ABSTRACT
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.
ABSTRACT
Introduction Inappropriate use and dependence to prescription drugs has been considered as a growing health problem in recent years. It has been recognized that benzodiazepines (BZD) are one of the most commonly prescribed drugs due to their rapid therapeutic effect, high efficacy and favorable side effect profile when compared to other psychotropic medications. Despite the desirable therapeutic actions of BZD, mainly for the treatment of anxiety disorders, concerns about the dependence producing or addictive nature of these drugs have been expressed for decades. BZD dependence, unlike dependence to other substances, is a condition generally circumscribed to a therapeutic framework. It is well known that BZD use generally starts legitimately by a medical prescription for the treatment of anxiety symptoms or insomnia. Persons with psychiatric disorders are at a greater health risk for BZD dependence than other groups as BZD are highly used for the treatment of several psychiatric symptoms. BZD dependence in these patients may have a negative clinical impact in the medical treatment of the primary psychiatric disorder and may also affect patients' quality of life as the BZD dependence is added as a comorbid diagnosis that also requires clinical management. In this way, the need for clinical useful information for the prevention or early detection of BZD dependence emerges. Although inconsistent associations have been encountered in the scientific literature, some sociodemographic variables, such as gender and level of education, as well as the characteristics of BZD use, have been identified as potential risk factors for the development of BZD dependence. This information is of easy access for the mental health professional during the initial or subsequent clinical interview with patients, and if significant findings are obtained in Mexican psychiatric patients, these variables may become useful clinical tools for a closer follow-up of those patients with high risk of presenting BZD dependence. Objective To determine sociodemographic variables and characteristics of BZD use that may be risk factors for the development of BZD dependence in a sample of psychiatric patients from Mexico City. Method Subjects. Subjects were consecutively recruited at the outpatient services of the Instituto Nacional de Psiquiatría Ramón de la Fuente (INPRF) in Mexico City. All patients with BZD consumptions were included indistinctly of their psychiatric diagnosis of attendance in the institution. All patients gave their written informed consent after receiving a comprehensive explanation of the nature of the study. The Ethics Review Board of the INPRF approved the study. Assessment procedure Psychiatric diagnoses were made with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and BZD dependence was determined with an adapted version of the substance dependence section of the SCID-I designed to assess BZD use exclusively. Sociodemographic features and characteristics of BZD use were registered in a previously designed format and information was obtained by a personal interview with each patient and main caregiver. The Benzodiazepine Dependence Questionnaire in its Mexican version (BDEPQ-MX) is a self-administered questionnaire used to assess the subjective experience with BZD in the last month in three main areas: perceived dependence, BZD pleasant effects and perceived need of BZD consumption. Results The sample comprised 150 psychiatric patients. A total of 70.0% (n=105) were women and 30.0% (n = 45) were men. Their mean age was 45.9±14.1 with a mean educational level of 11.6±3.9 years. Diagnoses of the sample were mainly anxiety disorders (n = 76, 50.7%) and affective disorders (38.0%). According to the SCID-I, a total of 73 (48.7%) patients met the diagnostic criteria for BZD dependence. Sixty seven percent of the men included in the study reported BZD dependence in contrast to 41.0% of the women. Also, patients with BZD dependence exhibited a higher level of education and a longer time consumption of BZD. A longer duration of BZD consumptions was the main indicator for BZD dependence conferring a risk 10.4 higher for its development. Male gender and psychiatric diagnoses different to anxiety and affective disorders were also significant predictors for BZD dependence. Discussion Numerous potential risk factors relating to BZD dependence have been found and our results support the influence of sociodemographic features and characteristics of BZD consumption for dependence development in a Mexican sample of psychiatric patients. In general, it has been described that men are more prone to substance abuse and dependence and our results showed this same pattern. Nevertheless, this result must be replicated in future studies as for BZD dependence men and women may exhibit similar patterns of consumption and dependence. High rates of BZD prescription, coupled with an elevated risk of substance dependence in diagnoses different to anxiety disorders, highlight the need for a careful review of the costs-benefits of BZD use for the treatment of anxiety emergent symptoms, as other additional medications with lower dependence effect can be used to minimize the potential risk of BZD dependence in these patients. One of the biggest controversies surrounding BZD use has been its long-term use, which has been reported and replicated in our studies as the main indicator for BZD dependence development. Treatment with BZD may be useful for short-term periods of time, and specific goals and objectives of their therapeutic benefits must be established since the initial treatment plans for each patient. The clinical relevance of the present study relies in standing out the high prevalence of BZD dependence found in patients treated with BZD and had not been treated for this comorbid condition. It is important to promote in the mental health professional attendance team strategies for the prevention and early detection of BZD dependence in psychiatric patients.
Introducción El uso inapropiado de los fármacos de prescripción y la dependencia a ellos conforman un problema de salud que va en aumento en la actualidad. A diferencia de la dependencia a otras sustancias, la dependencia a BZD es una condición generalmente circunscrita a un marco terapéutico, ya que el primer contacto frecuentemente se presenta en un contexto clínico. Por el es necesario contar con información que pudiera ser de utilidad clínica para prevenir o detectar de forma oportuna la dependencia en pacientes tratados con BZD. Objetivo Determinar las variables sociodemográficas relacionadas con el patrón de consumo de BZD que pudieran ser predictoras de dependencia a BZD en una muestra de pacientes psiquiátricos de la Ciudad de México. Método Sujetos. Se reclutó a los pacientes que acudieron de forma consecutiva al servicio de Consulta Externa del Instituto Nacional de Psiquiatría Ramón de la Fuente (INPRF) que presentaron uso de BZD, indistintamente del diagnóstico psiquiátrico por el que acudieron a recibir atención especializada. Instrumentos El diagnóstico psiquiátrico y de dependencia a BZD de los pacientes se realizó mediante la entrevista SCID-I. Los principales datos sociodemográficos y las características del consumo de BZD fueron registrados en un formato diseñado ad hoc. El Cuestionario de Dependencia a Benzodiazepinas en su versión para México (BDEPQ-MX) se utilizó para evaluar la experiencia subjetiva del consumo de BZD. Resultados Se incluyó a un total de 150 pacientes con una edad promedio de 45.9±14.1 años. El 48.7% de los pacientes presentaron dependencia a BZD. Los pacientes con dependencia a BZD fueron con mayor frecuencia hombres, con una mayor escolaridad y presentaron un mayor tiempo de consumo. El ser hombre, presentar un diagnóstico distinto a un trastorno de ansiedad o afectivo y tener un mayor tiempo de consumo de BZD fueron los principales factores predictores de dependencia en el presente estudio. Discusión Los hallazgos del presente estudio sustentan la influencia de variables demográficas y del consumo de BZD en el riesgo para desarrollar dependencia. Se observa un mayor riesgo para el desarrollo de dependencia en los hombres. Para los pacientes con diagnósticos distintos a los trastornos de ansiedad es necesario evaluar el costo-beneficio de utilizar las BZD como parte del tratamiento para el manejo de síntomas relacionados con la ansiedad. El uso crónico de BZD fue el principal predictor de dependencia en la presente investigación, lo que pone de manifiesto la importancia de restringir el uso de BZD a periodos cortos de tiempo, estableciendo metas y objetivos claros de sus beneficios terapéuticos. Es fundamental fomentar en el personal médico y paramédico la prevención y detección oportuna de la dependencia a BZD en pacientes psiquiátricos.
ABSTRACT
Misuse and potential abuse of prescription drugs are growing problems in elderly people over 65 years old. Although the prevalence of this condition is difficult to estimate, drug misuse is most common in elderly women. A great proportion of the psychoactive prescriptions in old people include tranquilizers and hypnotics. There are several risk factors related to increased risk misuse, abuse, and dependence of prescription drugs. The following are among these risk factors: the female gender, social isolation, history of substance abuse or dependence, history of mental illness and medical exposure to prescription drugs with abuse potential. Also, BDZ consumption for a period longer than four weeks has also been associated to BDZ dependence, even at therapeutic doses. Until now, BDZ dependence in the elderly has been poorly studied, so the present study may increase our knowledge of this complex phenomenon. Objective The aim of the present study was to describe and compare sociodemographic and clinical features related to the prescription and benzodiazepines use in old people with and without dependence to these drugs in an outpatients psychogeriatric service. Method A total of 39 patients from the outpatients service at the psychogeriatric clinic of the National Institute of Psychiatry Ramón de la Fuente in Mexico City were recruited. All of the participants signed an informed consent to be included in the study. Several assessments were performed to determine the psycho-pathological status. Diagnosis of BDZ dependence was obtained with the SCID-I Interview, the severity of depression and anxiety symptoms were evaluated through the Montgomery & Asberg Scale (MADRS) and the Hamilton Anxiety Scale, respectively. For the evaluation of the functionality level, the Katz Index and GAF were used. Results No significant differences were found between patients with and without BDZ dependence in terms of social and demographic characteristics and medical comorbidity. The main Axis I diagnoses of the patients were depressive disorder or anxiety disorders. The first medical prescription of BDZ in patients with BDZ dependence was the presence of anxiety symptoms, while for patients without BDZ dependence the aim of BDZ prescription was the treatment of insomnia. The mean age of BDZ use onset and the time of consumption were 57.5 years and 675.2 weeks, respectively. The average dose of BDZ used by the patients was 14.4mg of diazepam equivalents. Significant differences were found between groups in terms of BDZ consumption features. Patients with BDZ dependence exhibited more drug seeking behavior, more abandonment of daily activities, and more tolerance and abstinence symptoms. Patients with BDZ dependence exhibited more prominent symptoms of anxiety and depression than patients without BDZ dependence. Also, these patients had a poorer cognitive performance and lower psychosocial functioning. Discussion BDZ dependence is a complex phenomenon related to the severity of depressive and anxiety symptoms. These symptoms were the main reason for the medical prescription of BDZ. Although BDZ use was indicated for the treatment of anxiety disorders, the use of BDZ in the elderly has been contraindicated for the treatment of depression with anxiety features. The potential risk to develop BDZ dependence in elderly patients can be related to pharmacological variations due to changes in the metabolism process of aging and the interactions with other drugs. Both factors could increase half life of BDZ and their pharmacological effect in the organism. There were statistical differences in the drug-taking pattern of BDZ consumption in the patients. Patients with BDZ dependence had an earlier onset of BDZ consumption and longer use. The chronic use of BDZ is one of the most important risk factors for dependence development. For the present study, BDZ dependence was clinically defined in terms of tolerance and abstinence symptoms. This definition is in accordance to what has been described in international scientific literature as BDZ physiologic dependence. In this way, tolerance and abstinence symptoms might be the main reason why patients with BDZ dependence needed higher BDZ dosages for the treatment of anxiety symptoms. Sociodemographic characteristics in this sample were not related to the presence of BDZ dependence; nevertheless, it has been reported that the female gender and the presence of chronic pain are risk factors for BDZ abuse and dependence. Future longitudinal studies with an increased number of patients should assess the effect of these variables in BDZ dependence development in the elderly. Differences found in terms of cognitive performance may be related to the psychomotor retardation conferred by the use of BDZ, which may in turn have a direct impact on the velocity of mental performance in the patients. Also, the presence and severity of depressive and anxiety symptoms may also have a negative impact on cognitive performance. Generalization of the findings of the present research is limited by sample size. Nevertheless, the relevance of the present results highlight the importance of the careful prescription and inherent risks related to potentially addictive medications. Increasing our knowledge in the prescription of these medications will improve our medical attention and our patients' quality of life.
El abuso potencial y el uso inapropiado de fármacos de prescripción en adultos mayores de 65 años o más está en aumento. Aunque la prevalencia de esta condición es difícil de estimar, se sabe que es más frecuente en mujeres. Una gran proporción de los tranquilizantes e hipnóticos son prescritos a adultos mayores. El género femenino, el aislamiento social y una historia de abuso de sustancias y de trastornos mentales son los principales factores de riesgo asociados al uso inapropiado de fármacos. Por otro lado, el uso prolongado de benzodiazepinas (BDZ) -mayor a cuatro semanas- también se ha asociado al desarrollo de dependencia, aun cuando las BDZ se utilicen a dosis terapéuticas Objetivo El objetivo del presente estudio es describir y comparar las características sociodemográficas y clínicas relacionadas con la prescripción y el uso de benzodiazepinas en adultos mayores con y sin dependencia a las mismas en un servicio especializado de psicogeriatría. Método Se reclutó un total de 39 pacientes de la Clínica de Psicogeriatría del Instituto Nacional de Psiquiatría Ramón de la Fuente en la Ciudad de México. Todos los participantes consintieron por escrito su participación en el estudio. El diagnóstico de dependencia a BDZ se realizó a partir del SCID-I; la gravedad de los síntomas de depresión se evaluó mediante la Escala de Montgomery y Asberg (MADRS); los síntomas de ansiedad, con la Escala de Ansiedad de Hamilton (HAM-A), y el nivel de funcionalidad, mediante el Índice de Katz y el GAF. Resultados No se encontraron diferencias significativas entre los grupos en las variables sociodemográficas y la comorbilidad médica. Los pacientes incluidos cursaron en su mayoría con un cuadro depresivo o algún trastorno de ansiedad como diagnóstico principal. La indicación médica inicial para el consumo de BDZ fue el tratamiento de la ansiedad para los pacientes con dependencia y del insomnio para los no dependientes. La edad de inicio del consumo de las BDZ y el tiempo de consumo fue de 57.5 años y 675.2 semanas en promedio, respectivamente. La dosis promedio utilizada por los pacientes fue de 1 4.4mg en equivalentes de diazepam. Los pacientes con dependencia a las BDZ mostraron una mayor gravedad de los síntomas de depresión y ansiedad, menor desempeño cognoscitivo y menor funcionamiento psicosocial, así como conductas de búsqueda y abandono de actividades relacionadas con el consumo y mayores síntomas de tolerancia y abstinencia a las BDZ. Discusión La dependencia a las BDZ se presentó como un fenómeno complejo relacionado con la intensidad de los síntomas de depresión y ansiedad, un consumo crónico y una mayor dosificación. La depresión con síntomas de ansiedad en el adulto mayor no debería tratarse con BDZ, ya que, además del riesgo de desarrollar dependencia, éstas pueden efectuar negativamente el desempeño cognoscitivo y el funcionamiento global de los pacientes. Al momento de prescribir una BDZ a la población geriátrica se deben tomar en consideración variables sociodemográficas y clínicas de los pacientes. De la misma forma, será necesario evaluar en futuros estudios la influencia de la personalidad y otras variables clínicas sobre el desarrollo de esta dependencia.
ABSTRACT
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.