Neuron-microglia interactions in motor neuron degeneration. The inflammatory hypothesis in amyotrophic lateral sclerosis revisited.

Research into the pathogenesis of amyotrophic lateral sclerosis (ALS) has obtainedd notable gene discoveries, although, to date, only progress with regard to treatment has been very modest. Currently ALS is considered a multifactorial disease that presents diverse clinical presentations, ranging from a monogenic inherited disease to an autoimmune pathology, and develops with misfolded protein aggregation and neuroinflammation. An important factor related to ALS pathogenesis is the microglial activation associated with degenerative motor neurons. This activation leads to changes in the expression of a wide range of genes related to phagocytosis and inflammation, and to profound modifications in the dynamic interactions between neurons and glial cells. Overactivation and deregulation of microglial activity causes deleterious effects and leads to neuronal death. However, the involvement of microglia in non-inflammatory functions challenges our concept of neuroinflammation and opens up new possibilities for the study of the pathophysiological mechanisms of ALS. In this review we summarize the current knowledge on the adaptive interactions between neurons and microglia in ALS. We also discuss the hypothesis that controlling the extent of microglial activation and neuroinflammation may have clinical and therapeutic benefits for the condition

Neuroprotection: A New Therapeutic Approach of Relapsing Remitting Multiple Sclerosis

Neurodegenerative changes occurring early from primary acute immune-mediated inflammation support the hypothesis that multiple sclerosis (MS) is a complex disease. Axonal loss progresses with the disease course and represents the principal driver of disability. In this context, the pursuit of neuroprotective therapies in multiple sclerosis provides new valid alternatives that could significantly impact on disease progression and neurodegenerative changes, including the promotion of restoration of myelin sheaths through the remyelination process. This chapter reviews promising drugs with proposed neuroprotective or neuroregenerative effects that are currently approved or in clinical trials for the treatment of multiple sclerosis. Although the chapter highlights the diazoxide action on neuroinflammation and the results of a clinical trial with this drug, the review also includes other molecules with oral or parenteral administration

Aprenentatge de bioquímica fent servir Viquipèdia en el grau de Medicina

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524El profesional de la medicina moderno ha de saber trabajar en grupo de forma colaborativa. Las wikis son excelentes herramientas de colaboración en línea y se están utilizando cada vez más para el trabajo en grupo de los estudiantes en la educación superior. Dado que Wikipedia es un excelente modelo de construcción de conocimiento dentro de una comunidad, en 2009 diseñamos una actividad de aprendizaje basada en Wikipedia para estudiantes de medicina en el primer año académico. La actividad ha implicado planificación de sesiones formativas del uso de Wikipedia y la tutorización de los alumnos en sesiones presenciales y utilizando el foro de la plataforma virtual de la asignatura. La evaluación de la actividad se ha hecho por parte de los profesores e implementando un sistema de evaluación anónima por pares. En los últimos seis cursos académicos, 1.084 alumnos (un promedio de 181 alumnos por año) han trabajado organizados en pequeños grupos para traducir, ampliar y generar nuevos artículos bioquímicos y moleculares en la Wikipedia catalana, española e inglesa. Eso significa 604 nuevas contribuciones a los artículos de Wikipedia. Además de los conocimientos bioquímicos adquiridos, la actividad con Wikipedia ha permitido trabajar competencias transversales como la gestión de la información y la integración de conocimientos, y también aspectos éticos como el respeto a la propiedad intelectual, el plagio, la difusión de los Principios de la Wikipedia y la sensibilización a la licencia Creative Commons dentro de los futuros profesionales de la medicina. En las Jornadas se presentará el trabajo realizado por el equipo docente, los resultados del sistema de evaluación, la evolución de la actividad a lo largo de los seis años de implementación de la actividad y las conclusiones del equipo

Calcium homeostasis in the central nervous system: adaptation to neurodegeneration

En aquest article, després d'una revisió dels nostres coneixements bàsics sobre moviments del alci neuronal, s'ha resentat el treball fet pel nostre grup durant els últims anys sobre neurodegeneració, juntament amb les dades obtingudes en models animals i humans en l'estudi de la precipitació cerebral del calci. Per tal d'explicar la precipitació del calci s'ha presentat i discutit un model que integra els diversos mecanismes implicats en neurodegeneració des del punt de vista de la rellevància funcional.Here we review the results of our recent studies on neurodegeneration together with data on cerebral calcium precipitation in animal models and humans. A model that integrates the diversity of mechanisms involved in neurodegeneration is presented and discussed based on the functional relevance of calcium precipitation

Adaptation of Camelus dromedarius pars nervosa of the hypophysis to winter and summer living conditions

The aim of this work is to study the characteristics of the dromedary nervous lobe and determine how the seasons condition its organization. To this end, electron microscopy was performed and examined quantitatively on animals from winter and summer periods. The results show a higher number of cells in the nervous lobe in summer than in winter. The most abundant glial elements in winter are light pituicytes engulfing neurosecretory nerve fibers making neuroglial contact, and dark pituicytes containing numerous heterogeneous light bodies. In summer, the most distinctive glial cells may be pituicytes in a phagocytic state making contact with characteristic large light bodies that could represent a degenerative process of large neuropeptide storage. Granular pituicytes were also observed in contact with glial and neuronal components. However, lipid droplets, described in pituicytes of other mammals, were not observed in our samples. Quantitative analysis of neurovascular contacts revealed that the number of nerve terminals contacting the basal lamina did not differ between summerand winter, but the mean number of glial processes increased in winter. Our data provides evidence that the storage of neuropeptides is very marked in summer and that, associated with an autophagic and phagocytic phenomenon, this suggests an adaptation to anticipate any situation that would cause dehydration of the dromedary. Thus, in its tough environment, the animal remains permanently prepared to avoid any large water loss

Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia

Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6mg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro specific binding of glibenclamide to microglia increased after pro-inflammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome

Dogs with cognitive dysfunction syndrome: a natural model of Alzheimer's Disease

In the search for appropriate models for Alzheimer's disease (AD) involving animals other than rodents, several laboratories are working with animals that naturally develop cognitive dysfunction. Among the animals tested, dogs are quite unique in helping to elucidate the cascade of events that take place in brain amyloid-beta (Aβ)deposition aging, and cognitive deficit. Recent innovative research has validated human methods and tools for the analysis of canine neuropathology and has allowed the development of two different approaches to investigate dogs as natural models of AD. The first approach relates AD-like neuropathy with the decline in memory and learning ability in aged housed dogs in a highly controlled laboratory environment. The second approach involves research in family-owned animals with cognitive dysfunction syndrome. In this review, we compare the strengths and limitations of housed and family-owned canine models, and appraise their usefulness for deciphering the early mechanisms of AD and developing innovative therapies

Aβ immunotherapy reduces amyloid plaques and astroglial reaction in aged domestic dogs

Background: Alzheimer's disease (AD) is characterized by the dynamic accumulation of extracellular amyloid deposits from the interplay between amyloid-β (Aβ) plaques, reactive astrocytes and activated microglia. Several immunotherapies against Aβ have been shown to reduce amyloid neuropathology. However, the role of the associated glia in the recovery process requires clarification. Previously, we described the safety and effectiveness in aged domestic canine with cognitive dysfunction syndrome of a new active vaccine candidate for the treatment of AD in humans. Objective: The aim of this article is to gain a better understanding of how immunotherapy modifies the amyloid burden and its effects on astroglial and microglial reactivity in immunized dogs. Methods: In order to achieve this, we compared and quantified amyloid plaques and astroglial and microglial reactions in the frontal cortex of unimmunized and immunized aged domestic dogs. Results: We found amyloid plaques from immunized dogs to be smaller and more compact than those from unimmunized dogs. In these new plaques, the associated astrocytes were closer and less immunoreactive to the β subunit of S100 protein (S100B). We also found no modification in the microglial reaction associated with immunization. Conclusion: The anti-Aβ immunotherapy developed in our laboratory modifies the equilibrium between soluble and insoluble Aβ in aged dogs in close correlation with S100B-negative astrocytosis and microglial reaction

KATP channel expression and genetic polymorphisms associated with progression and survival in amyotrophic lateral sclerosis.

The ATP-sensitive potassium (KATP) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the KATP channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in KATP channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the KATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of KATP channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the KATP channel plays a role in the pathophysiological mechanisms of ALS