RESUMEN

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups.

RESUMEN

Major Depressive Disorder (MDD) is a heterogeneous disorder with a considerable symptomatic overlap with other psychiatric and somatic disorders. This study aims at providing evidence for association of a set of serum and urine biomarkers with MDD. We analyzed urine and serum samples of 40 MDD patients and 47 age- and sex-matched controls using 40 potential MDD biomarkers (21 serum biomarkers and 19 urine biomarkers). All participants were of Caucasian origin. We developed an algorithm to combine the heterogeneity at biomarker level. This method enabled the identification of correlating biomarkers based on differences in variation and distribution between groups, combined the outcome of the selected biomarkers, and calculated depression probability scores (the "bio depression score"). Phenotype permutation analysis showed a significant discrimination between MDD and euthymic (control) subjects for biomarkers in urine (P < .001), in serum (P = .02) and in the combined serum plus urine result (P < .001). Based on this algorithm, a combination of 8 urine biomarkers and 9 serum biomarkers were identified to correlate with MDD, enabling an area under the curve (AUC) of 0.955 in a Receiver Operating Characteristic (ROC) analysis. Selection of either urine biomarkers or serum biomarkers resulted in AUC values of 0.907 and 0.853, respectively. Internal cross-validation (5-fold) confirmed the association of this set of biomarkers with MDD.

Asunto(s)

Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/orina , Adulto , Algoritmos , Área Bajo la Curva , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC

RESUMEN

Physical exercise is now generally considered as a strategy to maintain cognitive abilities and to prevent age-related cognitive decline. In the present study, Wistar rats were subjected to moderate intensity treadmill exercise for 6 months prior to sacrifice at 12-, 24- and 32-month of age. This chronic physical intervention was tested on motility in the Open field (OF). Cognitive functions were measured in the Morris water maze (MWM) for spatial learning and in the Novel object recognition (NOR) tests. Since learning and memory are closely associated with cholinergic forebrain function ChAT fiber density after exercise training was assessed in hippocampus, and motor- and somatosensory cortical areas. Furthermore, quantification of ChAT-positive fiber aberrations as a neuropathological marker was also carried out in these brain areas. Our results show that in OF chronic exercise maintained horizontal locomotor activity in all age groups. Rearing activity, MWM and notably NOR performance were improved only in the 32-months old animals. Regarding cholinergic neuronal innervation, apart from a general age-related decline, exercise increased ChAT fiber density in the hippocampus CA1 area and in the motor cortex notably in the 32-months group. Massive ChAT fiber aberrations in all investigated areas which developed in senescence were clearly attenuated by exercise. The results suggest that moderate intensity chronic exercise in the rat is especially beneficial in advanced age. In conclusion, chronic exercise attenuates the age-related decline in cognitive and motor behaviors as well as age-related cholinergic fiber reduction, reduces malformations of cholinergic forebrain innervation.

Asunto(s)

Envejecimiento/fisiología , Neuronas Colinérgicas/fisiología , Cognición/fisiología , Condicionamiento Físico Animal/fisiología , Prosencéfalo/metabolismo , Animales , Colina O-Acetiltransferasa/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Ratas Wistar

RESUMEN

PURPOSE: Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET). PROCEDURES: Time-dependent uptake of [(11)C]SA4503 was measured in the brain of young (1.5 to 3 months) and aged (18 to 32 months) Wistar Hannover rats, and tracer-kinetic models were fitted to this data, using metabolite-corrected plasma radioactivity as input function. RESULTS: In aged animals, the injected probe was less rapidly metabolized and cleared. Logan graphical analysis and a 2-tissue compartment model (2-TCM) fit indicated changes of total distribution volume (V T) and binding potential (BP ND) of the tracer. BP ND was reduced particularly in the (hypo)thalamus, pons, and medulla. CONCLUSIONS: Some areas showed reductions of ligand binding with aging whereas binding in other areas (cortex) was not significantly affected.

Asunto(s)

Envejecimiento/metabolismo , Encéfalo/metabolismo , Piperazinas/farmacocinética , Tomografía de Emisión de Positrones/métodos , Receptores sigma/agonistas , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Radioisótopos de Carbono , Imagenología Tridimensional , Cinética , Masculino , Metaboloma , Modelos Biológicos , Piperazinas/sangre , Ratas Wistar , Receptores sigma/metabolismo , Distribución Tisular , Receptor Sigma-1

RESUMEN

PURPOSE: Sigma-1 receptors are involved in learning and memory processes. We assessed sigma-1 receptor expression and memory function in two animal models of cognitive impairment. PROCEDURES: Male Wistar-Hannover rats were either lesioned by unilateral injection of N-methyl-D-aspartic acid in the nucleus basalis, or deprived of rapid eye movement sleep for 48 h, using the modified multiple platform method. Sigma-1 receptor expression was examined with the positron emission tomography radiotracer [(11)C]SA4503, immunohistochemistry, and Western blotting. RESULTS: Cortical tracer uptake after 1 week was not significantly affected by lesioning. Immunohistochemistry revealed moderate increases of sigma-1 receptors at bregma level -2.8, in parietal cortex layer V of the lesioned hemisphere. Sleep deprivation lowered passive avoidance test scores and reduced [(11)C]SA4503 accumulation and sigma-1 receptor expression in pons. CONCLUSIONS: Cholinergic lesioning causes an increase of sigma-1 receptor expression in a small cortical area which may be neuroprotective. Sleep deprivation decreases receptor expression in midbrain and pons.

Asunto(s)

Trastornos del Conocimiento/metabolismo , Receptores sigma/metabolismo , Animales , Western Blotting , Colina/metabolismo , Modelos Animales de Enfermedad , Cinética , Masculino , Ratas Wistar , Tiempo de Reacción , Privación de Sueño/metabolismo , Corteza Somatosensorial/metabolismo , Corteza Somatosensorial/patología , Distribución Tisular , Receptor Sigma-1

RESUMEN

The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain.

Asunto(s)

Neuronas Colinérgicas/citología , Galanina/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Terminales Presinápticos/metabolismo , Prosencéfalo , Ácido gamma-Aminobutírico/metabolismo , Animales , Animales Recién Nacidos , Muerte Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Neuronas Colinérgicas/efectos de los fármacos , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Galanina/farmacología , Glutamato Descarboxilasa/genética , Ratones , Ratones Transgénicos , Factor de Crecimiento Nervioso/farmacología , Terminales Presinápticos/efectos de los fármacos , Prosencéfalo/citología , Prosencéfalo/embriología , Prosencéfalo/crecimiento & desarrollo , Ratas , Ratas Wistar , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Proteínas de Transporte Vesicular de Acetilcolina/metabolismo

RESUMEN

TNF-α plays important functional roles in the central nervous system during normal physiological circumstances via intricate signaling mechanisms between its receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Although the roles of TNFR1 and TNFR2 in the diseased brain have received considerable attention, their functions on behavior and cognition in a non-inflammatory physiological aged environment are still unknown. In the present study we investigated the functional roles of TNFR1 and TNFR2 in learning and memory, motor performance and anxiety-like behavior via several behavioral and cognitive assessments in young and aged mice, deficient of either TNFR1 or TNFR2. Results from this study show that deletion of TNFR2 impairs novel object recognition, spatial memory recognition, contextual fear conditioning, motor performance and can increase anxiety-like behavior in young adult mice. Concerning the functions of TNFR1 and TNFR2 functioning in an aged environment, age caused memory impairment in spatial memory recognition independent of genotype. However, both young and aged mice deficient of TNFR2 performed poorly in the contextual fear conditioning test. These mice displayed decreased anxiety-like behavior, whereas mice deficient of TNFR1 were insusceptible to the effect of aging on anxiety-like behavior. This study provides novel knowledge on TNFR1 and TNFR2 functioning in behavior and cognition in young and aged mice in a non-inflammatory physiological environment.

Asunto(s)

Ansiedad/genética , Cognición/fisiología , Actividad Motora/genética , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Animales , Ansiedad/fisiopatología , Conducta Animal/fisiología , Condicionamiento Psicológico/fisiología , Miedo/fisiología , Ratones , Ratones Noqueados

RESUMEN

Patients experiencing an acute myocardial infarction (AMI) have a three times higher chance to develop depression. Vice versa, depressive symptoms increase the risk of cardiovascular events. The co-existence of both conditions is associated with substantially worse prognosis. Although the underlying mechanism of the interaction is largely unknown, inflammation is thought to be of pivotal importance. AMI-induced peripheral cytokines release may cause cerebral endothelial leakage and hence induces a neuroinflammatory reaction. The neuroinflammation may persist even long after the initial peripheral inflammation has subsided. Among those selected brain regions that are prone to blood-brain barrier dysfunction, the paraventricular nucleus of the hypothalamus (PVN), a major center for cardiovascular autonomic regulation, is indicated to play a mediating role. Optimal cardiovascular therapy improves cardiovascular prognosis without major effects on depression. By the same token, antidepressant therapy in cardiovascular disease is associated with modest improvement in depressive symptoms, however without improvement in cardiac outcome. The failure of current antidepressants and the growing number of patients suffering from both conditions legitimize the search for better antidepressive therapies, from patients as well as society perspectives. Though we appreciate the mutual character of the interaction between depression and AMI, the present review focuses on the side of AMI induced depression and discusses the role of inflammation, represented by the proinflammatory cytokine TNF-α, as potential underlying mechanism. It is conceivable that inhibition of the inflammatory response post-AMI, through targeted anti-inflammatory pharmacotherapeutical agents may prevent the development of depressive symptoms and ultimately may improve cardiovascular outcomes.

Asunto(s)

Barrera Hematoencefálica/fisiología , Depresión/etiología , Infarto del Miocardio/complicaciones , Factor de Necrosis Tumoral alfa/fisiología , Corticoesteroides/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Antidepresivos/uso terapéutico , Barrera Hematoencefálica/patología , Depresión/fisiopatología , Depresión/terapia , Humanos , Inmunidad/genética , Inmunidad/fisiología , Inflamación/patología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/psicología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores

RESUMEN

Brain microvasculature plays a critical role in the regulation of homeostasis of neural tissues. The present study focuses on characteristic microvascular basement membrane (bm) aberrations in the midbrain periaqueductal gray matter (PAG) and their relation to aging. The PAG can be considered a caudal extension of the limbic system and is a key structure in the regulation of a myriad of autonomic and motor control functions. In an ultrastructural study, morphologic changes in mesencephalic PAG capillaries were assessed in aged and young hamster and compared with those in caudal brainstem areas. Bm aberrations were studied in 1200 capillaries (n = 600 young hamsters; n = 600 aged hamsters). A new, never reported variant of bm degeneration was found that presented itself as foamy-like structures accumulating within the lamina densa of notably PAG capillaries. We classified these foamy structures as 'spumiform basement membrane degenerations' (sbmd) in which we could distinguish 4 stages depending on the size and intramembranous localization, ranging from split bm (stage I), intermediate stages II and III, to extensive stage IV, affecting almost the complete capillary bm outline. In the PAG of senescent animals various stages of sbmd were observed in 92 ± 3% of all capillaries. Stage II was most prominently present (59%), followed by stage III (20%), and stage IV (13%). These bm aberrations were clearly age-dependent because in young animals, only 5% of the PAG capillaries showed characteristics of sbmd. For comparison, in the pontine reticular formation at the PAG-level, 41% of the capillaries showed a form of sbmd, but these defects were significantly less severe (stages I-II, 98%), and caudal brainstem structures displayed no sbmd at all. In addition to sbmd, diffuse endothelial changes, disrupted tight junctions, thickening of the bm, pericyte degeneration, and gliosis were observed in PAG capillaries. It is hypothesized that selective bm permeability of PAG capillaries results in a sequence of bm damage events that start with split bm, gradually changing into more and more extensive sbmd accumulations that eventually almost completely surround the capillary. Progressive sbmd in PAG capillaries might lead to a loss of blood-brain barrier function and consequently to impairment of autonomic and motor control functions exerted by the PAG.

Asunto(s)

Membrana Basal/ultraestructura , Tronco Encefálico/irrigación sanguínea , Tronco Encefálico/ultraestructura , Capilares/ultraestructura , Trastornos Cerebrovasculares/patología , Animales , Cricetinae , Femenino , Mesocricetus

RESUMEN

Rabbit liver carboxylesterase (rCE) was evaluated as the catalyst for the enantioselective hydrolysis of (+/-)-3-endo-acetyloxy-1 ,8-cineole [(+/-)-4], which yields (1S,3S,4R)-(+)-3-acetyloxy-1,8-cineole [(+)-4] and (1R,3R,4S)-(-)-3-hydroxy-1,8-cineole [(-)-3]. Enantioselective asymmetrization of meso-3,5-diacetoxy-1,8-cineol (5) gives (1S,3S,4R,5R)-(-)-3-acetyloxy-5-hydroxy-1,8-cineole (6), with high enantioselectivity. rCE has been chosen to perform both experiments and molecular modeling simulations. Docking simulations combined with molecular dynamics calculations were used to study rCE-catalyzed enantioselective hydrolysis of cineol derivatives. Both compounds were found to bind with their acetyl groups stabilized by hydrogen bond interactions between their oxygen atoms and Ser221.

Asunto(s)

Biocatálisis , Carboxilesterasa/metabolismo , Ciclohexanoles/química , Hígado/enzimología , Monoterpenos/química , Animales , Carboxilesterasa/química , Eucaliptol , Hidrólisis , Modelos Moleculares , Conejos , Estereoisomerismo

RESUMEN

Sex differences in stress reactivity may be one of the factors underlying the increased sensitivity for the development of psychopathologies in women. Particularly, an increased hypothalamic-pituitary-adrenal (HPA) axis reactivity in females may exacerbate stress-induced changes in neuronal plasticity and neurogenesis, which in turn may contribute to an increased sensitivity to psychopathology. The main aim of the present study was to examine male-female differences in stress-induced changes in different aspects of hippocampal neurogenesis, i.e. cell proliferation, differentiation and survival. Both sexes were exposed to a wide variety of stressors, where after differences in HPA-axis reactivity and neurogenesis were assessed. To study the role of oestradiol in potential sex differences, ovariectomized females received low or high physiological oestradiol level replacement pellets. The results show that females in general have a higher basal and stress-induced HPA-axis activity than males, with minimal differences between the two female groups. Cell proliferation in the dorsal hippocampus was significantly higher in high oestradiol females compared to low oestradiol females and males, while doublecortin (DCX) expression as a marker of cell differentiation was significantly higher in males compared to females, independent of oestradiol level. Stress exposure did not significantly influence cell proliferation or survival of new cells, but did reduce DCX expression. In conclusion, despite the male-female differences in HPA-axis activity, the effect of repeated stress exposure on hippocampal cell differentiation was not significantly different between sexes.

Asunto(s)

Glucocorticoides/metabolismo , Hipocampo/patología , Neurogénesis/fisiología , Caracteres Sexuales , Estrés Psicológico/patología , Hormona Adrenocorticotrópica/metabolismo , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Electrochoque/efectos adversos , Estradiol/sangre , Estradiol/farmacología , Conducta Exploratoria/efectos de los fármacos , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Ovariectomía , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Wistar , Estrés Psicológico/etiología , Factores de Tiempo

RESUMEN

Calcium-activated potassium (K(Ca)) channels are present throughout the central nervous system as well as many peripheral tissues. Activation of K(Ca) channels contribute to maintenance of the neuronal membrane potential and was shown to underlie the afterhyperpolarization (AHP) that regulates action potential firing and limits the firing frequency of repetitive action potentials. Different subtypes of K(Ca) channels were anticipated on the basis of their physiological and pharmacological profiles, and cloning revealed two well defined but phylogenetic distantly related groups of channels. The group subject of this review includes both the small conductance K(Ca)2 channels (K(Ca)2.1, K(Ca)2.2, and K(Ca)2.3) and the intermediate-conductance (K(Ca)3.1) channel. These channels are activated by submicromolar intracellular Ca(2+) concentrations and are voltage independent. Of all K(Ca) channels only the K(Ca)2 channels can be potently but differentially blocked by the bee-venom apamin. In the past few years modulation of K(Ca) channel activation revealed new roles for K(Ca)2 channels in controlling dendritic excitability, synaptic functioning, and synaptic plasticity. Furthermore, K(Ca)2 channels appeared to be involved in neurodegeneration, and learning and memory processes. In this review, we focus on the role of K(Ca)2 and K(Ca)3 channels in these latter mechanisms with emphasis on learning and memory, Alzheimer's disease and on the interplay between neuroinflammation and different neurotransmitters/neuromodulators, their signaling components and K(Ca) channel activation.

RESUMEN

Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to ß-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

Asunto(s)

Proteínas de Fase Aguda/metabolismo , Enfermedad de Alzheimer/metabolismo , Lipocalinas/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Fase Aguda/líquido cefalorraquídeo , Proteínas de Fase Aguda/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/toxicidad , Animales , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Células Cultivadas , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Ácido Glutámico/toxicidad , Humanos , Mediadores de Inflamación/líquido cefalorraquídeo , Mediadores de Inflamación/metabolismo , Lipocalina 2 , Lipocalinas/líquido cefalorraquídeo , Lipocalinas/genética , Masculino , Ratones , Modelos Neurológicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Oncogénicas/genética , Proteínas Proto-Oncogénicas/líquido cefalorraquídeo , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/agonistas , Receptores Tipo II del Factor de Necrosis Tumoral/agonistas , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología

RESUMEN

Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [(11)C]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.

Asunto(s)

Depresión/enzimología , Modelos Animales de Enfermedad , Encefalitis/enzimología , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Animales , Depresión/etiología , Depresión/prevención & control , Encefalitis/complicaciones , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Triptófano/análogos & derivados , Triptófano/farmacología , Triptófano/uso terapéutico

RESUMEN

Adult brain-derived neural stem cells have acquired a lot of interest as an endurable neuronal cell source that can be used for central nervous system repair in a wide range of neurological disorders such as ischemic stroke. Recently, we identified injury-induced neural stem/progenitor cells in the poststroke murine cerebral cortex. In this study, we show that, after differentiation in vitro, injury-induced neural stem/progenitor cells express pyramidal cell markers Emx1 and CaMKIIα, as well as mature neuron markers MAP2 and Tuj1. 5-bromo-2-deoxyuridinine-positive neurons in the peristroke cortex also express such pyramidal markers. The presence of newly regenerated pyramidal neurons in the poststroke brain might provide a noninvasive therapeutic strategy for stroke treatment with functional recovery.

Asunto(s)

Isquemia Encefálica/metabolismo , Corteza Cerebral/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Células Piramidales/metabolismo , Animales , Biomarcadores/metabolismo , Isquemia Encefálica/patología , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones SCID , Células-Madre Neurales/patología , Cultivo Primario de Células , Células Piramidales/patología

RESUMEN

The antidepressant agomelatine acts as a melatonergic receptor (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist. Agomelatine has demonstrated efficacy in treating depression, but its neurobiological effects merit further investigation. Preclinical studies reported that agomelatine enhances adult hippocampal neurogenesis and increases expression of several neuroplasticity-associated molecules. Recently, we showed that agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in the stress-compromised brain. To characterize further the effects of this antidepressant in the stressed brain, here we investigated whether it induces changes in the expression of synapsin I (SynI), a regulator of synaptic transmission and plasticity. Adult male rats were subjected to daily footshock stress and agomelatine treatment for 3 weeks. Their brains were subsequently stained for total and phosphorylated SynI. Chronic footshock and agomelatine induced region-specific changes in SynI expression. Whereas chronic stress increased total SynI expression in all layers of the medial prefrontal cortex, agomelatine treatment abolished some of these effects. Furthermore, chronic agomelatine administration decreased total SynI expression in the hippocampal subregions of both stressed and nonstressed rats. Importantly, chronic stress decreased the fraction of phosphorylated SynI in all layers of the medial prefrontal cortex as well as selectively in the outer and middle molecular layers of the hippocampal dentate gyrus. These stress effects were at least partially abolished by agomelatine. Altogether, our data show that chronic stress and agomelatine treatment induce region-specific changes in SynI expression and its phosphorylation. Moreover, agomelatine partially counteracts the stress effects on SynI, suggesting a modulation of synaptic function by this antidepressant.

Asunto(s)

Acetamidas/farmacología , Antidepresivos/farmacología , Química Encefálica/efectos de los fármacos , Química Encefálica/genética , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Estrés Psicológico/tratamiento farmacológico , Sinapsinas/genética , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Estrés Psicológico/metabolismo , Sinapsinas/biosíntesis , Sinapsinas/metabolismo

RESUMEN

A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora(+/sg), heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora(+/sg)), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora(+/sg) Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora(+/sg) cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora(+/sg) their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency.

Asunto(s)

Envejecimiento/fisiología , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Cerebelo/metabolismo , Hormonas Esteroides Gonadales/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Células de Purkinje/fisiología , Animales , Castración , Recuento de Células , Cerebelo/citología , Estradiol/sangre , Femenino , Hormonas Esteroides Gonadales/metabolismo , Terapia de Reemplazo de Hormonas , Masculino , Ratones , Ratones Mutantes , Ratones Mutantes Neurológicos , Progesterona/sangre , Células de Purkinje/citología , Testosterona/sangre

RESUMEN

Extensive research has been performed to unravel the mechanistic signaling pathways mediated by tumor necrosis factor receptor 1 (TNFR1), by contrast there is limited knowledge on cellular signaling upon activation of TNFR2. Recently published data have revealed that these two receptors not only function independently, but also can influence each other via cross-talk between the different signaling pathways initiated by TNFR1 and TNFR2 stimulation. Furthermore, the complexity of this cross-talk is also dependent on the different signaling kinetics between TNFR1 and TNFR2, by which a delicate balance between cell survival and apoptosis can be maintained. Some known signaling factors and the kinetics that are involved in the receptor cross-talk between TNFR1 and TNFR2 are the topic of this review.

Asunto(s)

Receptor Cross-Talk/fisiología , Receptores Tipo II del Factor de Necrosis Tumoral/fisiología , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Supervivencia Celular/fisiología , Humanos , Ratones , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Factor 1 Asociado a Receptor de TNF/fisiología , Factor 2 Asociado a Receptor de TNF/fisiología

RESUMEN

Stressful events during childhood are thought to increase the risk for the development of adult psychopathology. A widely used animal model for early life stress is maternal separation (MS), which is thought to affect development and cause alterations in neuroendocrine stress reactivity and emotionality lasting into adulthood. However, results obtained with this paradigm are inconsistent. Here we investigated whether this variation may be related to the type of stressor or the tests used to assess adult stress sensitivity and behavioral performance. Rat pups were exposed to a 3h daily MS protocol during postnatal weeks 1-2. In adulthood, animals were subjected to a wide variety of stressors and tests to obtain a better view on the effects of MS on adult hypothalamic-pituitary-adrenal (HPA) axis regulation, anxiety-like behavior, social interaction and cognition. Also, the influence of MS on adult hippocampal neurogenesis was studied because it might underlie changes in neuroendocrine regulation and behavioral performance. The results show that, independent of the nature of the stressor, MS did not affect the neuroendocrine response. MS did not influence anxiety-like behavior, explorative behavior and social interaction, but did affect cognitive function in an object recognition task. The amount of new born cells in the hippocampal dentate gyrus was significantly decreased in MS animals; yet, cell differentiation and survival were not altered. In conclusion, while interfering with the mother-infant relationship early in life did affect some aspects of adult neuroplasticity and cognitive function, it did not lead to permanent changes in stress sensitivity and emotionality.

Asunto(s)

Período Crítico Psicológico , Hipocampo/citología , Privación Materna , Neurogénesis/fisiología , Reconocimiento en Psicología/fisiología , Estrés Psicológico/fisiopatología , Células Madre Adultas/citología , Células Madre Adultas/fisiología , Factores de Edad , Análisis de Varianza , Animales , Ansiedad/fisiopatología , Ansiedad/psicología , Investigación Conductal/métodos , Conducta Exploratoria/fisiología , Femenino , Hipocampo/fisiología , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Plasticidad Neuronal/fisiología , Sistema Hipófiso-Suprarrenal/fisiopatología , Distribución Aleatoria , Ratas , Ratas Wistar , Conducta Social

Asunto(s)

Enfermedades Neurodegenerativas/tratamiento farmacológico , Receptores Tipo II del Factor de Necrosis Tumoral/antagonistas & inhibidores , Animales , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ratones , Modelos Biológicos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal/efectos de los fármacos , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo