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1.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-38338735

RESUMEN

The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-ß, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos-positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.


Asunto(s)
Corticosterona , Resistencia a la Insulina , Menopausia , Microglía , Proteínas Proto-Oncogénicas c-fos , Animales , Femenino , Ratas , Ansiedad/etiología , Ansiedad/psicología , Peso Corporal , Depresión/etiología , Dieta/efectos adversos , Lípidos , Menopausia/metabolismo , Microglía/metabolismo , Estrés Psicológico/metabolismo , Factor de Necrosis Tumoral alfa , Proteínas Proto-Oncogénicas c-fos/metabolismo
2.
Front Pharmacol ; 14: 1211663, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37900157

RESUMEN

Introduction: Natural products such as phytoestrogens-enriched foods or supplements have been considered as an alternative therapy to reduce depressive symptoms associated with menopause. It is known that the aqueous extract of Punica granatum (AE-PG) exerts antidepressant-like effects by activating ß-estrogen receptors and facilitates the antidepressant response of the clinical drug citalopram (CIT). However, the effects on neuroplasticity are unknown. Objectvie investigated the antidepressant-like response of combining AE-PG and CIT at sub-optimal doses, analyzing their effects on the formation and maturation of dendrite spines in granule cells as well as on the dendrite complexity. Methods: Ovariectomized Wistar rats (3-month-old) were randomly assigned to one of the following groups: A) control (saline solution as vehicle of CIT and AE-PG, B) AE-PG at a sub-threshold dose (vehicle of CIT plus AE-PG at 0.125 mg/kg), C) CIT at a sub-threshold dose (0.77 mg/kg plus vehicle of AE-PG), and D) a combination of CIT plus AE-PG (0.125 mg/kg and 0.77 mg/kg, respectively). All rats were treated intraperitoneally for 14 days. Antidepressant-like effects were evaluated using the force swimming test test (FST). The complexity of dendrites and the number and morphology of dendrite spines of neurons were assessed in the dentate gyrus after Golgi-Cox impregnation. The expressions of the mature brain-derived neurotrophic factor (mBDNF) in plasma and of mBDNF and synaptophysin in the hippocampus, as markers of synaptogenesis, were also determined. Results: Administration of CIT combined with AE-PG, but not alone, induced a significant antidepressant-like effect in the FST with an increase in the dendritic complexity and the number of dendritic spines in the dentate gyrus (DG) of the hippocampus, revealed by the thin and stubby categories of neurons at the granular cell layer. At the same time, an increase of mBDNF and synaptophysin expression was observed in the hippocampus of rats that received the combination of AE-PG and CIT.

3.
Int J Mol Sci ; 24(17)2023 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-37686181

RESUMEN

Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2' 3'-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin's beneficial effects for counteracting temozolomide's side effects.


Asunto(s)
Depresión , Melatonina , Animales , Ratones , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Proteínas de Dominio Doblecortina , Melatonina/farmacología , Ratones Endogámicos BALB C , Neuronas , Temozolomida/efectos adversos , Temozolomida/farmacología
4.
Int J Mol Sci ; 22(20)2021 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-34681636

RESUMEN

Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified.


Asunto(s)
Anhedonia/efectos de los fármacos , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estrés Psicológico/fisiopatología , Anhedonia/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Calbindina 2/metabolismo , Proliferación Celular , Proteína Doblecortina/metabolismo , Ambiente , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Antígeno Ki-67/metabolismo , Ratones , Ratones Endogámicos BALB C , Estrés Fisiológico
5.
Eur J Neurosci ; 54(4): 5293-5309, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34302304

RESUMEN

Menopause, natural or surgical, might facilitate the onset of psychiatric pathologies. Some reports suggest that their severity could increase if the decline of ovarian hormones occurs abruptly and before natural endocrine senescence. Therefore, we compared the effects of ovariectomy on microglia's morphological alterations, the complexity of newborn neurons, and the animal's ability to cope with stress. Young adult (3 months) and middle-aged (15 months) female Wistar rats were subjected to an ovariectomy (OVX) or were sham-operated. After 3 weeks, animals were assigned to one of the following independent groups: (1) young adult OVX + no stress; (2) young adult sham + no stress; (3) young adult OVX + stress; (4) young adult sham + stress; (5) middle-aged OVX + no stress; (6) middle-aged sham + no stress; (7) middle-aged OVX + stress; (8) middle-aged sham + stress. Acute stress was induced by forced swimming test (FST) exposure. Immobility behavior was scored during FST and 30 min after; animals were euthanized, their brains collected and prepared for immunohistochemical detection of Iba-1 to analyze morphological alterations in microglia, and doublecortin (DCX) detection to evaluate the dendrite complexity of newborn neurons. OVX increased immobility behavior, induced microglia morphological alterations, and reduced dendrite complexity of newborn neurons in young adult rats. FST further increased this effect. In middle-aged rats, the main effects were related to the aging process without OVX or stress exposure. In conclusion, surgical menopause favors in young adult rats, but not in middle-aged, the vulnerability to develop immobility behavior, retracted morphology of microglial cells, and decreased dendrite complexity of newborn neurons.


Asunto(s)
Microglía , Estrés Psicológico , Animales , Dendritas , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Femenino , Humanos , Proteínas Asociadas a Microtúbulos , Neuronas , Neuropéptidos , Ovariectomía , Ratas , Ratas Wistar
6.
Neuroscience ; 440: 316-336, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32417342

RESUMEN

Depression may be precipitated by the negative impact of chronic stress, which is considered to play a key role in this neuropsychiatric disorder. Interestingly, depressed patients show decreased levels of melatonin. This hormone acts pro-neurogenic and exhibits anti-depressant effects in rodent models of predictive antidepressant-like effects. However, the benefits of melatonin in reversing the deleterious effects of chronic mild stress on the alterations in behaviour and in the neurogenic niche of the hippocampus in male BALB/c mice are unknown. In this study, we compared the effects of melatonin (2.5 mg/kg) and citalopram (5 mg/kg), an antidepressant drug belonging to the selective serotonin reuptake inhibitors, in male BALB/c mice exposed to chronic mild stress (CMS). We also investigated the potential effects of melatonin and citalopram on microglial cells, hippocampal neurogenesis and peripheral cytokine profiles. Melatonin and citalopram induced similar antidepressant-like activities that occurred with some of the the following findings: (1) reversal of the morphological alterations in microglia; (2) reversal of the decreased immunoreactivity to CX3CL1 and CX3CR1 in the dentate gyrus; (3) positive regulation of cell proliferation, survival and complexity of the dendritic trees of doublecortin-cells; and (4) modifications of peripheral CX3CL1 expression. This outcome is consistent with the hypothesis about the antidepressant-like effect of melatonin and supports its relevance as a modulator of the niche in the dentate gyrus.


Asunto(s)
Quimiocina CX3CL1 , Melatonina , Animales , Depresión/tratamiento farmacológico , Hipocampo , Masculino , Melatonina/farmacología , Ratones , Ratones Endogámicos BALB C , Microglía , Neurogénesis
7.
Int J Mol Sci ; 21(5)2020 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-32138332

RESUMEN

Adult neurogenesis occurs in the dentate gyrus (DG) of the hippocampus. New neurons help to counteract the effects of stress and several interventions including antidepressant drugs, environmental modifications and internal factors act pro-neurogenic with consequences in the dorsal and ventral DG. Melatonin, the main product synthesized by the pineal gland, induces antidepressant-like effects and modulates several events of the neurogenic process. However, the information related to the capability of melatonin to modulate dendrite maturation and complexity in the dorsal and ventral regions of the DG and their correlation with its antidepressant-like effect is absent. Thus, in this study, we analyzed the impact of melatonin (0, 0.5, 1, 2.5, 5 or 10 mg/kg) administered daily for fourteen days on the number, dendrite complexity and distribution of doublecortin (DCX)-cells in the dorsal-ventral regions of the DG in male Balb/C mice. Doublecortin is a microtubule-associated protein that is expressed during the course of dendritic maturation of newborn neurons. Also, we analyzed the impact of melatonin on despair-like behavior in the forced swim test. We first found a significant increase in the number and higher dendrite complexity, mainly with the doses of 2.5, 5 and 10 mg/kg of melatonin (81%, 122%, 78%). These cells showed more complex dendritic trees in the ventral- and the dorsal- DG. Concomitantly, the doses of 5 and 10 mg/kg of melatonin decreased depressant-like behavior (76%, 82%). Finally, the data corroborate the antidepressant-like effect of melatonin and the increasing number of doublecortin-associated cells. Besides, the data indicate that melatonin favors the number and dendrite complexity of DCX-cells in the dorsal- and ventral- region of the DG, which may explain part of the antidepressant-like effect of melatonin.


Asunto(s)
Antidepresivos/uso terapéutico , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Melatonina/uso terapéutico , Animales , Depresión/tratamiento farmacológico , Depresión/metabolismo , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos/metabolismo , Neurogénesis/efectos de los fármacos , Neuropéptidos/metabolismo
8.
Neural Plast ; 2018: 8205245, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30627149

RESUMEN

Several interventions have been shown to counteract the effects of stress that may be related to improved neuroplasticity and neuronal activation. In this sense, environmental enrichment (ENR) protects against acute stress and increases neuroplasticity. It has been suggested that the use of patterned auditory stimuli (PAS) may be beneficial in increasing the effectiveness of ENR on disorders related to stress, such as depression and anxiety. Examples of PAS are classical music compositions that have interesting effects at both clinical and preclinical levels. Thus, we analyzed the effects of the exposure to PAS, represented in this study by Mozart's compositions, during ENR housing for 35 days in adult male Balb/C mice to evaluate depression-associated behavior using the forced-swim test (FST) paradigm with an additional short exposure to PAS. We found that the ENR mice that were exposed to PAS during both housing and behavioral task (ENR + PAS/FST + PAS) show decreased immobility and the number of despair episodes within a higher latency to show the first bout of immobility. Additionally, we found increased neuronal activation evaluated by the identification of activity-regulated cytoskeleton-associated protein- (Arc-) labeled cells in the prefrontal cortex (PFC) in mice exposed to PAS during housing and in the absence or presence of PAS during FST. Moreover, we found increased neuronal activation in the auditory cortex (AuCx) of mice exposed to PAS during FST. Our study suggests that the exposure to PAS during an emotional challenge decreases despair-like behavior in rodents that were previously housed in an enriched environment in combination with auditory stimuli. Thus, our data indicate that the role of the exposure to PAS as an intervention or in combination with positive environment to aid in treating neuropsychiatric disorders is worth pursuing.


Asunto(s)
Estimulación Acústica/métodos , Depresión , Vivienda para Animales , Estrés Fisiológico/fisiología , Estrés Psicológico/fisiopatología , Animales , Corticosterona/sangre , Ambiente , Masculino , Ratones , Ratones Endogámicos BALB C , Neuronas/fisiología , Estrés Psicológico/psicología , Natación
9.
Neuroscience ; 355: 84-100, 2017 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-28499977

RESUMEN

Neurogenesis constitutively occurs in the olfactory epithelium of mammals, including humans. The fact that new neurons in the adult olfactory epithelium derive from resident neural stem/progenitor cells suggests a potential use for these cells in studies of neural diseases, as well as in neuronal cell replacement therapies. In this regard, some studies have proposed that the human olfactory epithelium is a source of neural stem/progenitor cells for autologous transplantation. Although these potential applications are interesting, it is important to understand the cell biology and/or whether human neural stem/progenitor cells in the olfactory epithelium sense external signals, such as brain-derived neurotrophic factor (BDNF), that is also found in other pro-neurogenic microenvironments. BDNF plays a key role in several biological processes, including cell migration. Thus, we characterized human neural stem/progenitor cells derived from the olfactory epithelium (hNS/PCs-OE) and studied their in vitro migratory response to BDNF. In the present study, we determined that hNS/PCs-OE express the protein markers Nestin, Sox2, Ki67 and ßIII-tubulin. Moreover, the doubling time of hNS/PCs-OE was approximately 38h. Additionally, we found that hNS/PCs-OE express the BDNF receptor TrkB, and pharmacological approaches showed that the BDNF-induced (40ng/ml) migration of differentiated hNS/PCs-OE was affected by the compound K252a, which prevents TrkB activation. This observation was accompanied by changes in the number of vinculin adhesion contacts. Our results suggest that hNS/PCs-OE exhibit a migratory response to BDNF, accompanied by the turnover of adhesion contacts.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Movimiento Celular/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Mucosa Olfatoria/citología , Receptor trkB/metabolismo , Carbazoles/farmacología , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colchicina/farmacología , Inhibidores Enzimáticos/farmacología , Histonas/metabolismo , Humanos , Alcaloides Indólicos/farmacología , Antígeno Ki-67/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factores de Tiempo , Tubulina (Proteína)/metabolismo , Vinculina/metabolismo
10.
Neurotox Res ; 31(1): 122-135, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27663583

RESUMEN

The generation of new neurons during adulthood involves local precursor cell migration and terminal differentiation in the dentate gyrus. These events are influenced by the hippocampal microenvironment. Brain-derived neurotrophic factor (BDNF) is relevant for hippocampal neuronal development and behavior. Interestingly, studies that have been performed in controlled in vitro systems that involve isolated precursor cells that were derived from the dentate gyrus (AHPCs) have shown that BDNF induces the activation of the TrkB receptor and, consequentially, might activate signaling pathways that favor survival and neuronal differentiation. Based on the fact that the cellular events of AHPCs that are induced by single factors can be studied in this controlled in vitro system, we investigated the ability of BDNF and the involvement of protein kinase C (PKC), as one of the TrkB-downstream activated signaling proteins, in the regulation of migration, here reflected by motility, of AHPCs. Precursor cells were cultured following a concentration-response curve (1-640 ng/ml) for 24 or 96 h. We found that BDNF favored cell survival without altering the viability under culture proliferative conditions of the AHPCs. Concomitantly, glial- and neuronal-differentiated precursor cells increased as a consequence of survival promoted by BDNF. Additionally, pharmacological approaches showed that BDNF (40 ng/ml)-induced migration of AHPCs was blocked with the compounds K252a and GF109203x, which prevent the activation of TrkB and PKC, respectively. The results indicate that in the in vitro migration of differentiated AHPCs it is involved the BDNF and TrkB cascade. Our results provide additional information about the mechanism by which BDNF impacts adult neurogenesis in the hippocampus.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Movimiento Celular/fisiología , Supervivencia Celular/fisiología , Hipocampo/metabolismo , Neurogénesis/fisiología , Neuronas/metabolismo , Células Madre Adultas/citología , Células Madre Adultas/efectos de los fármacos , Células Madre Adultas/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Carbazoles/farmacología , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Femenino , Hipocampo/citología , Hipocampo/efectos de los fármacos , Alcaloides Indólicos/farmacología , Indoles/farmacología , Maleimidas/farmacología , Ratones Endogámicos C57BL , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neurogénesis/efectos de los fármacos , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo
11.
Behav Brain Res ; 301: 72-83, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26721469

RESUMEN

Because stress may underlie the presence of depressive episodes, strategies to produce protection against or to reverse the effects of stress on neuroplasticity and behavior are relevant. Preclinical studies showed that exposure to stimuli, such as physical activity and environmental enrichment (ENR), produce beneficial effects against stress causing antidepressant-like effects in rodents. Additionally, ENR induces positive effects on neuroplasticity, neurochemistry and behavior at any age of rodents tested. Here, we analyzed whether ENR exposure prevents the development of depressive-like behavior produced by unpredictable, chronic mild stress (CMS) exposure as well as changes in hippocampal neurogenesis in a six-month-old female Balb/C mice, strain that shows low baseline levels of hippocampal neurogenesis. Mice were assigned to one of four groups: (1) normal housing-normal housing (NH-NH), (2) NH-CMS, (3) ENR-NH, or (4) ENR-CMS. The animals were exposed over 46 days to ENR or NH and subsequently to NH or CMS for 4 weeks. ENR induces long-term effects protecting against CMS induction of anhedonia and hopelessness behaviors. Independent of housing conditions, ENR increased the number of proliferative cells (Ki67), and CMS decreased the number of proliferative cells. ENR increased the newborn cells (BrdU) and mature phenotypes of neurons; these effects were not changed by CMS exposure. Similarly, the number of doublecortin-positive cells was not affected by CMS in ENR mice, which showed more cells with complex dendrite arborizations. Our study suggests that ENR induces protection against the effects of CMS on behavior and neuroplasticity in six-month-old Balb/C mice.


Asunto(s)
Ambiente , Neuronas/fisiología , Estrés Psicológico/fisiopatología , Estrés Psicológico/terapia , Anhedonia/fisiología , Animales , Análisis Químico de la Sangre , Bromodesoxiuridina , Proliferación Celular/fisiología , Enfermedad Crónica , Corticosterona/sangre , Giro Dentado/patología , Giro Dentado/fisiopatología , Trastorno Depresivo/patología , Trastorno Depresivo/fisiopatología , Trastorno Depresivo/terapia , Proteínas de Dominio Doblecortina , Ensayo de Inmunoadsorción Enzimática , Femenino , Vivienda para Animales , Inmunohistoquímica , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos/metabolismo , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Neuronas/patología , Neuropéptidos/metabolismo , Estrés Psicológico/patología
12.
Salud ment ; Salud ment;36(4): 331-336, jul.-ago. 2013.
Artículo en Español | LILACS-Express | LILACS | ID: lil-691284

RESUMEN

Depression refers to a mood disorder characterized by deep sadness and loss of interest and pleasure. Epidemiologic studies show that this disorder represents a public health problem affecting 12% of the world population in a proportion of 2:1 of women to men. Depression is a complex disease in which it has been observed that the noradrenergic system appears to play an important role. Thus, a decrease in the noradrenergic tone, changes in noradrenaline (NA) synthesis, reduction in its turn-over, and modulation of its receptors can induce this disease. On the other hand, estrogens are a wide hormones family with multiple biologic functions which include those related to mood states. Clinical studies suggest that hormonal fluctuations, such as the premenstrual phase, puerperium and perimenopause, are associated with an increase in the vulnerability to depression. Conversely, estrogens have shown antidepressant effects in different preclinical models. Binding and electrophysiology studies suggest that estrogens are able to modulate noradrenergic transmission, through an increase of NA neurons' firing rate, a regulation of noradrenergic receptors and the synthesis and catabolism of this neurotransmitter. Additionally, behavioral studies support the interaction of estrogens with the noradrenergic system. Thus, the purpose of this review is to analyze the participation of noradrenalin, estrogens and their interaction in the treatment of depression in both, clinical and preclinical studies.


La depresión se define como un trastorno del estado de ánimo caracterizado por un estado de tristeza profunda y una pérdida de interés o placer. Este trastorno psiquiátrico afecta al 12% de la población mundial, siendo las mujeres quienes más la padecen. La depresión es una patología compleja, en la que se ha observado que el sistema noradrenérgico cumple un papel importante. Así, una disminución en el tono noradrenérgico, los cambios en la síntesis y el metabolismo de la noradrenalina (NA), así como en la modulación de sus receptores, pueden conducir a un estado depresivo. Por otro lado, los estrógenos son un grupo de hormonas gonadales con diversas funciones fisiológicas, incluidas las que se relacionan con los estados afectivos. Diversos estudios clínicos sugieren que las fluctuaciones hormonales, como la etapa premenstrual, el puerperio y la perimenopausia, se asocian con un aumento en la vulnerabilidad a presentar depresión y se ha demostrado que los estrógenos presentan efectos antidepresivos en diversos modelos conductuales. En estudios electrofisiológicos y de unión de ligando se reporta que los estrógenos son capaces de modular la transmisión noradrenérgica a través de diferentes mecanismos, los cuales incluyen un aumento en la frecuencia de disparo de las neuronas noradrenérgicas, la regulación de la densidad de los receptores noradrenérgicos, así como en los procesos de síntesis y metabolismo de este neurotransmisor. Además, diversos estudios conductuales han aportado información que apoya la participación de los estrógenos en la modulación del sistema noradrenérgico e incluso se ha propuesto que a través de esta vía podrían inducir sus efectos antidepresivos. De esta forma, el propósito de esta revisión es analizar, a nivel clínico y preclínico, la participación de la noradrenalina y de los estrógenos, y la relación entre ambos en el tratamiento de la depresión.

13.
Salud ment ; Salud ment;35(6): 527-533, nov.-dic. 2012. ilus
Artículo en Español | LILACS-Express | LILACS | ID: lil-675553

RESUMEN

Estrogens produce a wide range of biological effects throughout the body, including the Central Nervous System (CNS). In the brain, besides acting as neuroprotective agents, estrogens play an important role in many neuronal processes and certain psychiatric disorders such as depression. The precise mechanism by which estrogens induce their positive effects on depressive disorders has not been elucidated; however, it is known that estrogens act on the CNS through the activation of specific receptors. These actions occur in genomic and non-genomics mechanisms through the modulation of synthesis and metabolism of neurotransmitters, neuropeptides, neurosteroids and influencing the morphological features of neurons and synaptic function. In addition, it is known that estrogens can act as modulators of processes related to neuroplasticity and neurogenesis. Adult hippocampal neurogenesis is a neuroplastic process that is affected by antidepressant drugs. These drugs increase the number of new neurons following a temporal course that correlates within the time in which antidepressants cause a behavioral improvement in rodents and in humans. Interestingly, whereas the behavioral antidepressant effects require 2-4 weeks to appear, after treatment initiation, estrogen reduce the depressive-like behavior and induce cell proliferation in terms of days. Thus, antidepressant drugs and the estrogens replacement during the adulthood could influence in a similar manner the new neuron formation. Furthermore, recent works have indicated that the combination of antidepressants plus estrogens could exert beneficial actions at lower doses of estrogens (physiological range). This evidence is important due to the combination of non-effective doses of antidepressants plus estrogens could decrease the side-effects of both compounds, and facilitate the behavioral action of antidepressant drugs shortening the latency to onset their action. The present review discusses recent information about the implication of estrogens in depression, and on their effects as positive regulators of new neuron formation in the adult hippocampus. In addition, we will review the possible implication of last effect of estrogens on their antidepressant effects.


Los estrógenos producen una amplia gama de efectos biológicos en todo el cuerpo, incluyendo el Sistema Nervioso Central (SNC). En el cerebro, además de actuar como agentes neuroprotectores, los estrógenos desempeñan un papel importante en la regulación de procesos neuronales constituyéndose así como posibles factores relacionados con la etiología de algunos trastornos neuropsiquiátricos, tales como la depresión. Durante los últimos años se ha generado evidencia de la relación existente entre los niveles fisiológicos de los estrógenos y el desarrollo de episodios depresivos. Por otra parte, los estrógenos tienen un papel importante en la inducción de cambios a nivel de la plasticidad neuronal y de la neurogénesis en el hipocampo adulto. A este respecto se ha observado que los estrógenos regulan el desarrollo, la maduración y la sobrevivencia de las nuevas neuronas en el cerebro adulto, de la misma manera que lo hacen los tratamientos antidepresivos. Los efectos de los estrógenos sobre la neurogénesis y la plasticidad neuronal podrían estar regulados por los receptores a estrógenos, tanto el receptor alfa (REα), como el receptor beta (REβ). Ambos subtipos de receptores se expresan en el hipocampo del cerebro adulto. Así mismo, el hipocampo es una estructura que participa en procesos cognitivos y de memoria y existe evidencia que muestra su participación en la etiología de la depresión y sobre el efecto de los fármacos antidepresivos. La neurogénesis ha sido considerada como un proceso dinámico por medio del cual se forman neuronas funcionales. De tal modo que este proceso también involucra los eventos de sobrevivencia, maduración dendrítica y axonal, así como el establecimiento de conexiones sinápticas para la integración final de las nuevas neuronas en los circuitos neuronales existentes, eventos que son modulados por los fármacos antidepresivos. En el presente artículo se revisa información reciente acerca de los efectos de los estrógenos sobre la depresión y sobre su relación con la neurogénesis hipocámpica.

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