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Salud mental
Print version ISSN 0185-3325
Salud Ment vol.30 n.2 México Mar./Apr. 2007
Artículos originales
El neurocitoesqueleto: un nuevo blanco terapéutico para el tratamiento de la depresión
* Departamento de Neurofarmacología, Subdirección de Investigaciones Clínicas y Unidad de Servicios Clínicos. Instituto Nacional de Psiquiatría Ramón de la Fuente. Correspondencia: Dra. Gloria Benítez-King. Instituto Nacional de Psiquiatría Ramón de la Fuente. Subdirección de Investigaciones Clínicas. Departamento de Neurofarmacología. Calzada México-Xochimilco 101, San Lorenzo Huipulco, 14370, México D.F. Teléfono (525) 573 2437, Fax (525) 513 3722, E-mail: bekin@imp.edu.mx
Estudios preclínicos y de neuroimágenes cerebrales, han demostrado que las regiones corticales de áreas cerebrales como el hipocampo (corteza límbica), la corteza prefrontal (neocorteza de asociación), y la corteza del cíngulo (componente clave del sistema límbico) están involucradas en la neuropatología de la depresión y en la respuesta al estrés. Estas estructuras muestran alteraciones morfológicas como disminución en el volumen y en el tamaño del soma neuronal. Lo anterior, aunado a la reducción en las ramificaciónes dendríticas, la complejidad de las espinas dendríticas y en los procesos gliales, explican la reducción en el volumen del hipocampo, la corteza prefrontal y la corteza del cíngulo en la depresión, y sugiere actividad neuronal disminuida.
La forma neuronal y la organización de las moléculas y proteínas estructurales en sitios específicos subcelulares está determinada por el citoesqueleto. Este fenómeno de polarización estructural es esencial para que las neuronas adopten una forma asimétrica y para su funcionamiento. La pérdida de la polaridad neuronal, manifestada como una pérdida de las dendritas en la corteza frontal y en el hipocampo, así como la disminución del volumen celular, es uno de los sucesos histopatológicos que ocurren en la depresión mayor. La formación de las dendritas y de los axones depende de la organización de los microtúbulos y los microfilamentos. Asociados a estos cambios estructurales, la depresión produce una pérdida de la conectividad sináptica interneuronal y un incremento en el estrés oxidativo. Recientemente, se ha descrito que el estrés oxidativo origina alteraciones en la organización de los microtúbulos y los microfilamentos. Estos cambios originados a nivel celular se traducen en alteraciones del funcionamiento cerebral, como son la pérdida de las capacidades cognitivas y las alteraciones afectivas. Ambos sintomas están presentes en la depresión.
Esta evidencia sugiere que la depresión es una enfermedad del citoesqueleto y que esta estructura celular puede ser un blanco terapéutico en el tratamiento de la depresión, para reestablecer las dendritas y los axones perdidos y la conectividad sináptica. Se ha descrito que la plasticidad neuronal es un proceso en el que el citoesqueleto tiene un papel primordial, ya que genera nuevas conexiones sinápticas a través de la formación de axones y dendritas. En este sentido, se ha sugerido que la plasticidad neuronal de la formación hipocampal se modifica por la acción de compuestos antidepresivos, ya que estos bloquean y revierten la atrofia de las neuronas hipocampales e incrementan la supervivencia celular en esta región; e indica que la organización del citoesqueleto también es modificada por los fármacos antidepresivos. Por otro lado, los experimentos con modelos animales, sometidos a estrés, han establecido que en la depresión la neurogénesis está alterada, ya que se ha observado una inhibición en la proliferación de nuevas neuronas en el cerebro adulto. Se ha demostrado que el tratamiento con antidepresivos incrementa la neurogénesis en el hipocampo adulto y que las crisis electroconvulsivas incrementan la neurogénesis hipocampal en la rata adulta. Lo anterior plantea el uso de fármacos que estimulen la neurogénesis para promovre la plasticidad neuronal, la migración y la diferenciación de las células de la glía radial en las neuronas, como alternativa en el tratamiento de la depresión. De esta forma, el empleo de fármacos cuyo blanco sea el citoesqueleto y que estimulen la neurogénesis, son alternativas terapéuticas para el tratamiento de la depresión. La melatonina es un compuesto que actúa como un potente captador de radicales libres, como modulador del citoesqueleto y como promotor de la formación de nuevas neuritas que eventualmente madurarán en los axones y las dendritas. En esta revisión se describirá la evidencia que indica que en la depresión está alterado el citoesqueleto neuronal. También se presentarán los datos que apoyan el empleo de moduladores del arreglo del citoesqueleto como una nueva alternativa terapéutica. En particular se presentará evidencia de la función de la melatonina como neuroprotector y no sólo como agente antioxidante, sino que además previene y reestablece la estructura del neurocitoesqueleto, dañado por los radicales libres y por las altas concentraciones de antipsicóticos. Los resultados obtenidos hasta ahora indican la necesidad de realizar estudios clínicos controlados, para determinar la posible utilidad de la melatonina en el tratamiento de enfermedades neuropsiquiátricas.
Palabras clave: Depresión; citoesqueleto; melatonina; hipocampo; neuronas
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.
Key words: Depression; cytoskeletal; melatonin; hippocampus; neurites
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