RESUMEN
Strigolactone is a newly discovered type of plant hormone that has multiple roles in modulating plant responses to abiotic stress. Herein, we aimed to investigate the effects of exogenous GR24 (a synthetic analogue of strigolactone) on plant growth, photosynthetic characteristics, carbohydrate levels, endogenous strigolactone content and antioxidant metabolism in cucumber seedlings under low light stress. The results showed that the application of 10 µM GR24 can increase the photosynthetic efficiency and plant biomass of low light-stressed cucumber seedlings. GR24 increased the accumulation of carbohydrates and the synthesis of sucrose-related enzyme activities, enhanced antioxidant enzyme activities and antioxidant substance contents, and reduced the levels of H2O2 and MDA in cucumber seedlings under low light stress. These results indicate that exogenous GR24 might alleviate low light stress-induced growth inhibition by regulating the assimilation of carbon and antioxidants and endogenous strigolactone contents, thereby enhancing the tolerance of cucumber seedlings to low light stress.
Asunto(s)
Adaptación Ocular/efectos de los fármacos , Cucumis sativus/efectos de los fármacos , Cucumis sativus/crecimiento & desarrollo , Cucumis sativus/metabolismo , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Lactonas/metabolismo , Productos Agrícolas/efectos de los fármacos , Productos Agrícolas/crecimiento & desarrollo , Productos Agrícolas/metabolismoRESUMEN
MicroRNAs (miRNAs), a class of single-stranded non-coding RNA of 20-24 nucleotides, regulate gene expression by target gene transcript cleavage or translation inhibition. The phytohormone auxin is a crucial regulator of almost every process involved in plant growth and development. Several studies have demonstrated the involvement of miRNA(s) in the regulation of the auxin signaling pathway and plant development. However, very few studies have identified the auxin-mediated regulation of miRNA(s). In this study, we reveal the detailed mechanism of auxin-mediated regulation of the cell wall-related miR775- Galactosyl transferase (GalT) module, which plays an important role in root growth in Arabidopsis thaliana. We also showed two interdependent mechanisms by which miR775 regulates root growth: miR775-GalT and light-mediated sucrose-dependent pathways. Treatment of GUS reporter lines with Indole Acetic Acid (IAA), sucrose, and light apparently enhanced the abundance of miR775 in root tissue. miR775 overexpressing (miR775OX) lines showed changes in root architecture, including increased primary root growth and root hair, by targeting GalT. miR775OX lines also showed tolerance toward low Pi. These results provide new insights into the auxin regulation of cell wall-related miR775 and suggest its significant role in plant root growth and development by modifying the cell wall.
Asunto(s)
Arabidopsis/crecimiento & desarrollo , Arabidopsis/genética , Ácidos Indolacéticos/metabolismo , MicroARNs/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/genética , Sacarosa/metabolismo , Adaptación Ocular/efectos de los fármacos , Adaptación Ocular/genética , Regulación de la Expresión Génica de las Plantas , Variación Genética , Genotipo , Crecimiento y Desarrollo/genética , Redes y Vías Metabólicas/genéticaRESUMEN
Driving under the influence of alcohol (DUIA) and drugs (DUID) is considered an elevated risk for traffic safety. When assessing a driver's fitness to drive, standardized and objective measurement methods are still required, in order to clarify the question whether an individual is under the influence of substances acting on the central nervous system (CNS). We exposed healthy test subjects (n=41) as well as persons who were under the influence of cannabis after repeated inhalation to multiple light stimuli using infrared technology and measured the pupillary light reflex (PLR). Toxicological tests of blood samples taken from every subject followed. The aims of this study were to assess the differences in pupillography response between cannabis consumers after a washout period and no cannabis consumers as well as the dose related effects on pupillography parameters of cannabis in cannabis consumers. All four pupillary parameters changed according to a weakened pupil function after acute administration of cannabis in all test subjects. Furthermore, it could be observed that habitual cannabis consumers showed an altered pupillary function just before the first dose was taken, suggesting that the long-term effects and addiction also have to be taken into account, when effects of the CNS are discussed. The results of the present study show that almost all pupil parameters could be reliable indicators for the detection of subjects under the acute effect of cannabis.
Asunto(s)
Adaptación Ocular/efectos de los fármacos , Luz , Uso de la Marihuana , Pupila/efectos de los fármacos , Reflejo/efectos de los fármacos , Adaptación Ocular/fisiología , Adulto , Cannabinoides/sangre , Estudios de Casos y Controles , Conducir bajo la Influencia , Femenino , Humanos , Masculino , Pupila/fisiología , Reflejo/fisiología , Adulto JovenRESUMEN
Purpose: The purpose of this study was to investigate the acute effects of caffeine on retinal hemodynamics during dark to light adaptation using optical coherence tomography angiography (OCTA). Methods: Thirteen healthy individuals (13 eyes) underwent OCTA imaging after dark adaptation and at repeated intervals during the transition to ambient light in two imaging sessions: control and after ingesting 200 mg of caffeine. We analyzed the parafoveal vessel density (VD) and adjusted flow index (AFI) of the superficial capillary plexus (SCP), middle capillary plexus (MCP), and deep capillary plexus (DCP), as well as the vessel length density (VLD) of the SCP. After adjusting for age, refractive error, and scan quality, we compared parameters between control and caffeine conditions. Results: In the dark, MCP VD decreased significantly after caffeine (-2.63 ± 1.28%). During the transition to light, initially, DCP VD increased (12.55 ± 2.52%), whereas SCP VD decreased (-2.09 ± 0.91%) significantly with caffeine compared to control. By 15 minutes in light, DCP VD reversed and was significantly decreased (-5.45 ± 2.62%), whereas MCP VD increased (4.65 ± 1.74%). There were no differences in AFI or VLD. Conclusions: We show that, overall, caffeine causes a trend of delayed vascular response in all three macular capillary plexuses in response to ambient light. Whereas the MCP is constricted in the dark, during the transition from dark to light, there is initially delay followed by prolonged constriction of the DCP and constriction followed by slow dilation of the SCP. We posit that these delayed vascular responses may present potential risk of capillary ischemia.
Asunto(s)
Adaptación Ocular/efectos de los fármacos , Cafeína/efectos adversos , Adaptación a la Oscuridad/efectos de los fármacos , Vasos Retinianos/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodos , Adulto , Factores de Edad , Cafeína/administración & dosificación , Femenino , Angiografía con Fluoresceína/métodos , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Acoplamiento Neurovascular , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
Chronic itch is clinically correlated with the development of mood disorders such as anxiety and depression. Nonetheless, whether this relevance exists in rodents is unknown, and evidence demonstrating chronic itch can affect mood is lacking. The aim of this study is to characterize the affective consequences of chronic itch, and explore potential mechanisms and interventional strategy. We subjected mice to chronic itch by repetitive cutaneous treatment with acetone and diethylether followed by water (AEW) that models "dry skin." After 3 to 4 weeks AEW treatment, the mice developed behavioral phenotypes of anxiety and depression assessed by a battery of behavioral paradigms, such as light-dark box and forced swim test. These behavioral symptoms of mood disturbance were independent of cutaneous barrier disruption, but correlated well with the degree of the irritating itch sensation. Although AEW mice showed normal circadian hypothalamic-pituitary-adrenal (HPA) axis activity, their neuroendocrine functionality was dampened, including impaired endocrine stress responsivity, altered neuroendocrine-immune interaction, and blunted corticosterone response to both dexamethasone and CRF. Parameters of HPA functionality at the level of mRNA transcripts are altered in stress-related brain regions of AEW mice, implying an overdrive of central CRF system. Remarkably, chronic treatment of AEW mice with antalarmin, a CRFR1 antagonist, ameliorated both their mood impairment and stress axis dysfunction. This is the first evidence revealing mood impairment, HPA axis dysfunction, and potential therapeutic efficacy by CRFR1 antagonist in mice with chronic itch, thus providing a preclinical model to investigate the affective consequence of chronic itch and the underlying mechanisms.
Asunto(s)
Diterpenos/uso terapéutico , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Trastornos del Humor/etiología , Sistema Hipófiso-Suprarrenal/diagnóstico por imagen , Prurito/tratamiento farmacológico , Prurito/patología , Acetona/toxicidad , Adaptación Ocular/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Conducta Alimentaria/efectos de los fármacos , Fiebre/etiología , Preferencias Alimentarias , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Prurito/inducido químicamente , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Estrés Psicológico/complicaciones , Factores de TiempoRESUMEN
Repetitive and perseverative behaviors are common features of a number of neuropsychiatric diseases such as Angelman's syndrome, Tourette's syndrome, obsessive-compulsive disorder, and autism spectrum disorders. The oxytocin system has been linked to the regulation of repetitive behavior in both animal models and humans, but many of its downstream targets have still to be found. We report that the melanin-concentrating hormone (MCH) system is a target of the oxytocin system in regulating one repetitive behavior, marble burying. First we report that nearly 60% of MCH neurons express oxytocin receptors, and demonstrate using rabies mediated tract tracing that MCH neurons receive direct presynaptic input from oxytocin neurons. Then we show that MCH receptor knockout (MCHR1KO) mice and MCH ablated animals display increased marble burying response while central MCH infusion decreases it. Finally, we demonstrate the downstream role of the MCH system on oxytocin mediated marble burying by showing that central infusions of MCH and oxytocin alone or together reduce it while antagonizing the MCH system blocks oxytocin-mediated reduction of this behavior. Our findings reveal a novel role for the MCH system as a mediator of the role of oxytocin in regulating marble-burying behavior in mice.
Asunto(s)
Conducta Exploratoria/efectos de los fármacos , Hormonas Hipotalámicas/farmacología , Melaninas/farmacología , Oxitocina/farmacología , Hormonas Hipofisarias/farmacología , Adaptación Ocular/efectos de los fármacos , Análisis de Varianza , Animales , Toxina Diftérica/farmacología , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Aseo Animal/efectos de los fármacos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Pirimidinonas/farmacología , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismo , Receptores de Somatostatina/antagonistas & inhibidores , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Conducta Estereotipada/efectos de los fármacos , Tiofenos/farmacología , Proteína Fluorescente RojaRESUMEN
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, with additional symptoms including attention deficit and hyperactivity, anxiety, impulsivity, and repetitive movements or actions. The majority of FXS cases are attributed to a CGG expansion that leads to transcriptional silencing and diminished expression of fragile X mental retardation protein (FMRP). FMRP, an RNA binding protein, regulates the synthesis of dendritically-translated mRNAs by stalling ribosomal translation. Loss of FMRP leads to increased translation of some of these mRNAs, including the CNS-specific tyrosine phosphatase STEP (STriatal-Enriched protein tyrosine Phosphatase). Genetic reduction of STEP in Fmr1 KO mice have diminished audiogenic seizures and a reversal of social and non-social anxiety-related abnormalities. This study investigates whether a newly discovered STEP inhibitor (TC-2153) could attenuate the behavioral and synaptic abnormalities in Fmr1 KO mice. TC-2153 reversed audiogenic seizure incidences, reduced hyperactivity, normalized anxiety states, and increased sociability in Fmr1 KO mice. Moreover, TC-2153 reduced dendritic spine density and improved synaptic aberrations in Fmr1 KO neuronal cultures as well as in vivo. TC-2153 also reversed the mGluR-mediated exaggerated LTD in brain slices derived from Fmr1 KO mice. These studies suggest that STEP inhibition may have therapeutic benefit in FXS.
Asunto(s)
Potenciales Postsinápticos Excitadores/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/complicaciones , Síndrome del Cromosoma X Frágil/patología , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Sinapsis/patología , Adaptación Ocular/efectos de los fármacos , Adaptación Ocular/genética , Animales , Animales Recién Nacidos , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Benzotiepinas/farmacología , Conducta de Elección/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/genética , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Epilepsia Refleja/tratamiento farmacológico , Epilepsia Refleja/etiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Hipocampo/patología , Hipocampo/ultraestructura , Ratones , Ratones TransgénicosRESUMEN
PURPOSE: Retinal dystrophy through outer photoreceptor cell death affects 1 in 2,500 people worldwide with severe impairment of vision in advanced stages of the disease. Optogenetic strategies to restore visual function to animal models of retinal degeneration by introducing photopigments to neurons spared degeneration in the inner retina have been explored, with variable degrees of success. It has recently been shown that the non-steroidal anti-inflammatory and non-selective gap-junction blocker meclofenamic acid (MFA) can enhance the visual responses produced by an optogenetic actuator (channelrhodopsin) expressed in retinal ganglion cells (RGCs) in the degenerate retina. Here, we set out to determine whether MFA could also enhance photoreception by another optogenetic strategy in which ectopic human rod opsin is expressed in ON bipolar cells. METHODS: We used in vitro multielectrode array (MEA) recordings to characterize the light responses of RGCs in the rd1 mouse model of advanced retinal degeneration following intravitreal injection of an adenoassociated virus (AAV2) driving the expression of human rod opsin under a minimal grm6 promoter active in ON bipolar cells. RESULTS: We found treated retinas were light responsive over five decades of irradiance (from 1011 to 1015 photons/cm2/s) with individual RGCs covering up to four decades. Application of MFA reduced the spontaneous firing rate of the visually responsive neurons under light- and dark-adapted conditions. The change in the firing rate produced by the 2 s light pulses was increased across all intensities following MFA treatment, and there was a concomitant increase in the signal to noise ratio for the visual response. Restored light responses were abolished by agents inhibiting glutamatergic or gamma-aminobutyric acid (GABA)ergic signaling in the MFA-treated preparation. CONCLUSIONS: These results confirm the potential of MFA to inhibit spontaneous activity and enhance the signal to noise ratio of visual responses in optogenetic therapies to restore sight.
Asunto(s)
Ácido Meclofenámico/farmacología , Opsinas de Bastones/metabolismo , Relación Señal-Ruido , Vías Visuales/efectos de los fármacos , Vías Visuales/fisiología , Potenciales de Acción/efectos de los fármacos , Adaptación Ocular/efectos de los fármacos , Animales , Humanos , Ratones , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismoRESUMEN
Hydrogen therapy is a new medical approach for a wide range of diseases. The effects of hydrogen on central nervous system-related diseases have recently become increasingly appreciated, but little is known about whether hydrogen affects the morphine withdrawal process. This study aims to investigate the potential effects of hydrogen-rich saline (HRS) administration on naloxone-precipitated withdrawal symptoms and morphine withdrawal-induced anxiety-like behaviors. Mice received gradually increasing doses (25-100 mg/kg, i.p.) of morphine over 3 days. In the naloxone-precipitated withdrawal procedure, the mice were treated with three HRS (20 µg/kg, i.p.) injections, and naloxone (1 mg/kg, i.p.) was given 30 min after HRS administration. Body weight, jumping behavior and wet-dog shakes were immediately assessed. In the spontaneous withdrawal procedure, the mice were treated with HRS (20 µg/kg, i.p.) every 8-h. Mice underwent naloxone-precipitated or spontaneous withdrawal were tested for anxiety-like behaviors in the elevated plus-maze (EPM) and light/dark box (L/D box) paradigm, respectively. In addition, the levels of plasma corticosterone were measured. We found that HRS administration significantly reduced body weight loss, jumping behavior and wet-dog shakes in mice underwent naloxone-precipitated withdrawal, and attenuated anxiety-like behaviors in the EPM and L/D box tests after naloxone-precipitated withdrawal or a 2-day spontaneous withdrawal period. Hypo-activity or motor impairment after HRS administration was not observed in the locomotion tests. Furthermore, HRS administration significantly decreased the levels of corticosterone in morphine-withdrawn mice. These are the first findings to indicate that hydrogen might ameliorate withdrawal symptoms and exert an anxiolytic-like effect in morphine-withdrawal mice.
Asunto(s)
Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Hidrógeno/uso terapéutico , Morfina/efectos adversos , Síndrome de Abstinencia a Sustancias/complicaciones , Adaptación Ocular/efectos de los fármacos , Animales , Corticosterona/sangre , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Movimientos de la Cabeza/efectos de los fármacos , Hidrocortisona/sangre , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Naloxona/uso terapéutico , Cloruro de Sodio/uso terapéutico , Estadísticas no Paramétricas , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24 h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.
Asunto(s)
Ansiedad/inducido químicamente , Hipnóticos y Sedantes/toxicidad , Propofol/toxicidad , Conducta Estereotipada/efectos de los fármacos , Sinapsis/metabolismo , alfa-Sinucleína/metabolismo , Adaptación Ocular/efectos de los fármacos , Animales , Animales Recién Nacidos , Ansiedad/patología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Cadherinas/metabolismo , Conducta Exploratoria/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Actividad Motora/efectos de los fármacos , Neuropéptidos/metabolismo , Ratas , Ratas Wistar , Sinapsis/efectos de los fármacos , Sinaptofisina/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. METHODS: We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. RESULTS: Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ9-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. CONCLUSIONS: Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.
Asunto(s)
Ansiedad/tratamiento farmacológico , Ácidos Araquidónicos/metabolismo , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Transducción de Señal/efectos de los fármacos , Adaptación Ocular/efectos de los fármacos , Animales , Ansiolíticos/uso terapéutico , Ansiedad/metabolismo , Ansiedad/fisiopatología , Benzodioxoles/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiología , Agonistas de Receptores de Cannabinoides/uso terapéutico , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Dronabinol/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Piperidinas/uso terapéutico , Alcamidas Poliinsaturadas , Piridinas/uso terapéuticoRESUMEN
Recent studies about the novel antidepressant agomelatine, which is a mixed MT1 and MT2 melatonin receptor agonist and 5HT2C serotonin receptor antagonist possessing an anticonvulsant and neuroprotective action, suggest that it may have potential to contribute against epileptogenesis and epilepsy-induced memory impairment. In order to ascertain whether protection of some brain structures could suppress epileptogenesis, in the present study, we evaluated the effect of chronic post-status treatment with agomelatine on epileptogenesis, behavioral and neuronal damage induced by kainate acid (KA) status epilepticus (SE). Agomelatine/vehicle treatment (40mg/kg, i.p.) started one hour after SE and continued up to 10weeks in Wistar rats. Latency for onset of spontaneous motor seizures (SMS) and their frequency was detected by a 24-h video-recording. Locomotor activity, anxiety and hippocampus-dependent spatial memory in open field (OF), elevated plus maze (EPM), light-dark test (LDT) and radial arm maze (RAM) test, respectively, were evaluated during the last two weeks after SE. Agomelatine significantly decreased the latency for onset of SMS and increased the seizure frequency during the 2nd and the 3rd week of treatment. The MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist exacerbated the KA-induced hyperlocomotion and impulsive behavior and it was unable to prevent spatial memory impairment of epileptic rats. However, agomelatine induced a neuroprotection in the dorsal hippocampus, specifically in the CA1, septal CA2 and partially in the CA3c region, the hilus of the dentate gyrus, piriform cortex and septo-temporal and temporal basolateral amygdala. Our findings suggest that the beneficial impact against SE-induced neuronal loss exerted by agomelatine is not crucial for the suppression of epileptogenesis and its deleterious consequences in KA model of temporal lobe epilepsy.
Asunto(s)
Acetamidas/uso terapéutico , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/prevención & control , Hipocampo/patología , Neuronas/efectos de los fármacos , Adaptación Ocular/efectos de los fármacos , Análisis de Varianza , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Agonistas de Aminoácidos Excitadores/toxicidad , Conducta Exploratoria/efectos de los fármacos , Hipnóticos y Sedantes/uso terapéutico , Ácido Kaínico/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Emerging research provides strong evidence that activation of CNS glial cells occurs in neurological diseases and brain injury and results in elevated production of neuroimmune factors. These factors can contribute to pathophysiological processes that lead to altered CNS function. Recently, studies have also shown that both acute and chronic alcohol consumption can produce activation of CNS glial cells and the production of neuroimmune factors, particularly the chemokine ligand 2 (CCL2). The consequences of alcohol-induced increases in CCL2 levels in the CNS have yet to be fully elucidated. Our studies focus on the hypothesis that increased levels of CCL2 in the CNS produce neuroadaptive changes that modify the actions of alcohol on the CNS. We utilized behavioral testing in transgenic mice that express elevated levels of CCL2 to test this hypothesis. The increased level of CCL2 in the transgenic mice involves increased astrocyte expression. Transgenic mice and their non-transgenic littermate controls were subjected to one of two alcohol exposure paradigms, a two-bottle choice alcohol drinking procedure that does not produce alcohol dependence or a chronic intermittent alcohol procedure that produces alcohol dependence. Several behavioral tests were carried out including the Barnes maze, Y-maze, cued and contextual conditioned fear test, light-dark transfer, and forced swim test. Comparisons between alcohol naïve, non-dependent, and alcohol-dependent CCL2 transgenic and non-transgenic mice show that elevated levels of CCL2 in the CNS interact with alcohol in tests for alcohol drinking, spatial learning, and associative learning.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Sistema Nervioso Central/patología , Quimiocina CCL2/metabolismo , Etanol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Adaptación Ocular/efectos de los fármacos , Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/etiología , Alcoholismo/genética , Alcoholismo/fisiopatología , Animales , Astrocitos/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Quimiocina CCL2/genética , Conducta de Elección/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Natación/psicologíaRESUMEN
The neuropeptide, galanin, is widely expressed in the central and peripheral nervous systems and is involved in a range of different functions including nociception, neurogenesis, hormone release, reproduction, cognitive function and appetite. Given the overlap between galanin expression and reward circuitry in the brain, galanin has been targeted for alcohol use disorder (AUD) and opioid dependency. Furthermore, the galanin-3 receptor (GAL3) specifically regulates emotional states and plays a role in motivation, reward and drug-seeking behaviour. We have previously shown that the GAL3 antagonist, SNAP 37889, reduces ethanol self-administration and cue-induced re-instatement in alcohol-preferring (iP) rats with no alterations in locomotor activity or anxiety-like behaviour. The aim of this study was to investigate whether SNAP 37889 reduces binge drinking and/or self-administration of morphine in mice. Using the Scheduled High Alcohol Consumption (SHAC) procedure, SNAP 37889 (30 mg/kg) treated mice drank significantly less ethanol, sucrose and saccharin than vehicle treated mice. Using an operant paradigm, SNAP 37889 reduced morphine self-administration but failed to impact cue-induced relapse-like behaviour. SNAP 37889 had no significant effect on locomotor activity, motor co-ordination, anxiety, nor was SNAP 37889 itself positively reinforcing. Liver assays showed that there was no alteration in the rate of hepatic ethanol metabolism between SNAP 37889 and vehicle treated mice suggesting that the reduction in ethanol intake via SNAP 37889 is due to a central effect of GAL3 signalling. This study implicates the GAL3 receptor in consummatory drive which may have wider implications for the treatment of different addictions.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Indoles/uso terapéutico , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Receptor de Galanina Tipo 3/antagonistas & inhibidores , Adaptación Ocular/efectos de los fármacos , Alcohol Deshidrogenasa/metabolismo , Animales , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Indoles/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor de Galanina Tipo 3/metabolismo , Esquema de Refuerzo , Sacarina/administración & dosificación , Sacarina/metabolismo , Autoadministración , Sacarosa/administración & dosificación , Sacarosa/metabolismo , Factores de TiempoRESUMEN
The neuropeptide S system has been implicated in a number of centrally mediated behaviors including memory consolidation, anxiolysis, and increased locomotor activity. Characterization of these behaviors has been primarily accomplished using the endogenous 20AA peptide (NPS) that demonstrates relatively equal potency for the calcium mobilization and cAMP second messenger pathways at human and rodent NPS receptors. This study is the first to demonstrate that truncations of the NPS peptide provides small fragments that retain significant potency only at one of two single polymorphism variants known to alter NPSR function (NPSR-107I), yet demonstrate a strong level of bias for the calcium mobilization pathway over the cAMP pathway. We have also determined that the length of the truncated peptide correlates with the degree of bias for the calcium mobilization pathway. A modified tetrapeptide analog (4) has greatly attenuated hyperlocomotor stimulation in vivo but retains activity in assays that correlate with memory consolidation and anxiolytic activity. Analog 4 also has a bias for the calcium mobilization pathway, at the human and mouse receptor. This suggests that future agonist ligands for the NPS receptor having a bias for calcium mobilization over cAMP production will function as non-stimulatory anxiolytics that augment memory formation.
Asunto(s)
Ansiolíticos/farmacología , Locomoción/efectos de los fármacos , Memoria/efectos de los fármacos , Neuropéptidos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Adaptación Ocular/efectos de los fármacos , Análisis de Varianza , Animales , Reacción de Prevención/efectos de los fármacos , Calcio/metabolismo , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Neuropéptidos/química , Receptores Acoplados a Proteínas G/genética , Transfección , alfa-Fetoproteínas/metabolismoRESUMEN
Autism spectrum disorder (ASD) is a developmental disorder that is characterized by symptoms of impaired social interactions, restricted interests and repetitive behaviors. Recent studies in humans and animal-models suggest that reduced GABAergic neurotransmission in the brain may underlie autism-related behavioral symptoms. It has been shown that propofol, a commonly used anesthetic, facilitates γ-aminobutyric acid-mediated inhibitory synaptic transmission. The present study investigated whether propofol improved autistic phenotypes in BTBR T + Itpr3tf/J (BTBR) mice, a model of idiopathic autism. We found that i.p. injection of propofol in BTBR mice significantly improved aspects of social approach and repetitive behaviors without affecting reciprocal social interactions and without any detrimental effects in C57BL/6J mice. The ability of propofol to improve autistic phenotypes in BTBR mice through GABAergic neurotransmission suggests a potential pharmacological target for interventions to treat symptoms of autism.
Asunto(s)
Anestésicos Intravenosos/uso terapéutico , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/fisiopatología , Propofol/uso terapéutico , Adaptación Ocular/efectos de los fármacos , Análisis de Varianza , Animales , Trastorno Autístico/genética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Aseo Animal/efectos de los fármacos , Relaciones Interpersonales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Proteínas del Tejido Nervioso/genéticaRESUMEN
Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80-95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300µg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300µg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood.
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Ansiedad/metabolismo , Conducta Animal/fisiología , Depresión/metabolismo , Receptores de GABA-A/metabolismo , Adaptación Ocular/efectos de los fármacos , Adaptación Ocular/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Bicuculina/efectos adversos , Peso Corporal/efectos de los fármacos , Corticosterona/sangre , Depresión/inducido químicamente , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Femenino , Antagonistas de Receptores de GABA-A/efectos adversos , Suspensión Trasera , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Factores Sexuales , Natación/psicología , Testosterona/sangreRESUMEN
Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3ß (GSK-3ß) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/ß-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.
Asunto(s)
Maleato de Dizocilpina/farmacología , Hipocampo/efectos de los fármacos , Trastornos del Humor/tratamiento farmacológico , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Vía de Señalización Wnt/efectos de los fármacos , Adaptación Ocular/efectos de los fármacos , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Antígeno Ki-67/metabolismo , Masculino , Trastornos del Humor/etiología , Actividad Motora/efectos de los fármacos , Oxidopamina/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/patología , Ratas , Ratas Sprague-Dawley , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
AIM: To evaluate functional and morphometric parameters of the central retina in patients with postocclusive macular edema treated with dexamethasone intravitreal implant injection. MATERIAL AND METHODS: We examined 5 patients (5 eyes) with newly diagnosed central retinal vein occlusion complicated by macular edema, including 4 men and 1 woman aged 55.8±3.65 years (experimental group). All the patients received a single injection of dexamethasone intravitreal implant. The maximum follow-up period was 12 months. The control group consisted of 5 presbiopic patients (10 eyes) aged 59.14±3.14 years. RESULTS: One month after injection, the best corrected visual acuity (BCVA) and central retinal light sensitivity improved (from 0.09±0.03 to 0.19±0.05 and from 3.18±0.19 to 11.07±0.97 dB, correspondingly), while foveolar thickness decreased from 425.36±57.87 to 273.75±36.65 µm. One year after the treatment, BCVA remained high and averaged 0.21±0.14. The total light sensitivity also remained higher than that at baseline, however, decreased down to 4.8±0.76 dB. Optical coherence tomography showed some flatness of the fovea. Foveolar thickness appeared 1.5 times higher than that in the control group and 1.2 times higher than that at the 1-month follow-up after dexamethasone intravitreal implant injection. Over the whole follow-up period, IOP has never significantly exceeded the baseline, optical media remained clear. CONCLUSION: 1. Dexamethasone intravitreal implant has been shown effective in resolving postocclusive macular edema, improving visual functions, and increasing central retinal light sensitivity within the first month after injection. 2. Positive changes in morphometric parameters of the central retina induced by the injection involve inner segments of photoreceptors as well as the outer nuclear, outer plexiform and inner nuclear layers. The morphofunctional effect persists for no less than 12 months after injection. 3. Over the 1-year follow-up period, there has been no negative influence of the implant on either intraocular pressure level, or lens transparency.
Asunto(s)
Dexametasona/administración & dosificación , Fóvea Central , Inyecciones Intravítreas/métodos , Oclusión de la Vena Retiniana , Adaptación Ocular/efectos de los fármacos , Femenino , Estudios de Seguimiento , Fóvea Central/efectos de los fármacos , Fóvea Central/patología , Glucocorticoides/administración & dosificación , Humanos , Bombas de Infusión Implantables , Masculino , Persona de Mediana Edad , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/fisiopatología , Tomografía de Coherencia Óptica/métodos , Resultado del Tratamiento , Agudeza Visual/efectos de los fármacosRESUMEN
UNLABELLED: Many factors exist that are associated with higher risk of glaucoma progression. Arterial hypotension, low perfusion pressure, vasospastic syndrome, diabetes mellitus, myopia, etc. increase the need for neuroprotective therapy, which is aimed at stabilizing the pathological process and creating favorable conditions for maintaining visual functions. The aim of this study was to assess the therapeutic efficacy of Gliatilin as part of the complex treatment of progressive glaucomatous optic neuropathy. MATERIAL AND METHODS: A total of 240 patients were randomly selected and divided into 2 groups, 120 patients each. Both groups were matched for age, somatic comorbidity, and the gravity of the glaucomatous process. Patient age averaged 71.3±1.6 years. Advanced glaucoma prevailed in both groups: 70.0 and 76.6% correspondingly. Neuroprotective therapy included drugs from different pharmacological classes so that different aspects of pathogenesis were addressed. Apart from that, patients from Group I first received intravenous Gliatilin (1000 mg/4ml, 12--15 doses) and then switched to oral (1 capsule b.i.d. for 4 months). All patients underwent standard ophthalmic examination and static perimetry. RESULTS: No adverse effects were observed over the first two weeks of Gliatilin course, during which the patients stayed in the hospital. IOP level was normal and stable. Although neuroprotective therapy does not directly affect IOP, stability of the latter describes the dynamics of the glaucomatous process. When assessing changes in visual functions, particular attention was paid to the central visual field, foveolar and total light sensitivity, peripheral visual field, and MD and PSD indices. All mean values showed a tendency toward improvement, more pronounced in the Gliatilin group. CONCLUSION: A complex therapy cannot be limited to a single drug only, and to make better decisions, one should consider not only ocular, but also general condition of the patient. Adjuvant Gliatilin in the complex therapy of progressive glaucoma is appropriate and efficient, especially in case of systemic atherosclerosis and cerebrovascular insufficiency. The frequency of stabilization therapy depends on the efficacy of the latest course and clinical manifestations of the glaucomatous process.