Resumen: El artículo trata sobre las posibles perspectivas de análisis para el estudio de las escrituras de maestras entre fines del siglo XIX y primera mitad del siglo XX. Desde un enfoque interdisciplinar se estudia su constitución como sujeto histórico, político y educativo en tanto productoras de conocimiento. Desde la teoría de género y la historia sociocultural de la educación se proponen algunas pistas para profundizar su estudio. El texto se ordena en tres secciones: la primera desarrolla un tratamiento conceptual; la segunda aborda los elementos centrales del contexto, y, la última, una perspectiva concreta de investigación.

Abstract: The article deals with the possible perspectives of analysis for the study of the writings of teachers between the late nineteenth century and the first half of the twentieth century. From an interdisciplinary approach we study their constitution as historical, political and educational subjects and knowledge producers. From the gender theory and the socio-cultural history of education, we propose some clues to deepen their study. The text is organized into three sections: the first develops a conceptual treatment; the second addresses the central elements of the context, and the last, a concrete research perspective.

Resumo: O artigo trata das possíveis perspectivas de análise para o estudo da escrita dos professores entre o final do século XIX e a primeira metade do século XX. A partir de uma abordagem interdisciplinar, estuda-se sua constituição como sujeito histórico, político e educacional como produtor de conhecimento. A partir da teoria de gênero e da história sociocultural da educação, são propostas algumas pistas para aprofundar seu estudo. O texto está organizado em três seções: a primeira desenvolve um tratamento conceitual; a segunda trata dos elementos centrais do contexto, e a última, de uma perspectiva específica de pesquisa.

Resumo A democratização e a experiência descentralizada da mudança educacional baseada na educação experiencial é objeto de análise neste artigo. Integrou aspectos educacionais, culturais, de saúde, de participação da comunidade e contou com apoio estatal abrangente para beneficiar crianças e jovens de áreas rurais para contribuir com a superação da pobreza e a marginalização. O Plano experimental foi uma tentativa coerente de regulação social como modelo alternativo de desenvolvimento e democratização das relações sociais, mas não previu a resistência dos conservadores locais e nacionais que impediram a sua execução por considerarem uma ameaça para a ordem social rural da época. As evidências e as dificuldades históricas no Chile para desenvolver uma política de educação descentralizada e territorializada, contribuíram para a reflexão sobre a atual reorganização do sistema de educação pública em unidades administrativas e de gestão territorial chamado Serviço de Educação local, destinado a eliminar a descentralização administrativa neoliberal.

Abstract A democratizing and decentralized experience of educational change based on experimental education is analyzed. This experience integrated training, cultural and health aspects, the participation of the community and the integral support of the State to children and young people of the rural world to overcome poverty and marginality conditions. The experimental Plan was an attempt of social regulation consistent with the import substitution development model and the democratization of social relations, but that it did not foresee the resistance of local and national conservative sectors who blocked its execution by seeing it as a threat to the rural social order of the time. It also evidences the historical difficulties to develop a decentralized and territorial education policy in Chile, contributing to reflect on the current reorganization of the public education system in administrative units and based on territorial management, called Local Education Services, aimed at eliminating the neoliberal administrative decentralization.

Resumen Se analiza una experiencia democratizadora y descentralizada del cambio educativo basada en la educación experimental que integró aspectos formativos, culturales, sanitarios, la participación de la comunidad y el apoyo integral del Estado a niños y jóvenes del mundo rural para superar la pobreza y marginalidad. El Plan Experimental fue un intento de regulación social coherente con el modelo de desarrollo sustitutivo de importaciones y la democratización de las relaciones sociales, pero no previó la resistencia de sectores conservadores locales y nacionales quienes bloquearon su ejecución al verlo como una amenaza al orden social rural de la época. Evidencia también, las dificultades históricas en Chile para desarrollar una política educativa descentralizada con base territorial, aportando a la reflexión sobre la reorganización actual del sistema público de educación en unidades administrativas y de gestión territorial llamada Servicios Locales de Educación, orientados a eliminar la descentralización administrativa neoliberal.

The field of memory studies on human rights violations in Latin America is promoting new critical disciplinary areas in history, social sciences, and education. This article particularly analyzes "pedagogy of memory", which is developed from organizations in support of victims of political violence. The main characteristic of these organizations is that they are based on a problematization of the recent past (dictatorships and transitions to democracy) in a framework that considers the organizations' existential and political processes of the victims, their relatives and intellectual support.

El campo de los estudios de la memoria sobre la violación de los derechos humanos en América Latina está generando aperturas disciplinares críticas en la historia, las ciencias sociales y la educación. En particular, en este artículo se analiza la "pedagogía de la memoria" que se desarrolla desde las organizaciones de víctimas de la violencia política. Su característica principal es que está basada en una problematización del pasado reciente (dictaduras y transiciones a la democracia) en el marco de los procesos existenciales y políticos de las organizaciones que agrupan a las víctimas, a sus familiares e intelectuales de apoyo.

El artículo analiza las narrativas de memoria y perspectivas sobre la historia reciente presentes en el currículum escolar de historia y ciencias sociales y en dos contextos de trabajo de memoria en la sociedad civil. La memoria promovida en cada escenario evidencia las representaciones políticas del pasado reciente, las distancias entre la memoria hegemónica y las memorias sociales y las tensiones para la elaboración del recuerdo sobre el pasado reciente en las nuevas generaciones. Se discuten las connotaciones éticas y políticas presentes en el recuerdo elaborado y se exponen los desafíos pedagógicos y unas orientaciones que deben atenderse para la formación de una ciudadanía memorial responsable de su pasado heredado y de su futuro en construcción.

The article analyzes the narratives of memory and perspective on recent history present in the school currículum of history and social sciences and in two contexts of memory work in civil society. The memory in each scenario promoted political representations evidence of the recent past, the distances between the hegemonic memory and social memories and tensions for the elaboration of memories of the recent past in the new generations. Ethical and political connotations present in the memory are discussed and elaborated pedagogical challenges and orientations that must be addressed for the formation of a memorial responsible for its inherited past and future citizens are exposed under construction.

O artigo analisa as narrativas de memórias y perspectivas sobre a história recente presentes no currículo escolar da História e Ciências Sociais e em dois contextos de trabalho de memória na sociedade civil. A memória promovida em cada ambiente evidência as representações políticas do passado recente, as distâncias entre a hegemonia e as memórias sociais e as tensões para a elaboração do acordo sobre o passado recente nas novas gerações. As conotações éticas e políticas presentes no acordo são discutidas e se expõem os desafios pedagógicos e umas orientações que tem que atender-se para a formação duma cidadania memoriai responsável de sue passado herdado e de seu futuro em construção.

Recognizing the crisis in education and the need in current contexts of open reflection on modern institutionalized pedagogical frame, some of the principles developed by Ranciere in "The Ignorant Schoolmaster" are discussed. In particular, the paradox of the principle of social equality proclaimed by the Enlightenment project and its relation to inequality of intelligences legitimized by institutionalized pedagogy and "the explainer method" of teaching, as administrator of social and intellectual inequalities. From a pedagogical analysis, the text outstands the value and incidence that the learning among equals can reach, the text as a meeting point for the emancipation and the need to enhance the educational experience and revisit the critical view on educational thinking and educational practice springing from adjusted critical approaches, from the action, and open to a transitive reasoning to enhance thinking and the generation of a proper pedagogical knowledge.

Reconociendo la crisis de la educación y la necesidad en los contextos actuales, de abrir la reflexión sobre la trama pedagógica moderna institucionalizada, se analizan algunos de los postulados desarrollados por Rancière en "El maestro ignorante". En particular; la paradoja del principio de la igualdad social proclamada por el proyecto ilustrado y su relación con la desigualdad de las inteligencias legitimada por la pedagogía institucionalizada y "el método explicador" de la enseñanza, como administrador de las desigualdades sociales e intelectuales. Desde una reflexión pedagógica, se enfatiza el valor e incidencia que alcanzan el aprendizaje entre iguales, el texto como punto de encuentro para la emancipación y la necesidad de relevar la experiencia educativa y de revisitar la crítica del pensamiento sobre la educación y la práctica educativa desde enfoques críticos ajustados, desde la acción, y abiertos a una razón transitiva para potenciar la reflexión y generación de conocimiento propiamente pedagógico.

Reconhecendo a crise na educação e a necessidade nos contextos atuais, de ter uma reflexão aberta sobre a trama pedagógica moderna institucionalizada, discutem-se alguns dos postulados desenvolvidos por Ranciére em "O mestre ignorante". Em particular; o paradoxo do princípio da igualdade social proclamado pelo projeto iluminista e sua relação com a desigualdade das inteligências legitimada pela pedagogia institucionalizada e o "método explicador" do ensino, como administrador das desigualdades sociais e intelectuais. A partir de uma reflexão pedagógica, enfatiza-se o valor e o impacto atingindo; a aprendizagem entre pares, o texto como ponto de encontro para a emancipação e a necessidade de relevar a experiência educacional e de revisitar a crítica do pensamento educacional e prática educativa desde abordagens críticas ajustadas, a partir da ação e abertos a uma razão transitiva para promover a reflexão e a geração de um conhecimento propriamente pedagógico.

La investigación se inserta en los estudios de la memoria histórica realizando un análisis hermenéutico del discurso de las narrativas de memoria e historia que la discusión pública chilena ha utilizado para elaborar su pasado reciente dictatorial en el periodo 1991-2004. Se revisan fuentes de prensa, insertos editoriales, entrevistas a los actores sociales y políticos y, con especial énfasis, los Informes de Verdad y Reconciliación. Se reflexiona sobre los marcos oligárquicos vigentes del tiempo largo y corto elaborados para la representación de lo público y la ciudadanía, destacando la inviabilidad del perdón como categoría restitutiva de la comunidad política. Se consolida la debilidad simbólica de la democracia recuperada en la historia reciente chilena.

A pesquisa insere-se nos estudos da memória histórica realizando análise hermenêutico do discurso das narrativas de memória e história utilizado pela discussão pública chilena para elaborar seu passado recente ditatorial no período 1991-2004. Revisam-se fontes de imprensa, insertos editoriais, entrevistas aos atores sociais e políticos e, com ênfase especial, os Relatórios de Verdade e Reconciliação. Reflete-se sobre os quadros oligárquicos vigentes do longo e curto tempo elaborados para a representação do público e a cidadania, destacando a inviabilidade do perdão como categoria restituidora da comunidade política. Consolidase a fraqueza simbólica da democracia recuperada na história recente chilena.

Dementias are progressive and neurodegenerative neuropsychiatry disorders, with a high worldwide prevalence. These disorders affect memory and behavior, causing impairment in the performance of daily activities and general disability in the elders. Cognitive impairment in these patients is related to anatomical and structural alterations at cellular and sub-cellular levels in the Central Nervous System. In particular, amyloid plaques and neurofibrillar tangles have been defined as histopathological hallmarks of Alzheimer's disease. Likewise, oxidative stress and neuroinflammation are implicated in the etiology and progression of the disease. Neuronal precursors from human olfactory neuroepithelium have been recently characterized as an experimental model to identify neuropsychiatric disease biomarkers. Moreover, this model not only allows the study of neuropsychiatric physiopathology, but also the process of neurodevelopment at cellular, molecular and pharmacological levels. This review gathers the evidence to support the potential therapeutic use of melatonin for dementias, based on its antioxidant properties, its anti-inflammatory effect in the brain, and its ability to inhibit both tau hyper-phosphorylation and amyloid plaque formation. Furthermore, since melatonin stimulates neurogenesis, and promotes neuronal differentiation by inducing the early stages of neuritogenesis and dendrite formation, it has been suggested that melatonin could be useful to counteract the cognitive impairment in dementia patients.

Las demencias son enfermedades neuropsiquiátricas, progresivas, neurodegenerativas y con una alta prevalencia a nivel mundial. Ocupan uno de los primeros lugares como enfermedades que causan incapacidad en los adultos mayores. En estos pacientes el Sistema Nervioso Central presenta alteraciones anatómico-estructurales a nivel celular y subcelular que se asocian con deficiencias cognitivas. En particular, en la enfermedad de Alzheimer se han caracterizado marcadores histopatológicos como las placas amiloides y las marañas neurofibrilares. Se sabe que el estrés oxidativo y la neuroinflamación participan en la etiología y el desarrollo de la enfermedad. Recientemente se caracterizó a los precursores neuronales del neuroepitelio olfatorio humano como un modelo experimental adecuado para identificar biomarcadores de rasgo y para estudiar la fisiopatología de diversas enfermedades neuropsiquiátricas, así como el proceso del neurodesarrollo, a nivel celular, molecular y farmacológico. En este trabajo se presenta la evidencia que sustenta que la melatonina puede ser útil en el tratamiento de las demencias, por su capacidad antioxidante, por su efecto anti-inflamatorio, así como por el efecto inhibidor de la hiperfosforilación de la proteina tau y de la formación de placas amiloides. Además, al estimular la formación de nuevas neuronas, la neuritogénesis en sus etapas tempranas y la formación de dendritas, la melatonina podría contribuir a contrarrestar la pérdida de las funciones cognitivas que se observa en estos padecimientos.

A reflection about the recent past can be seen as historical experience, object of study, discursive building up and its perspectives of teaching in Chile. A critical and narrative hermeneutic pedagogy is proposed to direct the learning of that past from a reflexive memory.

Se reflexiona sobre el pasado reciente como experiencia histórica, objeto de estudio, elaboración discursiva y sus perspectivas de enseñabilidad en Chile. Se propone una pedagogía hermenéutica crítica y narrativa que oriente el aprendizaje de dicho pasado desde una memoria reflexiva.

Repensa-se o passado recente, como experiência histórica, objeto de estudo, elaboração discursiva e suas perspectivas de ensino no Chile. Propõe-se uma pedagogia hermenêutico-crítica e narrativa que orienta a aprendizagem de tal passado desde uma memória reflexiva.

Circadian rhythms are oscillations of physiological functions. The period of their oscillation is about 24 h, and can be synchronized by environmental periodic signals as night-day cycle. The endogenous periodical changes depend on various structural elements of the circadian system which consists of the effectors, the secondary oscillators, the synchronizers and the circadian pacemaker. In mammalian species, the physiological function better understood respect their oscillation pattern are the synthesis and release of several hormones (i.e. cortisol and melatonin), the body temperature, the sleep-awake cycle, the locomotive activity, cell proliferation, neuronal activity among other rhythms. The Suprachiasmatic nucleus is the main circadian pacemarker in mammals; its oscillation keeps the circadian system synchronized particularly with respect to the environment photo period. When light reaches the pigment melanopsin in ganglionar neurons in the retina, the photoperiod signal is sent to Suprachiasmatic nucleus, and its postsinaptic neurons distributes the temporal signal to pheripheral oscillators by nervous or humoral pathways. Among the oscillators, the pineal gland is a peripheral one modulated by Suprachiasmatic nucleus. At night, the indolamine melatonin is synthesized and released from pinealocytes, and reaches other peripheral oscillators. Melatonin interacts with membrane receptors on Suprachiasmatic nucleus pacemarker neurons, reinforcing the signal of the photoperiod. In mammals, exogenous melatonin synchronizes several circadian rhythms including locomotive activity and melatonin release. When this indolamine is applied directly into the Suprachiasmatic nucleus, it produces a phase advance of the endogenous melatonin peak and increases the amplitude of the oscillation. In humans, melatonin effect on the circadian system is evident because it changes the circadian rhythms phase in subjects with advanced sleep-phase syndrome, night workers or blind people. Also it reduces jet lag symptoms enhancing sleep quality and reseting the circadian system to local time. Melatonin effects on circadian rhythms indicate their role as a chronobiotic, since decreased daily melatonin levels that occur with age and in neuropsychiatric disorders are associated with disturbances in the sleep-awake cycle. In particular, it has been described that Alzheimer's disease patients have disturbed sleep-awake cycle and have decreased serum melatonin levels. Sleep disorders in Alzheimer's disease patients decrease when they are treated with melatonin. Moreover, sleep disturbances have been observed in bipolar disorder patients and often precede relapses of insomnia-associated mania and hypersomnia-associated depression. These disturbances are linked to delayed- and advanced- phases of circadian rhythms or arrhythmia; therefore, it has been suggested that bipolar disorder patients could be treated with light and dark therapy. In depressed patients, the levels of melatonin are low throughout the 24 hour period and have a delayed onset of the indolamine concentration and showed an advance of its peak. Schizophrenic patients have decreased levels in the plasmatic melatonin in both phases of the light-dark cycle. Melatonin administration to these patients increases their sleep efficiency. In addition, melatonin acts as a neuroprotector because of its potent antioxidant action and through its cytoskeletal modulation properties. In neurodegenerative animal models, its protector effect has been observed using okadaic acid. This neurotoxin is employed for reproducing cytoskeletal damage in neurons and increased oxidative stress levels, which are molecular events similar to those that occur in Alzheimer's disease. In N1E-115 cell cultures incubated with okadaic acid, the administration of melatonin diminishes hyperphosphorylated tau and oxidative stress levels, and prevents the neurocytoskeletal damage caused by the neurotoxin. Although it is known that melatonin plays a key role in the circadian rhythms entrainment, little is known about its synchronizing effects at molecular and structural level. In algae, it has been observed a link between morphological changes and the light-dark cycle and it is known that shape is determinated by the cytoskeletal structure. In particular, the alga Euglena gracilis changes its shape two times per day under the effect of a daily light-dark cycle. This alga has a long shape when there is a higher photosynthetic capacity at the half period of the day; on the contrary, it showed a rounded shape at the end of 24 h cycle. Also, the influence of the cell shape changes on the photosynthetic reactions was investigated by altering them with drugs that disrupt the cytoskeletal structure as cytochalasin B and colchicine. Both inhibitors blocked the rhythmic shape changes and the photo-synthetic rhythm. Moreover, there are some reports about cytoskeletal changes in plants targeted by circadian rhythms. Guarda cells of Vicia faba L. showed a diurnal cycle on the alpha and beta tubulin levels. In addition, it has been proposed that melatonin synchronizes different body rhythms through cytoskeletal rearrangements. In culture cells, nanomolar melatonin concentrations cause an increase in both the polimerization rate and microtubule formation through calmodulin antagonism. A cyclic pattern produced by melatonin in the actin microfilament organization has been demonstrated in canine kidney cells. Cyclic incubation of MDCK cells with nanomolar concentrations of melatonin, resembling the cyclic pattern of secretion and release to plasma produces a microfilament reorganization and the formation of domes. Studies in animals are controvertial regarding if the amount of microtubules in different tissues varies cyclically. In rats and baboons, melatonin administration or exposure of rats to darkness induced an increased number of microtubules in the pineal gland. However, in the hypothalamus, the exposure of rats to light resulted in an increase in the microtubular protein content. Similarly, (X-tubulin mRNA was augmented during the light phase in the hypothalamus, hippocampus and cortex. By contrast, in rats maintained in constant darkness, a decreased level in the tubulin content was observed in the visual cortex. Additional information on cycle variations observed in cytoskeletal molecules indicated that beta actin mRNA levels are lower during the day in the hippocampus and cortex. But no change was observed in actin protein levels in the cerebral cortex. However, increased levels of actin and its mRNA were observed in the hypothalamus. Exogenous melatonin administration at onset of night decreased the amount of actin in the hypothalamus, while the actin mRNA levels decreased when the administration was realized in the morning. In this review we will describe the synchronizer role of melatonin in the sleep-awake cycle and in the organization of cytoskeletal proteins and their mRNAs. Also, we will describe alterations in the melatonin secretion rhythm associated with a neuronal cytoskeleton disorganization in the neuropsychiatric diseases such as Alzheimer, depression, bipolar disorder and schizophrenia.

Los ritmos circadianos son patrones de oscilación con un periodo cercano a 24h que se observan en los procesos fisiológicos. En los mamíferos se han descrito funciones biológicas con regulación circádica tal como el ciclo sueño-vigilia. La administración de la melatonina, una indolamina secretada por la glándula pineal, sincroniza los ritmos circadianos. En los humanos, este efecto se ha estudiado en sujetos con síndrome de <<fase de retraso de sueño>>, personas que sufren el síndrome de jet lag, en los trabajadores nocturnos y en los invidentes. La melatonina puede reducir los síntomas de jet lag y mejorar la calidad del sueño, además de acelerar la sincronización de la fase circadiana al tiempo local. Los niveles de la melatonina disminuyen con la edad y en las enfermedades neurodegenerativas y psiquiátricas. Los pacientes con enfermedad de Alzheimer muestran alteraciones del sueño como cambios en su ritmicidad y en su estructura. La administración de la melatonina a estos pacientes provoca mejoría en los síntomas de agitación que se presentan al atardecer. Los pacientes con trastorno bipolar manifiestan insomnio asociado con la fase de manía e hipersomnia durante la fase de depresión. Estas alteraciones en el sueño se relacionan con un desfasamiento del ritmo circadiano y/o arritmia. En pacientes con depresión y con esquizofrenia existe una disminución en los niveles plasmáticos de la melatonina en ambas fases del ciclo luz-oscuridad. La administración de melatonina incrementa la eficiencia del sueño en ellos. Además de las alteraciones en el sueño y en el ritmo de secreción de la melatonina observado en pacientes neuropsiquiátricos, existen cambios estructurales y funcionales en regiones específicas cerebrales que son producidas por la pérdida neuronal o por alteraciones de la polaridad y de la morfología neuronal, que son funciones reguladas por el citoesqueleto. A pesar de la información que existe sobre el papel de la melatonina como un sincronizador de los ritmos biológicos, no se conoce si ésta sincroniza la citoarquitectura neuronal. Está descrito que en organismos unicelulares, en plantas y en especies de vertebrados, existen cambios rítmicos en la organización del citoesqueleto asociados con el fotoperiodo. En células en cultivo la melatonina produce un aumento en la formación de los microtúbulos. En roedores, la administración de esta indolamina y la exposición a la oscuridad constante produce un incremento en el contenido de los microtúbulos en la glándula pineal. Sin embargo la exposición constante a la luz, que inhibe la síntesis de la melatonina, produce un incremento en el contenido de los microtúbulos hipotalámicos, en tanto que el RNAm de α-tubulina en el hipotálamo, el hipocampo y la corteza cerebral, se incrementa durante el día. La regulación cíclica de la organización de los microfilament os de actina inducida por la melatonina se ha demostrado en células de riñón en cultivo. La melatonina provoca un incremento en la reorganización de actina asociado con un aumento en la formación de domos los cuales son un índice del transporte bidireccional de agua en las células epiteliales. En tanto que, en estudios en roedores, se ha observado que los niveles de RNAm de actina se incrementan durante la noche en el hipocampo y en la corteza. Sin embargo, otros estudios señalan que la melatonina tiene un efecto inhibitorio en la síntesis de actina en el hipotálamo. En esta revisión se describe el papel sincronizador de la melatonina en el ciclo sueño-vigilia y en la estructura del citoesqueleto neuronal. Asimismo, se menciona cómo en las enfermedades neuropsiquiátricas el ritmo de secreción de la melatonina se encuentra alterado, lo cual se puede asociar con una desorganización del citoesqueleto neuronal.

Alzheimer's disease is characterized by a progressive neuronal death and a lost of memory and cognition that unable the patient to perform daily tasks. Cytoskeleton alterations, identified as a major histopathologic hallmark of neurodegenerative diseases, occur in dementia. In this disease, neurons have pathologic inclusions containing fibrillar aggregates of hyperphosphorylated tau protein in absence of amyloid deposits. Abundant senile plaques and neurofibrillary tangles constitute the two major neuropathologic lesions present in hippocampal, neocortical, and forebrain cholinergic brain regions of Alzheimer's patients. Hyperphosphorylated tau and the subsequent formation of paired helical filaments loses the capabilities for maintaining highly asymmetrical neuronal polarity. Thus, in brains with a high content of hyperphosphorylated tau, microtubules are disassembled, the highly asymmetrical neural shape is lost and an impairment of axonal transport is produced together with a lost of dendrite arborizations. In addition, brain damage caused by free radicals occurs in Alzheimer's disease. This illness involves a reduction of the endogenous antioxidant enzyme system, increased senile-plaque formation, cytoskeletal collapse, and neuronal apoptosis induced by oxidative stress. Acetylcholinesterase inhibitors are the most commonly used compounds in the treatment of neurodegenerative diseases. However, despite their wide use in the treatment of Alzheimer's disease, these compounds have limited therapeutic effects and cause undesirable effects. Therefore it is necessary to investigate new alternatives in the Alzheimer's disease treatment. Considering that neurodegenerative diseases are cytoskeleton disorders, this cellular structure could be a drug target for therapeutic approaches by restoring normal cytoskeleton structure and by precluding damage caused by oxygen-reactive species. In this regard, melatonin, the indole secreted by the pineal gland during the dark phase of the photoperiod, has two important properties that may be useful for the treatment of mental disorders. One is that melatonin is a potent free-radical scavenger and the other is that this indole is a cytoskeletal modulator. A neuroprotective role for melatonin was initially suggested due to its free-radical scavenger properties. Melatonin detoxifies the highly toxic hydroxyl radical as well as the peroxyl radical, peroxynitrite anion, nitric oxide, and singlet oxygen, all of which can damage brain macromolecules. Moreover, melatonin stimulates the activity of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase. Also, it is a lipophilic molecule able to cross the blood-brain barrier. All these properties make melatonin a highly effective pharmacologic agent against free-radical damage in the brain. Also, it is a useful neuroprotector in dementia because it synchronize the body rhythms with the photoperiod, which are altered in Alzheimer's disease and because normal circadian secretion of melatonin and sleep-wake cycle can be restored by the indolamine administration. Additionally, cytoskeletal modulation by melatonin is another relevant property of the indole for neurodegenerative diseases treatment. Direct assessment of melatonin effects on cytoskeletal organization in neuronal cells indicated that the indole promotes neuritogenesis in N1E-115 neuroblastoma cells at plasma melatonin concentration. Neurite formation is a complex process critical to establish synaptic connectivity that is lost in Alzheimer's disease. Neuritogenesis takes place by a dynamic cytoskeletal organization that involves microtubule enlargement, microfilament arrangement, and intermediate-filament reorganization. In particular, microtubule assembly participates in neurite formation elicited by melatonin through antagonism to calmodulin. Also, selective activation of protein kinase C (PKC) alpha by melatonin participates in vimentin intermediate filament rearrangements and actin dynamics for neurite outgrowth in neuroblastoma cells. In N1E-115 cells, melatonin at plasma and cerebrospinal fluid concentration caused an increase in microfilament arrays in stress fibers and their thickening, as well as increased growth cone formation, and augmented number of cells with microspikes. Recently, it was demonstrated that melatonin increased both the number of N1E-115 cells with filopodia and with long neurites through both PKC activation and Rho-associated kinase (ROCK) stimulation. The utility of melatonin to prevent damage in the cytoskeletal structure produced by neurodegenerative processes was demonstrated in N1E-115 neuroblastoma cells cultured with okadaic acid (OA), a specific inhibitor of the serine/threonine proteins phosphatases 1 and 2A that induces molecular and structural changes similar to those found in Alzheimer's disease. Melatonin prevented microtubule disruption followed by cell-shape changes and increased lipid peroxidation and apoptosis induced by OA. Melatonin effects on altered cytoskeletal organization induced by OA are dose-dependent and effects were observed at plasma -and cerebrospinal-fluid concentrations of the indole. These data support that melatonin can be useful in the treatment of neurodegenerative diseases by both its action on the cytoskeleton and by its free-radical scavenger properties.

La enfermedad de Alzheimer es una enfermedad neurodegenerativa progresiva que cursa con una deficiencia en las capacidades cognitivas, así como con la presencia de síntomas psiquiátricos y alteraciones conductuales. Las características histopatológicas más importantes en la enfermedad de Alzheimer son la formación de placas seniles, los ovillos neurofibrilares y un incremento en el estrés oxidativo. La polaridad estructural y la morfología neuronal se pierden en la enfermedad de Alzheimer. La proteína tau se encuentra anormalmente fosforilada, los microtúbulos se despolimerizan, se pierden la forma asimétrica de las neuronas y la conectividad sináptica, y se interrumpe el transporte axoplasmático. Asimismo, se ha sugerido que la inhibición o la pérdida en el balance de la formación de neuronas en el hipocampo puede participar en la fisiopatología de la enfermedad de Alzheimer debido a que el cerebro no puede reparar el daño neuronal y consecuentemente induce la pérdida de la cognición. Los agentes colinérgicos son los medicamentos más aceptados en el tratamiento de la enfermedad de Alzheimer en una etapa en que los síntomas se clasifican de medios a moderados. Sin embargo, el tratamiento de pacientes con enfermedad de Alzheimer grave es limitado. Por lo anterior se requiere la búsqueda de nuevas alternativas para el tratamiento de esta enfermedad. La melatonina es una indolamina que actúa como un potente antioxidante, como un modulador de la organización del citoesqueleto así como un factor de diferenciación celular. Diversos estudios han sugerido que la melatonina tiene un efecto neuroprotector por su capacidad de captar radicales libres. La melatonina disminuye la lipoperoxidación y la apoptosis producida por la administración de ácido ocadáico (AO) o peróxido de hidrógeno (H2O2). Se sabe que las especies reactivas de oxígeno producen alteraciones en la organización del citoesqueleto e influyen el estado de fosforilación de la proteína tau y que la melatonina previene la fosforilación de la proteína tau debido a su actividad antioxidante. Se ha descrito que la melatonina modula el arreglo de los microfilamentos de actina y la formación de fibras de tensión en las células Madin-Darby canine kidney (MDCK) por medio de una interacción concertada de la indolamina con la calmodulina y con la proteína cinasa C (PKC) y la participación de la proteína cinasa dependiente de Rho (ROCK). Asimismo, la melatonina participa en las etapas tempranas de la formación de neuritas en las células N1E-115 por medio de ROCK. Otros estudios han indicado que la melatonina previene el daño en el citoesqueleto producido por el AO en las células N1E-115. El AO se ha utilizado para reproducir en células en cultivo las alteraciones en el citoesqueleto y el incremento en el estrés oxidativo que ocurren en las neuronas de pacientes con enfermedad de Alzheimer. La melatonina en estas células previene la retracción del citoesqueleto, efecto del AO. La red del citoesqueleto se mantiene en el citoplasma y en las neuritas de las células N1E-115 cultivadas con melatonina, no obstante que sean tratadas con el AO posteriormente. Recientemente, se demostró que en las células de neuroblastoma N1E-115 incubadas con melatonina se previene la hiperfosforilación de la proteína tau causada por el AO. Aunado a lo anterior, se ha demostrado que la melatonina modula la formación de neuronas nuevas en un modelo in vitro utilizando células embrionarias y de corteza cerebral de ratón. La formación de neuronas inducida por la melatonina se corroboró utilizando células precursoras aisladas de animales adultos así como en animales adultos, y se encontró que la indolamina moduló la sobrevida de las células nuevas formadas, así como la diferenciación de éstas en neuronas nuevas. Las evidencias presentadas en esta revisión indican que la melatonina puede ser útil como un coadyuvante en el tratamiento de las demencias.

Summary Postmortem and neuroimaging studies of Major Depressive Disorder patients have revealed changes in brain structure. In particular the reduction in prefrontal cortex and in hippocampus volume has been described. In addition, a variety of cytoarchitectural abnormalities have been described in limbic regions of major depressive patients. Decrease in neuronal density has been reported in the hippocampus, a structure involved in declarative, spatial and contextual memory. This structure undergoes atrophy in depressive illness along with impairment in cognitive function. Several studies suggest that reduction of hyppocampus volume is due to the decreased cell density and diminished axons and dendrites. These changes suggested a disturbance of normal neuronal polarity, established and maintained by elements of the neuronal cytoskeleton. In this review we describe evidence supporting that neuronal cytoskeleton is altered in depression. In addition, we present data indicating that the cytoskeleton can be a potential target in depression treatment. Neurons are structural polarized cells with a highly asymmetric shape. The cytoskeleton plays a key role in maintain the structural polarization in neurons which are differentiated in two structural domains: The somato-dendritic domain and the axonal domain. This differentiated asymmetric shape, depends of the cytoskeletal organization which support, transport and sorts various molecules and organelles in different compartments within the cell. Microtubules determine the asymmetrical shape and axonal structure of neurons and form the tracks for intracellular transport, of crucial importance in axonal flux. Actin microfilaments are involved in force generation during organization of neuronal shape in cellular internal and external movements and participate in growth cone formation. This important cytoskeletal organization preceed the formation of neurites that eventually will differentiated into axons or dendrites, a process that also comprises a dynamic assembly of the three cytoskeletal components. Intermediate filaments are known in neurons as neurofilaments spatially intercalated with microtubules in the axons and facilitate the radial axonal growth and the transport. Neurofilaments also act supporting other components of the cytoskeleton. All changes and movements of the cytoskeletal organization are coordinated by cytoskeletal associated proteins such as the protein tau and the microtubule associated proteins (MAPs). Also, specific interactions of microfilaments, microtubules and filaments which are regulated by extracellular signals take place in modulation of the cytoskeletal rearrangements. The polarized structure and the highly asymmetric shape of neurons are essentials for neuronal physiology and it appears to be lost in patients with a Major Depressive Disorder. Histopathological studies have shown that the hippocampus and frontal cortex of patients with major depressive disorder have diminished soma size, as well as, have decreased dendrites and cellular volume. Dendrite formation depends mainly in microfilaments organization as well as in polarization of the microtubule binding protein MAP2. In addition, there is a decreased synaptic connectivity and an increased oxidative stress, which originates abnormalities in the cytoskeletal structure. These neuronal changes originate alterations in the brain functionality such as decreased cognitive abilities and affective dis-regulations, usually encountered in patients with depression. Therefore, pathologic lesions implicating an altered cytoskeletal organization, may have an important role in decreased cognitive functions, observed in depression, as well as in changes in the brain volume, explained by a lost of neuronal processes such as axons, dendrite processes or dendritic spines, rather than by loss of neuronal or glial cell bodies. This explanation is supported by light immunomicroscopy of brain slices postmortem stained with specific antibodies. Psychological stress which causes oxidative stress has also been suggested to cause a decrease of neuronal volume in the prefrontal cortex, altering the synaptic connections established with the hippocampus. This conclusion was drawn from studies in animal models of psychological stress associated with molecular measurements where defects in the expression of MAP1 and sinaptophysin were found, suggesting that defects in cytoskeletal associated proteins could underlie some cytoarchitectural abnormalities described in depression. Together all the evidence accumulated indicates that major depression illness and bipolar depression are mental disorders that involve loss of axons and dendrites in neurons of the Central Nervous System, that in consequence cause disruption of synaptic connectivity. Thus is possible that depression can be considered as a cytoskeletal disorder, therefore this cellular structure could be a drug target for therapeutic approaches by restoring normal cytoskeleton structure and precluding damage caused by oxygen-reactive species. In this regard, melatonin, the hormone secreted by pineal gland during dark phase of the photoperiod, has two important properties that can be useful in treatment of mental disorders. First, the melatonin is a potent free-radical scavenger and second this hormone governs the assembly of the three main cytoskeletal components modulating the cytoskeletal organization. This notion is supported by direct action of melatonin effects on cytoskeletal organization in neuronal cells. In N1E-115 neuroblastoma cells, melatonin induced a two-fold increase in number of cells with neurites 1 day after plating; the effect lasting up to 4 days. Induction of neurite outgrowths is optimal at 1 nM melatonin and in presence of hormone the cells grew as clusters with long neurites forming a fine network to make contact with adjacent cells. Immunofluorescence of N1E-115 cells cultured under these conditions showed tubulin staining in long neurite processes connecting cells to each other. Neurite formation is a complex process that is critical to establish synaptic connectivity. Neuritogenesis takes place by a dynamic cytoskeletal organization that involves microtubule enlargement, microfilament arrangement, and intermediate- filament reorganization. In particular, it is known that vimentin intermediate filaments are reorganized during initial stages of neurite outgrowth in neuroblastoma cells and cultured hippocampal neurons. Evidence has been published indicating that increase in microtubule assembly participates in neurite formation elicited by melatonin antagonism to calmodulin. Moreover, recently it was reported that melatonin precludes cytoskeletal damage produced by high levels of free radicals produced by hydrogen peroxide, as well as, damage caused by higher doses of the antypsychotics haloperidol and clozapine. N1E-115 cells incubated with either 100 uM hydrogen peroxide, 100 uM haloperidol, or 100 uM clozapine undergo a complete cytoskeletal retraction around the nucleus. By contrast, NIE-115 cells incubated with hydrogen peroxide, clozapine, or haloperidol followed by the nocturnal cerebrospinal fluid concentration of melatonin (100 nM) showed a well preserved cytoskeleton and neuritogenesis. Thus melatonin is a neuroprotective compound, since protects the neurocytoskeletal organization against damage caused by high concentrations of antipsychotics and oxidative stress. As mentioned previously, polarity is intrinsic to neuronal function. In neurons, somatodendritic domain receives and decodes incoming information and axonal domain delivers information to target cells. Progressive loss of neuronal polarity is one of the histopathologic events in depression. Cytoskeletal collapse underlie the lost of structural polarity and it is known that precede neuronal death and disappearance of synaptic connectivity. Drugs that prevent the loss of polarity and cytoskeleton retraction intrinsic to these diseases, as well as damage in cytoskeletal structure produced by oxidative stress can be extremely useful in depression treatment. Melatonin is a potent free-radical scavenger that also acts as a cytoskeleton regulator; thus, we speculate that this hormone could be useful in prevention and alleviation of psychiatry diseases with synaptic connectivity disruption. Clinical trials show that melatonin administration is followed by alleviation of circadian disturbances and cognitive function in various neuropsychiatry diseases. Moreover, in depression, melatonin improves sleep. Thus, as suggestive as this information appears, controlled clinical trials will be necessary to investigate the beneficial effects of melatonin and other drugs in the depression treatment.

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