study was performed with 137 patients in each branch of the study. Differences between the study groups were analysed with the unpaired t-test, Fisher test or chi-square test as appropriate. RESULTS: Greater thermal stability in the skin-to-skin care group was found where an average temperature rise of 0.07°C was observed. Mothers in the skin-to-skin care group exclusively breastfed more frequently at discharge. Mean time to expel the placenta was lesser in the skin-to-skin care group. CONCLUSION: This study shows that skin-to-skin care implies better thermal regulation and a better proportion of exclusive breastfeeding at hospital discharge.
Asunto(s)
Regulación de la Temperatura Corporal , Lactancia Materna/estadística & datos numéricos , Cuidado del Lactante/métodos , Relaciones Madre-Hijo , Tacto/fisiología , Episiotomía , Femenino , Humanos , Recién Nacido , Tercer Periodo del Trabajo de Parto/fisiología , Madres , Dolor Postoperatorio/prevención & control , Embarazo , Piel , Factores de TiempoRESUMEN
Different cellular mechanisms have been described as being potentially involved in the progression of neurodegeneration in Parkinson's disease, although their role is still unclear. The present study aimed to identify in detail, through differentially expressed genes analysis by bioinformatics approaches, the molecular mechanisms triggered after a systemic insult in parkinsonian mice. To address this objective, we combined a dextran sodium sulfate (DSS)-induced ulcerative colitis experimental mice model with an acute 1-methyl-4-phenyl-1,2,3,6-tetradropyridine (MPTP) intoxication. The animals were divided into four experimental groups based on the different treatments: (i) control, (ii) DSS, (iii) MPTP and (iv) MPTP + DSS. The data obtained by microarray and functional enrichment analysis point out the implication of different molecular mechanisms depending on the experimental condition. We see, in the striatum of animals intoxicated only with DSS, dysfunction processes related to the blood. On the other hand, oxidative stress processes are more prominent at the MPTP intoxicated mice. Finally, differentially expressed genes within the MPTP + DSS show functional enrichment in inflammation and programmed cell death. Interestingly, we identify a significant synergistic negative effect of both toxins since the expression of differentially expressed genes (DEGs) related to balanced cellular homeostasis was not enough to prevent processes associated with cell death. This work provides detailed insights into the involvement of systemic inflammation, triggered after an insult in the colon, in the progression of the degeneration in Parkinsonism. In this way, we will be able to identify promising therapeutic targets that prevent the contribution of inflammatory processes in the progression of Parkinson's disease.
Asunto(s)
Colitis , Regulación de la Expresión Génica , Intoxicación por MPTP , Transcriptoma , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , Masculino , RatonesRESUMEN
After Alzheimer's disease, Parkinson's disease (PD) is the second most prevalent and incidental neurodegenerative disorder, affecting more than 2% of the population older than 65 years old. Since it was first described 200 years ago by Dr James Parkinson, great steps have been made in the understanding of the pathology. However, the cause(s) that initiates and perpetuates the neurodegenerative process is (are) still not clear. Thus, early diagnosis is not available, nor are there efficient therapies that can stop neurodegeneration. PD clinical features are defined by motor (like bradykinesia, resting tremor, gait impairment) and non-motor symptoms (like constipation, apathy, fathigue, olfactory dysfunction, depression and cognitive decline) that get more severe as the disease advances. Neuropathological hallmarks comprise selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and Lewy bodies (LB) in different nuclei of the nervous system. Numerous studies have shown that these pathological features are aggravated by the confluence of other contributing factors, such as a genetic component, exposure to environmental toxins, mitochondrial dysfunction, increase of oxidative stress, calcium imbalance and chronic neuroinflammation, among others. Here, we provide a summary of the actual state of PD's pathology, the most studied molecular mechanisms, classic and novel therapeutic strategies and diagnosis methods, especially highlighting recent advances in these 200 years.
Asunto(s)
Dopamina/metabolismo , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/historia , Enfermedad de Parkinson/fisiopatología , Animales , Calcio/metabolismo , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Terapia Genética , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Homeostasis , Humanos , Inflamación , Cuerpos de Lewy/metabolismo , Mitocondrias/metabolismo , Destreza Motora , Estrés Oxidativo , Enfermedad de Parkinson/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , alfa-Sinucleína/genéticaRESUMEN
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson's disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson's disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson's disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson's disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP-treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with L-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease.
Asunto(s)
Ganglios Basales/metabolismo , Intoxicación por MPTP/patología , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Análisis de Varianza , Animales , Antiparkinsonianos/uso terapéutico , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Levodopa/uso terapéutico , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis , Masculino , Fosfopiruvato Hidratasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
OBJECTIVES: To compare potentially inappropriate prescribing (PIP) according to the clinical judgement of the pharmacist with PIP according to explicit STOPP-START criteria in institutionalised and hospitalised patients with multiple pathologies. To describe and compare the main pharmacological groups involved and determine the factors associated with the detection of PIP in these patients. METHOD: A prospective multicentre observational study of institutionalised and hospitalised multipathology patients aged >65â years. A specialised pharmacist used his best clinical judgement to detect PIP based on a comprehensive review of the complete chronic treatment of patients, which is an essential activity in interdisciplinary care. STOPP-START criteria were used as an aid tool to detect PIP. The main variable was the number of PIP incidents detected. RESULTS: Detected PIP incidents were analysed in 338 patients. Clinical judgement detected more PIP incidents (35%) than did STOPP-START criteria. More PIP incidents unrelated to these criteria were detected in institutionalised patients than in hospitalised patients. Clinical judgement mainly detected PIP incidents related to incorrect doses and drug interactions (p<0.001); however, STOPP-START criteria mainly detected PIP incidents related to drug duplication and insufficiently treated diagnosis or symptoms (p=0.001 and p<0.001). In total, 93.8% of the PIP incidents were detected in polypharmacy patients (≥5 drugs). Institutionalised and high-level polypharmacy (≥10 drugs) patients were at the highest risk of PIP. CONCLUSIONS: A large number of PIP incidents were detected in institutionalised and hospitalised patients with multiple pathologies. The inclusion of a pharmacist in the multidisciplinary team facilitated the detection of PIP incidents, particularly in the institutionalised population and patients treated with high-level polypharmacy which were not detected by explicit STOPP-START criteria.
RESUMEN
OBJECTIVE: To assess an interdisciplinary follow-up programme for institutionalised elderly people on oral anticoagulant treatment. METHOD: The proposed follow-up treatment is of an interdisciplinary nature and includes INR, an interview with the patient and/or carer and an assessment of the treatment plan every week. The quality of drug treatment is assessed by the percentage of time and the percentage of measurements falling within the therapeutic range. The suitability of the programme in comparison to the traditional follow-up was studied in terms of the different proportions for the first variable and by analysing contingency tables for the second. RESULTS: Nine patients were recruited. Six patients (67%) showed a significant increase in the percentage of time they remained within the therapeutic range. 68.5% of INR measurements during the follow-up programme were within therapeutic range. The percentage of INR measurements below the therapeutic range was significantly reduced when compared to the traditional follow up. Thirteen pharmaceutical interventions were documented per patient. CONCLUSIONS: The complexity of oral anticoagulant treatment, the large number of interventions carried out together with elderly patients poor treatment compliance are evidence of the need to introduce follow-up programmes which include the professionals responsible for the patients care.
Asunto(s)
Anticoagulantes/administración & dosificación , Institucionalización , Evaluación de Programas y Proyectos de Salud , Administración Oral , Anciano , Estudios de Seguimiento , Humanos , Grupo de Atención al PacienteRESUMEN
OBJECTIVE: The purpose is to describe an own-developed scale for medication adherence evaluation of HIV patients under antiretroviral therapy, and to compare it with other previously described methods. METHODS: The six-item scale was compared with a pharmacy record about the delivery of medication. Accordance between scale and a four-item Morisky-type scale (measure 1) and a percentage of doses taken as prescribed during the past two weeks (measure 2) was computed. RESULTS: The own-scale showed 93% sensitivity, 70% specificity, a likelihood ratio of 3.08 and good agreement compared with the pharmacy record (k = 0.62, p < 0.001). Agreement between the scale and measure 1 and measure 2 was very weak (k = 0.12, p = 0.446 and k = 0.10, p = 0.273 respectively). 39.7% of patients was considered as adherent according with the own-scale and was observed correlation between adherence and clinical outcomes. CONCLUSION: The scale appears to be a valid instrument to check and detect adherence related problems compared with the pharmacy medication record. Easiness to use make feasible to consider as an adequate tool to detect non-adherent patients or patients with adherence related problems into the daily clinical practice.
Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Cooperación del Paciente/estadística & datos numéricos , Encuestas y Cuestionarios , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Satisfaction measurements attempt to establish patient views regarding health care. In the setting of pharmaceutical care, the measurements of the generically called "h umanistic"variables is scarce, and the number of validated instruments is inadequate. The goal of this study is to present a specifically-developed satisfaction survey regarding outpatient pharmaceutical care units, and to prove its applicability and inner consistency in a HIV-infected patient population on antiretroviral therapy. METHODS: The survey includes 19 questions within four groups - A. The unit's physical space, location, and organization; B. Dispensation; C. Pharmaceutical consultation, and D. Overall satisfaction with the unit. Each question is scored from 1 to 5. The study was carried out by administering 250 surveys to consecutive patients arriving at the OPCU, Castell6n General Hospital. RESULTS: Responses show a high degree of patient satisfaction with questions posed, with mean values oscillating between 3.0 and 4.8. The highest means corresponded to pharmacist valuation, and the lowest values corresponded to questions within the organizational module. All questions considered, the mean score obtained was 3.96 + 0.95 (median of 4). The survey exhibited high internal reproducibility both for each group and all questions. CONCLUSION: The satisfaction survey discussed here is an accessible, easy-to-use instrument that may be rapidly completed and used in pharmaceutical care units with outpatients as a measurement of patient satisfaction. The high scores HIV-infected patients assign to questions included in the survey suggest a benefit from standardized pharmaceutical care.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/psicología , Satisfacción del Paciente/estadística & datos numéricos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antirretrovirales/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pacientes Ambulatorios/psicología , Servicio de Farmacia en Hospital/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson's disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9(+) glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism.
Asunto(s)
Cuerpo Estriado/metabolismo , Encefalitis/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/metabolismo , Animales , Cuerpo Estriado/patología , Proteínas de Unión al ADN , Femenino , Técnicas de Inactivación de Genes , Macaca fascicularis , Masculino , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Neuronas/patología , Proteínas Nucleares/metabolismo , Trastornos Parkinsonianos/patología , ARN Mensajero/metabolismo , Especificidad de la Especie , Sustancia Negra/patologíaRESUMEN
Sleep is indispensable for maintaining regular daily life activities and is of fundamental physiological importance for cognitive performance. Sleep deprivation (SD) may affect learning capacity and the ability to form new memories, particularly with regard to hippocampus-dependent tasks. Transcranial magnetic stimulation (TMS) is a non-invasive procedure of electromagnetic induction that generates electric currents, activating nearby nerve cells in the stimulated cortical area. Several studies have looked into the potential therapeutic use of TMS. The present study was designed to evaluate how TMS could improve learning and memory functions following SD in Octodon degus. Thirty juvenile (18 months old) females were divided into three groups (control, acute, and chronic TMS treatment-with and without SD). TMS-treated groups were placed in plastic cylindrical cages designed to keep them immobile, while receiving head magnetic stimulation. SD was achieved by gently handling the animals to keep them awake during the night. Behavioral tests included radial arm maze (RAM), Barnes maze (BM), and novel object recognition. When TMS treatment was applied over several days, there was significant improvement of cognitive performance after SD, with no side effects. A single TMS session reduced the number of errors for the RAM test and improved latency and reduced errors for the BM test, which both evaluate spatial memory. Moreover, chronic TMS treatment brings about a significant improvement in both spatial and working memories.
Asunto(s)
Trastornos del Conocimiento/fisiopatología , Aprendizaje/fisiología , Memoria/fisiología , Privación de Sueño/complicaciones , Estimulación Magnética Transcraneal , Animales , Encéfalo/fisiopatología , Trastornos del Conocimiento/etiología , Femenino , Octodon , Reconocimiento en Psicología/fisiologíaRESUMEN
INTRODUCTION: Foreign accent syndrome (FAS) is a little known disorder affecting language which has been described in a few cases after acute strokes or traumatic brain injuries, but until now has not been reported in multiple sclerosis (MS). It is characterised by the appearance of what is perceived to be a foreign accent in the language of the patient. Although it could be included within the dysprosodias that accompany motor aphasias, it should be considered as an entity in its own right, since it may appear without the accompanying aphasia. Aphasia is an infrequent manifestation of MS and even less so when it appears as an initial symptom of the disease. When it does occur it usually accompanies large demyelinating lesions in the dominant hemisphere, and it is usually of a motor type. CASE REPORT: Patient, aged 38 years, who presented FAS that accompanied mild non fluent aphasia as the first manifestation of MS with pseudotumoral lesions. Initially the clinical features were interpreted as a somatoform disorder, which delayed diagnosis. CONCLUSIONS: Like aphasia, FAS can occur in MS as a manifestation of a cortical language disorder. It is important to recognise this in order to prevent mistaken diagnoses.
Asunto(s)
Trastornos del Lenguaje/etiología , Trastornos del Lenguaje/patología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/patología , Adulto , Corteza Cerebral , Femenino , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/fisiopatología , SíndromeRESUMEN
The pontine micturition center or Barrington's nucleus (BN) - besides regulating micturition - co-regulates the activity of other pelvic viscera such as the colon and genitals. At present, this issue is gaining particular importance due to: (i) recent findings of α-synuclein in BN, (ii) known urinary dysfunction in parkinsonian patients (part of the so-called non-motor symptoms), other patients with dementia and as in very old individuals; and (iii) its proximity to the pedunculopontine nucleus, a surgical target in deep brain stimulation for Parkinson's disease (PD). The structural and functional organization of the micturition reflex comprises a coordinating action of somatic motor activity with both divisions of the autonomic nervous system, modulated by trunk encephalic and cortical centers that involve the BN as locus coeruleus and periaqueductal gray matter, among other trunk encephalic structures. The involvement of dopaminergic activity (physiologic inhibition of the micturition reflex mediated by dopaminergic D1 activity) that diminishes in Parkinsonism and leads to overactivity of the micturition reflex is also well known. In this review, the integrating role of the BN in the context of vesical and gastrointestinal behavior is revisited, and the principal morpho-functional findings that associate dysfunction with the urinary disorders that appear during the pre-motor stages of PD are summarized.
Asunto(s)
Núcleo de Barrington/fisiopatología , Enfermedad de Parkinson/fisiopatología , Micción/fisiología , Animales , HumanosRESUMEN
In the present work we analyze the cerebellum of chronic parkinsonian monkeys in order to clarify whether chronic mesencephalic depletion is associated with long term activation of the cerebellar neurons in chronic Parkinsonism. In our study, we observed a persistent activation of Purkinje cells in the cerebellum of chronic parkinsonian macaques, characterized by the expression of c-Fos, which correlated with dopaminergic degeneration. These results are compatible with the results observed in fMRI in Parkinson's disease patients, and may contribute to the understanding of additional alterations in the brain circuitry in Parkinsonism.
Asunto(s)
Cerebelo/patología , Intoxicación por MPTP/patología , Células de Purkinje/patología , Sustancia Negra/patología , Animales , Cerebelo/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Dopamina/deficiencia , Femenino , Macaca , Masculino , Tamaño de los Órganos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Células de Purkinje/metabolismo , Sustancia Negra/metabolismoRESUMEN
To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.
RESUMEN
Neuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS(+) and Phospho-Thr34-DARPP-32(+) cells, accompanied by a consequent decrease of total DARPP-32(+) cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.
Asunto(s)
Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Dopamina/metabolismo , Indazoles/farmacología , Neostriado/efectos de los fármacos , Neuronas/efectos de los fármacos , Enfermedad de Parkinson Secundaria/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Masculino , Neostriado/metabolismo , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.