Radioprotective potential of probiotics against gastrointestinal and neuronal toxicity: a preclinical study

Purpose Radiotherapy is a critical component of cancer treatment, along with surgery and chemotherapy. Approximately, 90% of cancer patients undergoing pelvic radiotherapy show gastrointestinal (GI) toxicity, including bloody diarrhea, and gastritis, most of which are associated with gut dysbiosis. In addition to the direct effect of radiation on the brain, pelvic irradiation can alter the gut microbiome, leading to inflammation and breakdown of the gut–blood barrier. This allows toxins and bacteria to enter the bloodstream and reach the brain. Probiotics have been proven to prevent GI toxicity by producing short-chain fatty acids and exopolysaccharides beneficial for protecting mucosal integrity and oxidative stress reduction in the intestine and also shown to be beneficial in brain health. Microbiota plays a significant role in maintaining gut and brain health, so it is important to study whether bacterial supplementation will help in maintaining the gut and brain structure after radiation exposure. Methods In the present study, male C57BL/6 mice were divided into control, radiation, probiotics, and probiotics + radiation groups. On the 7th day, animals in the radiation and probiotics + radiation groups received a single dose of 4 Gy to whole-body. Posttreatment, mice were sacrificed, and the intestine and brain tissues were excised for histological analysis to assess GI and neuronal damage. Results Radiation-induced damage to the villi height and mucosal thickness was mitigated by the probiotic treatment significantly (p < 0.01). Further, radiation-induced pyknotic cell numbers in the DG, CA2, and CA3 areas were substantially reduced with bacterial supplementation (p < 0.001). Similarly, probiotics reduced neuronal inflammation induced by radiation in the cortex, CA2, and DG region (p < 0.01) (AU)

Erythropoietin (EPO) and Hippocampal Neurons: Effects on Sports Performance, Fitness, and Football Players with Vascular Cognitive Impairment

Objective: This study delves into the impact of erythropoietin (EPO) on hippocampal neurons and its potential implications for sports performance, fitness, and the cognitive well-being of football players facing vascular cognitive impairment. Methodology: The study employs a comprehensive approach, utilizing a rat model of vascular dementia (VaD) induced by bilateral carotid artery ligation. Exogenous EPO is administered to the VaD rat model. Observations of EPO's influence on hippocampal neurons are made, and in vitro experiments are conducted to validate the specific mechanisms at play, particularly under oxygen/glucose-deprived conditions. Results: The results reveal several noteworthy findings. VaD rats treated with EPO demonstrate significantly shorter escape latency, increased neuronal populations, and enhanced preservation of Nissl bodies in hippocampal subfields, specifically cortical area 1 (CA1) and CA2. Moreover, these rats exhibit a lower count of TUNEL-positive cells compared to the model group, with higher doses of EPO demonstrating more notable improvements in escape latency. Molecular analysis shows that EPO up-regulates key protein expressions, including phosphorylated EPO receptor (p-EPOR), p-phosphatidylinositol 3-kinase (p-PI3K), p-protein kinase B (Akt), and p-cyclic AMP response element binding protein (p-CREB). Simultaneously, it down-regulates expressions of apoptosis- and autophagy-related proteins, such as B-cell lymphoma-2-associated X protein (Bax), cleaved-Caspase 3, cleaved-Caspase 9, light chain 3β (LC3β), Beclin, autophagy-related gene 5 (ATG5), and ATG7. Notably, in vitro experiments confirm the role of the PI3K/AKT pathway in EPO's mechanisms, with implications for cognitive health. (AU)

El receptor nuclear NOR-1 (Neuron-derived Orphan Receptor-1) en el remodelado vascular patológico / Nuclear receptor NOR-1 (Neuron-derived Orphan Receptor-1) in pathological vascular remodelling and vascular remodelling

En el remodelado vascular patológico juegan un papel clave las células vasculares y su interacción con las células inflamatorias y del sistema inmune. En este proceso intervienen una gran cantidad de genes y proteínas regulados de forma coordinada por un reducido número de factores de transcripción. En los últimos años las investigaciones sobre una pequeña subfamilia de factores de transcripción, la subfamilia NR4A, han tenido un gran impacto sobre nuestra comprensión de la biología vascular. Los receptores NR4A1 (Nur77), NR4A2 (Nurr1) y NR4A3 (NOR-1) son productos de genes de respuesta temprana cuya expresión es inducida por múltiples estímulos fisiopatológicos y físicos. Su amplia distribución en los diferentes tejidos y células los sitúan en el control de numerosos procesos como la diferenciación, la proliferación, la supervivencia y la apoptosis celular, así como la inflamación y el metabolismo de lípidos y carbohidratos. Esta revisión analiza el papel de estos receptores, particularmente de NOR-1, en el remodelado vascular patológico asociado a la aterosclerosis, el aneurisma de aorta abdominal y la hipertensión arterial pulmonar. (AU)

Vascular cells and their interaction with inflammatory cells and the immune system play a key role in pathological vascular remodeling. A large number of genes and proteins regulated in a coordinated manner by a small number of transcription factors are involved in this process. In recent years, research on a small subfamily of transcription factors, the NR4A subfamily, has had a major impact on our understanding of vascular biology. The NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (NOR-1) receptors are products of early response genes whose expression is induced by multiple pathophysiological and physical stimuli. Their wide distribution in different tissues and cells places them in the control of numerous processes such as cell differentiation, proliferation, survival and apoptosis, as well as inflammation and the metabolism of lipids and carbohydrates. This review analyzes the role of these receptors, particularly NOR-1, in pathological vascular remodeling associated with atherosclerosis, abdominal aortic aneurysm and pulmonary arterial hypertension. (AU)

Carretera perdida: imagen de la degeneración neuronal secundaria / Imaging secondary neuronal degeneration

Objetivo: La degeneración neuronal distal (DND) define el proceso de desintegración de una neurona o un circuito neuronal como consecuencia de una noxa localizada a distancia. Es un hallazgo frecuente debido al creciente número de realización de pruebas de imagen y a que refleja un desenlace común a múltiples etiologías. El objetivo de este artículo es definir los distintos tipos de daño neuronal a distancia, revisar la anatomía y función de los tractos más frecuentemente afectados e ilustrar la DND con esquemas y casos representativos de la práctica habitual. Conclusión: El conocimiento de la respuesta a distancia esperable según la topografía de una lesión neuronal es crucial para evitar errores diagnósticos. La degeneración axonal y transináptica puede ser tanto anterógrada como retrógrada. Los estudios de metabolismo cerebral, las secuencias de perfusión y de difusión muestran cambios cada vez más precoces del mismo proceso con los que debemos estar familiarizados.(AU

Objective: Distal nerve degeneration refers to the process of disintegration of a neuron or neuronal circuit as a consequence of distal damage. The end result of multiple etiologies, this finding is becoming common due to the increasing number of imaging tests done. This paper aims to define the different types of distal nerve damage, review the anatomy and function of the most commonly affected tracts, and illustrate distal nerve damage through diagrams and representative cases from routine practice. Conclusion: Knowing the distant response that can be expected according to the topography of a neuronal lesion is crucial to avoid diagnostic errors. Axonal degeneration and transsynaptic degeneration can be both antegrade and retrograde. Studies of cerebral metabolism, perfusion sequences, and diffusion sequences are showing increasingly earlier changes related to the same process; radiologists need to be aware of these changes.(AU)

Orexina A como mediadora en el diálogo intestino-cerebro / Orexin A as mediator in the gut-brain dialogue

INTRODUCCIÓN: Entre los mediadores químicos que modulan el eje intestino-cerebro debe incluirse el sistema orexinérgico, ya que la orexina A (OXA) hipotalámica interviene en la motilidad y en la secreción gastrointestinal. También está presente en las células enteroendocrinas de la mucosa intestinal y en las neuronas aferentes primarias del plexo mientérico, y puede intervenir en la señalización intestino-cerebro. OBJETIVO: No se conoce con exactitud la fuente ni la señal que originan la liberación de OXA periférica, ni tampoco si actúa en los receptores orexinérgicos de los tejidos periféricos ante demandas fisiológicas o patológicas. Esta revisión intenta analizar estas cuestiones a la luz de nuevos datos que indican que la OXA en el eje intestino-cerebro puede tener funciones más allá de su participación en la homeostasis energética. DESARROLLO: La OXA en el sistema entérico protege de la inflamación sistémica y central, y en el hipotálamo orquesta numerosos efectos periféricos para suprimir la respuesta inflamatoria sistémica. Por ello, podría actuar como sustancia inmunomoduladora en inflamaciones crónicas o en enfermedades autoinmunitarias. La OXA también se relaciona con la respuesta de estrés, regulando las respuestas fisiológicas a estímulos emocionales o estresantes. CONCLUSIONES: Aunque la OXA tiene efectos antiinflamatorios y gastroprotectores de la mucosa intestinal, en procesos de inflamación crónica podría incrementar la respuesta a estímulos estresantes, tanto externos como internos, y exacerbar la inflamación gastrointestinal. Por ello, se han propuesto intervenciones farmacológicas sobre el sistema orexinérgico como tratamiento para enfermedades en las que la hipersensibilidad intestinal coexiste con pérdida de apetito, alteraciones del sueño, estrés y ansiedad

INTRODUCTION. The orexinergic system is one of the chemical mediators that modulate the gut-brain axis, given the involvement of hypothalamic orexin A (OXA) in gastrointestinal motility and secretion, and the presence of OXA in enteroendocrine cells of the intestinal mucosa and in primary afferent neurons of the mesenteric plexus, permitting its participation in gut-brain signaling. AIM. The source of OXA and the signal(s) triggering its peripheral release are not fully understood, and it is not known whether it acts on orexigenic receptors in peripheral tissues to meet physiological or pathological demands. The aim of this review is to address these questions in the light of new data indicating that OXA may have functions in the gut-brain axis that go beyond its participation in energy homeostasis. DEVELOPMENT. OXA in the enteric system protects against systemic and central inflammation, and hypothalamic OXA orchestrates numerous peripheral effects to suppress the systemic inflammatory response. For this reason, OXA may act as an immunomodulator in chronic inflammations or autoimmune diseases. OXA is also involved in the stress response, regulating physiological responses to emotional or stressful stimuli. CONCLUSIONS. OXA exerts anti-inflammatory and gastroprotective effects on the intestinal mucosa; however, it may increase the response to external and/or internal stress in individuals with chronic inflammation, exacerbating the gastrointestinal inflammation. Hence, pharmacologic interventions in the orexinergic system have been proposed to treat diseases in which intestinal hypersensitivity is combined with appetite loss, sleep disturbance, stress, and anxiety

Las neuronas espejo: una génesis biológica de la complementariedad relacional / Mirror neurons: a biological genesis of relational complementarity

La génesis de la complementariedad se explica desde complejos sistemas neuronales entre los que se encuentran las neuronas espejo. Esta red es mucho más que un espejo ya que, en su interacción con otras áreas cerebrales, posibilita configurar relaciones simétricas y asimétricas. Las primeras, son a partir de la mímica, incidental o intencional, que se despliegan conductas basadas en la mínima diferencia respecto de las percibidas, como también, al contagio emocional y a la empatía. Las segundas, son a partir de la inhibición de la mímica que controla las respuestas motoras de este sistema sensoriomotor. En cada caso se detallan las áreas y circuitos cerebrales involucrados. La originalidad se alcanza al entrelazar los diferentes subsistemas de acción neuronal con los tipos de relación que conforman la complementariedad. Asimismo, se afirma que todas las relaciones son complementarias desde un metanivel relacional. Además, estas conclusiones son plasmadas en la praxis de la psicoterapia sistémica, para reflexionar sobre el sustrato neurobiológico de las relaciones disfuncionales de los pacientes, como también, sobre las diferentes posiciones relacionales que puede adoptar el experto de manera estratégica

The genesis of complementarity is explained based on complex neuronal systems among which are mirror neurons. This network is much more than just a mirror because, in its interaction with other brain areas, it makes it possible to configure symmetric and asymmetric relationships. The former stem from incidental or intentional mimicry behaviors based on the minimum difference with respect to the displayed and perceived actions, as well as emotional contagion and empathy. Asymmetric relationships, however, are based on the inhibition of mimicry, which controls the motor responses of the sensorimotor system. We present the brain areas and circuits involved in each case. In this paper, the originality is achieved by interlacing the different subsystems of neuronal action with the types of relationships that make up the complementarity. It is confirmed that all relationships are complementary from a relational meta-level perspective. In addition, these conclusions are shown through the practice of systemic psychotherapy, in order to reflect on the neurobiological substratum of patients' dysfunctional relationships, as well, on the different relational positions that the expert can strategically adopt

Tumor glioneuronal papilar. Descripción de un caso / Papillary glioneuronal tumor. A case report

El tumor glioneuronal papilar (TGNP) es una neoplasia del sistema nervioso central de reciente descripción. En el año 2007, la Organización Mundial de la Salud clasificó este tumor como una neoplasia neuronal-glial de grado i. Los pacientes suelen ser niños o adultos jóvenes que presentan clínica de cefalea o crisis comiciales. Describimos el caso de un paciente varón de 13 años de edad que fue remitido a nuestro centro tras presentar un traumatismo craneal leve a consecuencia de un accidente de circulación. La tomografía computarizada realizada en urgencias mostraba una lesión temporo-occipital derecha hipointensa. La imagen de resonancia magnética confirmó la presencia de una lesión indicativa de un tumor cerebral primario. Se realizó una exéresis quirúrgica completa de la lesión, con adecuada recuperación postoperatoria. El estudio de anatomía patológica de la lesión demostró una estructura seudopapilar con astrocitos y neuronas, compatible con TGNP. Discutimos los hallazgos clínicos, radiológicos e histológicos de este tipo de tumores poco frecuentes

Papillary glioneuronal tumor (PGNT) is a recently described central nervous system neoplasm. In 2007, the World Health Organization classified this tumor as a grade I neuronal-glial neoplasm. Patients are usually juvenile and young adults who commonly present with headache or seizures. We report a case of a 13-year-old boy that was related to our hospital after suffering a mild head injury result of an automobile accident. Emergent CT scan showed a right hypointense temporo-occipital lesion. MRI confirmed the presence of a lesion suggestive of a primary brain tumor. The patient underwent total resection of the tumor, followed by an uneventful recovery. Pathological analysis of the lesion revealed characteristic pseudopapillary structure with astrocytes and neurons, compatible with PGNT. We discuss the clinical, Radiological and histological features of this infrequent type of tumors

Albert von Kölliker, Santiago Ramón y Cajal and Camillo Golgi, the main protagonists in the Neuron Theory debate

In the second half of the 19th century Spain was rather isolated from the rest of Europe, although there was remarkable scientific activity. In the midst of this scenario, the figure of Cajal emerged on the scene. During a visit to the laboratory of Luis Simarro in Madrid in 1887, Cajal became acquainted with a paper published by Golgi in 1873 dealing with his famous method. Cajal immediately recognized the value of this method and applied it with much success to the study of the nervous tissue. In the triennium 1887-1889 Cajal's discoveries were so sensational that he decided to attend the meeting of the Anatomische Gesellschaft (Germany Anatomical Society) in Berlin in 1889 in order to present them abroad. The trip proved a great success, and he was able to establish close relations with the president of the society, Alexander von Kölliker, who, in turn, mediated contacts with further renowned scientists such as Retzius, His, Waldeyer, van Gehuchten, etc. Prior to his trip to Berlin, he had already contacted Golgi, but the fact that Cajal's neuronal theory conflicted with Golgi's reticular theory not only prevented a normal relationship between them, but was also -especially on Golgi's part- the source of bitter rivalry between them. Von Kölliker immediately recognized and admired Cajal's stature as a scientist and generously helped him to publicize his ideas throughout the scientific world, and to attain the recognition he deserved. Von Kölliker's relationship with Golgi was of a different nature, and could be described as sincere friendship. Von Kölliker, in fact, proposed both Golgi and Cajal as candidates for the Nobel Prize in 1906, which was subsequently awarded to them jointly. Thanks to Von Kölliker, Cajal's great mentor, the neuronal theory entered the scientific world through the main door and continues to occupy a prevailing position

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Cajal in Barcelona: From yesterday to today, from the neuron to the network

The synaptic and network theories of memory, which Cajal first advanced in Barcelona around 1890, have been firmly established and elaborated by three generations of neuroscientists. This article outlines a corollary model of memory in the cerebral cortex that derives from those theories and is empirically supported by modern functional methods. The model posits that the elementary unit of memory or knowledge is a network of neurons of the cerebral cortex associated by life experience according to Hebbian principles of synaptic modulation (a cognit). Networks or cognits of perceptual memory are hierarchically organized and distributed in posterior association cortex; those of executive memory, also hierarchically organized, are distributed in frontal association cortex. In the course of goal-directed behavior and language, perceptual and executive cognits engage in the perception-action cycle, the cybernetic cycle that dynamically links the cortical cognitive networks with the environment in the pursuit of goals,. The prefrontal cortex, at the summit of that cycle, and interacting with cortical and subcortical structures, guides behavior and language to their goals by means of its executive functions of planning, executive attention, working memory, decision-making, and inhibitory control

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¿Por qué degeneran las motoneuronas? Actualización en la patogenia de la esclerosis lateral amiotrófica / Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis

Introducción: La esclerosis lateral amiotrófica (ELA) es la enfermedad degenerativa de las motoneuronas más frecuente. Aunque un pequeño porcentaje de los casos de ELA tienen un origen familiar y son secundarios a mutaciones en genes concretos, a la gran mayoría de ellos se les presupone un origen multifactorial, sin que su patogenia haya sido completamente aclarada. No obstante, en los últimos años varios estudios han aumentado el conocimiento sobre la patogenia de la enfermedad, planteando la cuestión de si se trata de una proteinopatía, una ribonucleinopatía, una axonopatía o una enfermedad del microambiente neuronal. Desarrollo: En el presente artículo revisamos los trabajos publicados tanto en pacientes como en modelos animales de ELA y discutimos la implicación de los principales procesos celulares que parecen contribuir a su patogenia (procesamiento génico, metabolismo de proteínas, estrés oxidativo, transporte axonal y relación con el microambiente neuronal). Conclusiones: Aunque la patogenia de la ELA dista de estar aclarada, los estudios recientes apuntan a la idea de que hay unos desencadenantes iniciales que varían de unos sujetos a otros, y unas vías finales de degeneración de las motoneuronas que están implicadas en la mayor parte de los casos de enfermedad

Introduction: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. Development: This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. Conclusions: ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established

Difference of acute dissociation and 1-day culture on the electrophysiological properties of rat dorsal root ganglion neurons

The dissociated dorsal root ganglion (DRG) neurons with or without culture were widely used for investigation of their electrophysiological properties. The culture procedures, however, may alter the properties of these neurons and the effects are not clear. In the present study, we recorded the action potentials (AP) and the voltage-gated Na+, K+, and Ca2+ currents with patch clamp technique and measured the mRNA of Nav1.6-1.9 and Cav2.1-2.2 with real-time PCR technique from acutely dissociated and 1-day (1-d) cultured DRG neurons. The effects of the nerve growth factor (NGF) on the expression of Nav1.6-1.9 and Cav2.1-2.2 were evaluated. The neurons were classified as small (DRG-S), medium (DRG-M), and large (DRG-L), according to their size frequency distribution pattern. We found 1-d culture increased the AP size but reduced the excitability, and reduced the voltage-gated Na+ and Ca2+ currents and their corresponding mRNA expression in all types of neurons. The lack of NGF in the culture medium may contribute to the reduced Na+ and Ca2+ current, as the application of NGF recovered some of the reduced transcripts (Nav1.9, Cav2.1, and Cav2.2). 1-d culture showed neuron-type specific effects on some of the AP properties: it increased the maximum AP depolarizing rate (MDR) and hyperpolarized the resting membrane potential (RP) in DRG-M and DRG-L neurons, but slowed the maximum AP repolarizing rate (MRR) in DRG-S neurons. In conclusion, the 1-d cultured neurons had different properties with those of the acutely dissociated neurons, and lack of NGF may contribute to some of these differences

Biochemical and histological changes produced by sweeteners and cytarabine in the brain of young rats / Cambios bioquímicos e histológicos producidos por edulcorantes y citarabina en el cerebro de ratas jóvenes

Objective: The aim of this study was to evaluate the effect of splenda and stevia on dopamine and 5-HIAA levels, and some biomarkers of oxidative stress in the presence of cytarabine. Methods: Forty-eight young male Wistar rats each with a weight of 80 g (four weeks of age), distributed in six groups of eight animals each, were treated as follows: group 1, control (NaCl 0.9% vehicle); group 2, cytarabine (0.6 g/kg); group 3, stevia (0.6 g/kg); group 4, cytarabine + stevia; group 5, splenda; and group 6, cytarabine + splenda. Cytarabine was given intravenously (IV) while stevia and splenda were administered orally for five days, using orogastric tube. At the end of treatment, the animals were sacrificed and glucose levels in blood were measured. The brains were dissected for histological analysis and homogenated to measure levels of dopamine, lipid peroxidation (TBARS), serotonin metabolite (5-HIAA), Na+, K+ ATPase activity, and glutathione (GSH), using validated methods. Results: Sweeteners increased the glucose in animals that received cytarabine. Dopamine increased in cortex and decreased in striatum of animals that received stevia alone and combined with cytarabine. 5-HIAA decreased in striatum and cerebellum/medulla oblongata of animals that received sweeteners and cytarabine alone or combined. GSH increased in animals that received sweeteners and decreased with cytarabine. Lipoperoxidation decreased in groups that received sweeteners and cytarabine. Histopathological changes revealed marked degeneration of neuronal cells in animals treated with cytarabine. Conclusion: These results show that sweeteners as stevia or splenda may lead to the onset of unfavorable changes in dopamine and 5-HIAA. Antioxidant effects may be involved. Besides, histological changes revealed marked lesions of neuronal cells in experimental animals treated with cytarabine (AU)

Objetivo: el objetivo fue evaluar el efecto de edulcorantes (splenda y stevia) sobre los niveles de dopamina, acido 5-hidroxiindolacetico (HIAA) y algunos biomarcadores de estrés oxidativo en presencia de citarabina. Métodos: cuarenta y ocho ratas Wistar machos con un peso aproximado de 80 g (cuatro semanas de edad), distribuidas en seis grupos de ocho animales cada uno, fueron tratados como sigue: grupo 1, control (NaCl 0,9% vehículo); grupo 2, citarabina (0,6 g/kg); grupo 3, stevia (0,6 g/kg); grupo 4, citarabina + stevia; grupo 5, splenda; y el grupo 6, citarabina + splenda. La citarabina fue administrada por vía intravenosa y la stevia y la splenda, por vía oral durante cinco días, utilizando una sonda orogastrica. Al final del tratamiento, los animales fueron sacrificados y se midieron los niveles de glucosa en sangre. Los cerebros fueron disecados para su análisis histológico y homogenizados para medir los niveles de dopamina, peroxidacion lipidica (TBARS), metabolito de la serotonina (5-HIAA), actividad de la Na+, K+ ATPasa y glutatión (GSH), usando métodos validados. Resultados: los edulcorantes aumentaron la glucosa en los animales que recibieron citarabina. La dopamina aumento en la corteza y disminuyo en el estriado de los animales que recibieron stevia sola y combinada con citarabina. La 5-HIAA disminuyo en el estriado y el cerebelo/ medula oblongata de animales que recibieron edulcorantes y citarabina sola o combinada. El GSH se incrementó en los animales que recibieron edulcorantes. La lipoperoxidacion disminuyo en los grupos que recibieron edulcorantes y citarabina. Estudios histopatológicos revelaron una degeneración neuronal importante en animales tratados con citarabina. Conclusión: los resultados muestran que los edulcorantes como stevia o splenda pueden conducir a la aparición de cambios desfavorables en los niveles de dopamina y 5-HIAA. Los cambios histológicos revelaron, además, lesiones marcadas de células neuronales en animales tratados con citarabina (AU)

La interleucina-1Beta aumenta la muerte neuronal en el giro dentado del hipocampo asociada al estado epiléptico en la rata en desarrollo / Interleukin-1Beta increases neuronal death in the hippocampal dentate gyrus associated with status epilepticus in the developing rat

Introducción: La interleucina 1β (IL-1Beta) aumenta la muerte neuronal necrótica debido al estado epiléptico (EE) en el área CA1 del hipocampo de ratas en desarrollo; sin embargo, se desconoce si ejerce un efecto similar en el giro dentado (GD) hipocampal. El objetivo de esta investigación fue analizar el efecto de IL-1Beta en la muerte neuronal inducida por el EE en el GD de ratas Wistar de 14 días de edad. Métodos: El EE se indujo con el modelo de litio-pilocarpina. Seis horas después del inicio del EE, la IL-1Beta se inyectó intracerebroventricularmente (0, 0,3, 3, 30 o 300 ng/μl); grupos adicionales se inyectaron con el antagonista natural del receptor tipoi (IL-1RI) de IL-1Beta (IL-1Ra, 30 ng/μl) en ausencia o presencia de IL-1Beta (3 ng/μl). La muerte neuronal se evaluó en la capa granular del GD 24 h después del EE mediante la tinción de hematoxilina-eosina. Las células muertas se caracterizaron por presentar citosol eosinofílico y núcleos condensados y fragmentados. Resultados: Se observó un incremento en el número de células eosinofílicas en el GD ipsilateral a la inyección de 3 y 300 ng/μl de IL-1Beta en comparación con el grupo vehículo; en el GD contralateral se observó un efecto similar únicamente con 3 ng/μl de IL-1Beta. La coadministración de IL-1Beta con el IL-1Ra no evitó el aumento en el número de células eosinofílicas. Conclusión: La IL-1Beta aumenta la muerte neuronal con morfología apoptótica provocada por el EE en el GD del hipocampo, mecanismo independiente de la activación del receptor IL-1RI (AU)

Background: Interleukin-1Beta (IL-1Beta) increases necrotic neuronal cell death in the CA1 area after induced status epilepticus (SE) in developing rats. However, it remains uncertain whether IL-1Beta has a similar effect on the hippocampal dentate gyrus (DG). In this study, we analysed the effects of IL-1Beta on 14-day-old Wistar rats experiencing DG neuronal death induced by SE. Methods: SE was induced with lithium-pilocarpine. Six hours after SE onset, a group of pups was injected with IL-1β (at 0, 0.3, 3, 30, or 300 ng/μL) in the right ventricle; another group was injected with IL-1Beta receptor (IL-1R1) antagonist (IL-1Ra, at 30 ng/μL) of IL-1RI antagonist (IL-1Ra) alone, and additional group with 30 ng/μL of IL-1Ra plus 3 ng/μL of IL-1Beta. Twenty-four hours after SE onset, neuronal cell death in the dentate gyrus of the dorsal hippocampus was assessed using haematoxylin-eosin staining. Dead cells showed eosinophilic cytoplasm and condensed and fragmented nuclei. Results: We observed an increased number of eosinophilic cells in the hippocampal DG ipsilateral to the site of injection of 3ng/μL and 300 ng/μL of IL-1Beta in comparison with the vehicle group. A similar effect was observed in the hippocampal DG contralateral to the site of injection of 3 ng/μL of IL-1Beta. Administration of both of IL-1Beta and IL-1Ra failed to prevent an increase in the number of eosinophilic cells. Conclusion: Our data suggest that IL-1Betaincreases apoptotic neuronal cell death caused by SE in the hippocampal GD, which is a mechanism independent of IL-1RI activation (AU)

Glicolípidos neuronales regulan negativamente la división glial durante el desarrollo y tras una lesión / Neuronal glycolipids regulate glial cell division negatively during development and following a lesion

En el sistema nervioso central de los mamíferos, las células gliales superan diez veces en número a las neuronas. Su número permanente estacionario durante la edad adulta, controlado por la presencia simultánea de mitógenos gliales e inhibidores de esos mitógenos. El inhibidor más abundante, la neurostatina, es el gangliósido GD1b O-acetilado en el grupo 9 del ácido siálico más externo. La neurostatina y los oligosacáridos sintéticos inhiben la proliferación de astroblastos en cultivo primario (citostáticos) y de células de gliomas (citotóxicos), tanto de roedores como de humanos, en concentración nanomolar. A esas concentraciones, la neurostatina no tuvo efecto sobre células de linaje no glial ni sobre glía madura. La neurostatina y sus análogos mostraron actividad antimitótica directa sobre las células tumorales, interfiriendo con la progresión del ciclo celular en múltiples sitios, pero también actuaron indirectamente, haciendo visibles las células tumorales al sistema inmune del huésped y activando linfocitos CD4+ y CD8+. Análogos de neurostatina podrían generar nuevos fármacos antiinflamatorios, con múltiples acciones directas e indirectas contra el crecimiento de gliomas, una patología todavía sin tratamiento clínico satisfactorio. La neurostatina es producida por las neuronas, pero el contacto de éstas con astrocitos estimula notablemente su expresión. La acción de la neurostatina puede estar mediada por numerosas proteínas receptoras, incluyendo integrinas, siglecs y receptores Toll-like (AU)

Glial cells in the central nervous system of adult mammals outnumber neurons 10-fold. Their number remains stationary throughout adulthood, controlled by the concomitant presence of mitogens and mitogen inhibitors. The most abundant inhibitor, neurostatin, is ganglioside GD1b O-acetylated on hydroxyl 9 of its outermost sialic acid. Neurostatin inhibited the proliferation of primary microglia and astroblasts in culture (cytostatic) as well as both rodent and human glioma cells (cytotoxic) at nanomolar concentrations. At those concentrations neurostatin had no effect on non-glial lineage cells or differentiated glia. Neurostatin shows direct antimitotic activity on tumoral cells, interfering with multiple signals regulating cell cycle progression. But it also promotes indirectly total destruction of experimental rat brain glioma, presumably by making it visible to the host immune system and activating CD4+ and CD8+ lymphocytes. Neurostatin could be a new anti-inflammatory agent, with multiple convergent direct and indirect actions on glioma growth, a pathology without satisfactory clinical treatment. Neurostatin is produced by neurons but its expression is up-regulated by neuron-astrocyte contact. The action of neurostatin could be mediated by a number of receptor proteins, including integrins, Toll-like receptors and siglecs (AU)

Understanding adult neurogenesis beyond its role in learning and memory formation / Comprendiendo la neurogénesis adulta más allá de su papel en la formación del aprendizaje y la memoria

There has been a shift in the understanding of brain, neurons, and their functional role over the last two decades. Earlier it was believed that the brain was a static organ and was not subject to any change throughout life. An understanding was developed later that brain reorganizes its structure by a specific property called neuroplasticity. Recent research shows that the brain generates new neurons even in the adult stage, and this process is called adult neurogenesis. Although researchers still not have all the answers about the newborn neurons, and why and how they are generated, and what is their role, some have highlighted the importance of these in learning and memory formation, and even in memories of fear and spatial navigation. A wide range of environmental experience influences the generation of newborn neurons and their functional variability. There are questions about how different environmental experiences cause the differences in the generation of new neurons. Recently the field of optogenetics attempted to answer the questions on adult neurogenesis. However there are still questions about adult neurogenesis which needs a more naturalistic approach, for their better understanding

No ha habido un cambio en la comprensión del cerebro, las neuronas y su papel funcional de las últimas 2 décadas. Anteriormente se creía que el cerebro es un órgano estático y no está sujeto a ningún cambio durante toda la vida. La comprensión se desarrolló más tarde, que el cerebro reorganiza su estructura por una propiedad específica llamada neuroplasticidad. Investigaciones recientes muestran que el cerebro genera nuevas neuronas, incluso en la etapa adulta, y este proceso se llama neurogénesis adulta. Aunque por ahora los investigadores no tienen todas las respuestas sobre las nuevas neuronas nacidas y por qué y cómo se generan, y cuál es su papel. Algunos han puesto de relieve la importancia de las neuronas recién nacidas en la formación del aprendizaje y la memoria, e incluso en los recuerdos de miedo y la navegación espacial. Una amplia gama de experiencia ambiental influye en la generación de neuronas recién nacidas y su variabilidad funcional. Hay preguntas acerca de cómo la variada experiencia ambiental ocasiona diferencias en la generación de nuevas neuronas. Recientemente, el campo de la optogenética intentó responder a las preguntas sobre la neurogénesis adulta. Sin embargo, todavía hay preguntas sobre la neurogénesis adulta que necesitan de un enfoque más naturalista para su mejor comprensión

IL-5 blocks apoptosis and tau hyperphosphorylation induced by Abeta25-35 peptide in PC12 cells

The primary features of Alzheimer’s disease (AD) are extracellular amyloid plaques consisting mainly of deposits of amyloid β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs). Sets of evidence suggest that interleukin-5 (IL-5) is involved in the pathogenesis of AD. Herein, we investigated the protective role of IL-5 in PC12 cells, to provide new insights into understanding this disease. Western blot was employed to assess the protein levels of Bax and phospho-tau as well as phospho-JAK2; MTT assay was performed to decipher cell viability. Treatment of IL-5 decreased Aβ25-35-induced tau phosphorylation and apoptosis, effects blunted by JAK2 inhibition. IL-5 prevents Aβ25-35-evoked tau protein hyperphosphorylation and apoptosis through JAK2 signaling (AU)

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Regulación de las fases del ciclo vigilia-sueño por la histamina / Regulation of the phases of the sleep-wakefulness cycle with histamine

Redes neurales distribuidas en el encéfalo sustentan la generación de la vigilia y dos estados de sueño: sueño no REM y sueño REM. Estos tres estados comportamentales se engranan conjuntamente en una secuencia regular que constituye el ciclo vigilia-sueño. Este trabajo revisa y actualiza el conocimiento sobre la implicación del sistema histaminérgico en la organización del ciclo vigilia-sueño. Las neuronas histaminérgicas se localizan exclusivamente en el núcleo tuberomamilar hipotalámico, pero son el origen de proyecciones extensas a numerosas regiones encefálicas. Las neuronas histaminérgicas están activas durante la vigilia, especialmente con alta demanda atencional, y permanecen silentes en sueño no REM y sueño REM. Se han descrito cuatro receptores histaminérgicos metabotrópicos, de los cuales H1R, H2R y H3R están presentes en el sistema nervioso. H1R y H2R son fundamentalmente heterorreceptores postsinápticos, mientras que se piensa que H3R es mayormente un auto y heterorreceptor presináptico. Las neuronas histaminérgicas son activadas por las neuronas hipocretinérgicas y se cree que muchos de los efectos activadores de las hipocretinas se deben a acciones histaminérgicas. Las interacciones entre los axones histaminérgicos y los núcleos colinérgicos en el prosencéfalo y el troncoencéfalo son particularmente importantes para la activación cortical. Por el contrario, las neuronas histaminérgicas tuberomamilares, al igual que otras neuronas aminérgicas del locus coeruleus o del núcleo dorsal del rafe, son inhibidas por las neuronas del área preóptica promotoras de sueño no REM. Acciones inhibidoras adicionales sobre las neuronas histaminérgicas proceden de la liberación de adenosina en la región tuberomamilar. Finalmente, las neuronas histaminérgicas inhiben a las neuronas hipotalámicas REM-on que contienen hormona concentradora de melanina, apoyando así un papel permisivo del núcleo tuberomamilar en el sueño REM. De hecho, ratones deficientes para descarboxilasa de histidina, la enzima de síntesis de la histamina, muestran un aumento significativo de sueño REM (AU)

Distributed neural networks in the brain sustain generation of wakefulness and two sleep states: non-REM sleep and REM sleep. These three behavioral states are jointly ingrained in a rhythmic sequence that constitutes the sleepwakefulness cycle. This paper reviews and updates knowledge about the involvement of the histaminergic system in sleep-wakefulness cycle organization. Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, but are the source of a widespread projection system to many brain regions. Histamine neurons are active during waking, especially with high attention need, and remain silent in both non-REM and REM sleep. There have been described four metabotropic histamine receptors, of which H1R, H2R and H3R are present in the nervous system. H1R and H2R are mainly postsynaptic heteroreceptors, whereas H3R is thought to be mostly a presynaptic auto- and hetero-receptor. Histaminergic neurons are excited by hypocretinergic neurons and most of the arousing hypocretin effects are thought to depend on histaminergic actions. Interactions among histaminergic axons and cholinergic nuclei within forebrain and brainstem are particularly important for cortical activation. In contrast, histaminergic tuberomammillary neurons, similarly to other aminergic neurons in locus coeruleus or dorsal raphe nucleus, are inhibited by non-REM sleep-promoting neurons of the preoptic region. Further inhibitory actions on histamine neurons come from adenosine release on tuberomammillary region. Finally, histaminergic neurons inhibit REM-on hypothalamic neurons containing melanine-concentrating hormone, thus supporting a permissive role of tuberomammillary nucleus in REM sleep. Actually, knockout mice for histidine decarboxylase, the enzyme synthetizing histamine, show a significant REM sleep increase (AU)

An iron-deficient diet during development induces oxidative stress in relation to age and gender in Wistar rats

Iron is a trace element and a structural part of antioxidant enzymes, and its requirements vary according to age and gender. We hypothesized that iron deficiency (ID) leads to an increase in free radicals which mainly affect the brain, and the severity of damage would therefore be dependent on age and gender. Two groups of Wistar rats were evaluated evolutionarily: 100 rats (50 males; 50 females) with ID diet and 100 rats (50 males; 50 females) with standard diet. Both groups were offspring from mothers who were previously under the same dietary intervention. The ages studied roughly correspond to stages of human development: birth (0 postnatal day "PND" in rats), childhood (21 PND), early adolescence (42 PND), late adolescence (56 PND), and adulthood (70 PND). The following biomarkers in the brain, blood, and liver were analyzed: lipid peroxidation products (LPO), protein carbonyl content and activity of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. It was demonstrated that ID subjects are born with high levels of LPO in the brain and low antioxidant activity, the damage being more severe in males. After birth, antioxidant defense focuses on the central level (brain) in ID females and on the peripheral level (blood and liver) in ID males. In two critical stages of development, birth and late adolescence, antioxidant protection is insufficient to counteract oxidative damage in ID subjects. Moreover, we observed that the variability of results in the literature on oxidative stress and ID comes from gender and age of the subjects under study. With this, we can establish patterns and exact moments to carry out studies or treatments (AU)

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Péptido relacionado con el gen de la calcitonina: un neuropéptido clave en la migraña / Calcitonin gene-related peptide: a key player neuropeptide in migraine

El péptido relacionado con el gen de la calcitonina (CGRP) es un neuropéptido multifuncional producido por el empalme alternativo del gen de la calcitonina. El CGRP está ampliamente distribuido en el sistema nervioso, particularmente en estructuras anatómicas posiblemente implicadas en la fisiopatología de la migraña, incluyendo el sistema trigeminovascular. En las últimas dos décadas, el conjunto de datos de estudios clínicos y de ciencias básicas ha establecido el papel fundamental del CGRP en migraña. El CGRP aumenta la sensibilidad a los estímulos sensoriales en múltiples niveles, tanto en el sistema nervioso periférico como en el central. En el cerebro, la amplia distribución del CGRP y de sus receptores indica varios sitios posibles en los cuales este péptido actúa como neuromodulador. En la actualidad, el CGRP ha surgido como un objetivo terapéutico para nuevos tratamientos en la migraña. El objetivo de la revisión es exponer la evidencia detrás del papel del CGRP en la migraña y el estado actual de las nuevas alternativas terapéuticas basadas en el CGRP (AU)

Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP is widely distributed in the nervous system, particularly at anatomical areas thought to be involved with migraine pathophysiology, including the trigeminovascular nociceptive system. Over the past two decades, a convergence of basic and clinical evidence has established the CGRP as a key player in migraine. CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Within the brain, the wide distribution of CGRP and CGRP receptors provides numerous possible targets for CGRP to act as a neuromodulator. Now, CGRP has emerged as a promising therapeutic target for a number of novel treatments for migraine. This review discusses the evidence behind the role of CGRP in migraine and the state of CGRP-based mechanism treatment development (AU)