RESUMO
Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.
Assuntos
Anedonia , Astrócitos , Animais , Humanos , Astrócitos/metabolismo , Córtex Pré-Frontal/metabolismo , Depressão/metabolismo , Estresse Psicológico/metabolismo , Comportamento AnimalRESUMO
AIMS: This study aimed to compare the serum thiol-disulfide homeostasis, total antioxidant status (TAS), and total oxidant status (TOS) in patients with pseudoexfoliation glaucoma (PEG) patients, primary open-angle glaucoma (POAG) patients, and healthy individuals (control). METHODS: Ninety subjects were included in this study. Three groups were separated as PEG, POAG, and control. All groups were chosen to be similar in terms of age and gender. Blood samples were obtained following an overnight fasting state and were collected on the ice at 4°C. The serum samples were separated from the cells by centrifugation at 3000 rpm for 15 min and were stored at -80°C. Serum samples analyzed for TAS and TOS, native thiol, total thiol, disulfide, and native thiol/disulfide ratio. RESULTS: TAS and TOS levels of PEG patients were 1.2892 ± 0.0905 mmol/L; 5.0191 ± 2.7722 µmol/L, respectively. TAS and TOS levels of POAG patients were 1.2741 ± 0.1252 mmol/L; 4.1674 ± 1.7723 µmol/L, respectively. TAS and TOS levels of the control group were 2.3414 ± 0.1409 mmol/L; 4.0931 ± 0.1107 µmol/L, respectively. The TAS level was significantly lower in PEG and POAG groups compared to control. TOS level showed no significant differ ¬ ence between PEG, POAG, and control groups (P > 0.05). The mean serum total thiol and native thiol levels were significantly lower in patients with PEG compared to POAG and control group; there was no significant difference between the POAG and control group (P > 0.05). The mean serum disulfide level was significantly lower in patients with PEG compared to POAG (P = 0.018). CONCLUSION: Low levels of TAS were observed in patients with glaucoma, which was likely a response to the increased oxidative stress observed in these patients. While total thiol and native thiol levels were higher in the PEG group, the disulfide level was higher in the POAG group. TAS and TOS levels showed no significant difference between POAG and PEG groups.
Assuntos
Antioxidantes/metabolismo , Dissulfetos/sangue , Síndrome de Exfoliação/sangue , Glaucoma de Ângulo Aberto/sangue , Homeostase/fisiologia , Compostos de Sulfidrila/sangue , Adulto , Antioxidantes/análise , Estudos de Casos e Controles , Dissulfetos/metabolismo , Síndrome de Exfoliação/metabolismo , Feminino , Glaucoma de Ângulo Aberto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Oxidantes/sangue , Estresse Oxidativo/fisiologia , Compostos de Sulfidrila/metabolismoRESUMO
Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-D-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized. Here we use a combination of neutralizing antibody (nAb), mutant mouse and pharmacological approaches to test the role of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TrkB) signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex (intra-mPFC) infusion of an anti-BDNF nAb or in mice with a knock-in of the BDNF Val66Met allele, which blocks the processing and activity-dependent release of BDNF. We also demonstrate that pharmacological inhibitors of BDNF-TrkB signaling or of L-type voltage-dependent Ca2+ channels (VDCCs) block the antidepressant behavioral actions of GLYX-13. Finally, we examined the role of the Rho GTPase proteins by injecting a selective inhibitor into the mPFC and found that activation of Rac1 but not RhoA is involved in the antidepressant effects of GLYX-13. Together, these findings indicate that enhanced release of BDNF through exocytosis caused by activation of VDCCs and subsequent TrkB-Rac1 signaling is required for the rapid and sustained antidepressant effects of GLYX-13.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Depressão/tratamento farmacológico , Ketamina/farmacologia , Masculino , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/antagonistas & inibidores , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkB/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: The aim was to assess the ganglion cell complex (GCC) thickness, retinal nerve fiber layer (RNFL) thickness and optic disk features in the affected eyes (AE) and unaffected fellow eyes (FE) of subjects with unilateral nonarteritic anterior ischemic optic neuropathy (NAION) and to compare with healthy control eyes (CE) using spectral domain-optical coherence tomography (SD-OCT). METHODS: This study included 28 patients and age, sex and refraction-matched 28 control subjects. Mean GCC thickness and peripapillary RNFL thickness in four quadrants measured by cirrus SD-OCT were evaluated in both AE and FE of patients and CE. In addition, optic disk measurements obtained with OCT were evaluated. RESULTS: Mean GCC thickness was significantly lower in AE compared with both FE and CE (P < 0.001), and mean GCC thickness in FE was significantly lower than CE (P = 0.022). In addition, mean RNFL thickness in superior and nasal quadrants significantly decreased in FE compared with CE (P = 0.020 and 0.010, respectively). Furthermore, AE had significantly greater optic disk cupping compared with both FE and CE (P < 0.001). CONCLUSIONS: GCC and RNFL thickness decreased significantly at late stages of NAION, in both AE and FE compared with CE, suggesting that some subclinical structural changes may occur in FE despite lack of obvious visual symptoms. In addition, there was no significant difference in optic disk features between the CE and FE. And significantly greater optic disk cupping in the AE compared with both FE and CE supports the acquired enlargement of cupping after the onset of NAION.
Assuntos
Macula Lutea/patologia , Disco Óptico/patologia , Neuropatia Óptica Isquêmica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Campos VisuaisRESUMO
Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in the medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1H-[13C]-nuclear magnetic resonance spectroscopy. Rats were acutely pretreated by intraperitoneal injection with a single dose of ketamine (1, 3, 10, 30 and 80 mg kg-1), Ro 25-6981 (1, 3 and 10 mg kg-1), scopolamine (5, 25 and 100 µg kg-1) or vehicle (controls). At fixed times after drug injection, animals received an intravenous infusion of [1,6-13C2]glucose for 8 min to enrich the amino-acid pools of the brain with 13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13C enrichments were measured. We found a clear dose-dependent effect of ketamine and Ro 25-6981 on behavior and the percentage of 13C enrichment of glutamate, glutamine and GABA (γ-aminobutyric acid). Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggest that the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity.
Assuntos
Antidepressivos/farmacologia , Ácido Glutâmico/metabolismo , Animais , Antidepressivos/metabolismo , Encéfalo/metabolismo , Glutamina/metabolismo , Ketamina/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Masculino , Fenóis/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Escopolamina/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
AIMS AND OBJECTIVES: The aim of the study was to analyze and quantify the pattern of corneal astigmatism in Caucasian cataract surgery patients using a new optical biometer (axial length [AL] Scan, NIDEK Co., Gamagori, Japan). PATIENTS AND METHODS: The datasets of cataract surgery patients acquired between March 1, 2014, and April 15, 2016, were collected and analyzed. The corneal power (flat keratometry, steep keratometry, and mean keratometry), negative cylinder power, and axis of astigmatism were recorded. Keratometry values were optically measured by optical low coherence interferometry (AL-Scan, NIDEK Co., Ltd.,) before cataract extraction. RESULTS: The study comprised 1233 eyes of 838 consecutive cataract candidates with a mean age of 66.8 ± 10.7 years (range 40-97 years). The mean keratometry value and corneal astigmatism were 43.69 ± 1.61 D and 0.84 ± 0.70 D, respectively. Corneal astigmatism of 1.00 D or greater was found in 344 eyes (27.9%), and 548 eyes (44.4%) had against-the-rule astigmatism. A trend toward decreasing J0 and J45 with age was found by linear regression models. The per-year increase in age was associated with a J0 and J45 decrease of 0.002 D and 0.001D, respectively. CONCLUSION: This study provides the distribution of astigmatism axis and power for cataract patients in age subsets from Turkey.
Assuntos
Astigmatismo/epidemiologia , Comprimento Axial do Olho/diagnóstico por imagem , Extração de Catarata , Catarata/epidemiologia , Córnea/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Astigmatismo/fisiopatologia , Biometria , Catarata/complicações , Catarata/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Físico , Estudos Retrospectivos , Turquia/epidemiologiaRESUMO
AIM: This study aimed to evaluate the clinical and pathological features of ocular adnexal lymphoma (OAL) and the treatment results in an eye care service center in Turkey. MATERIALS AND METHODS: The data sets of the patients diagnosed with OAL acquired between January 2008 and January 2016 were collected and analyzed. RESULTS: Fifteen patients were included in our study. The mean age was 55.80 ± 17.85 years. The age range was 7-85 years. Most of the lesions originated from orbital tissue, and histopathological and immunohistochemistry examinations of the lesions were consistent with non-Hodgkin's lymphoma in 14 patients and Hodgkin's lymphoma in 1 patient. The most common subtype of OAL, accounting for 40% of cases, is extranodular marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type. CONCLUSION: Most of our patients' histopathological and immunohistochemistry examinations are non-Hodgkin's type and also involve the orbits. Ocular adnexal lymphomatosis is not a rare disorder and could be treated if there is no systemic involvement at first diagnosis.
Assuntos
Neoplasias Oculares/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Neoplasias Orbitárias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Terapia Combinada , Neoplasias Oculares/classificação , Neoplasias Oculares/terapia , Feminino , Humanos , Imuno-Histoquímica , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Orbitárias/terapia , Radioterapia , Resultado do Tratamento , Turquia , Adulto JovemRESUMO
Phasing of novel macromolecular crystal structures has been challenging since the start of structural biology. Making use of anomalous diffraction of natively present elements, such as sulfur and phosphorus, for phasing has been possible for some systems, but hindered by the necessity to access longer X-ray wavelengths in order to make most use of the anomalous scattering contributions of these elements. Presented here are the results from a first successful experimental phasing study of a macromolecular crystal structure at a wavelength close to the sulfur K edge. This has been made possible by the in-vacuum setup and the long-wavelength optimised experimental setup at the I23 beamline at Diamond Light Source. In these early commissioning experiments only standard data collection and processing procedures have been applied, in particular no dedicated absorption correction has been used. Nevertheless the success of the experiment demonstrates that the capability to extract phase information can be even further improved once data collection protocols and data processing have been optimised.
RESUMO
Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.
RESUMO
BACKGROUND: Pseudotumor cerebri (PTC) occurs when the pressure inside the skull increases for no obvious reason. The aim of this study was to investigate three different methods: the optic nerve sheath diameter (ONSD) method, ONSD/eyeball transverse diameter (ETD) index, and ONSD/orbital transverse diameter (OTD) index for the initial detection of elevated intracranial pressure in patients with PTC. MATERIALS AND METHODS: A retrospective study of magnetic resonance data from adult PTC patients (n = 42) and control group (n = 40) was performed. ONSD and OTD measurements were made 3 mm and 10 mm posterior to the globe, after intracranial pressure was measured with lumbar puncture. The sensitivity, specificity, and overall accuracy of the findings on magnetic resonance imaging were calculated. RESULTS: The optic nerve sheath was enlarged in the PTC group compared with the control group. It showed 97% sensitivity and 100% specificity and 79% sensitivity and 87.5% specificity for 3 mm and 10 mm, respectively. The ONSD/ETD and ONSD/OTD indices were increased in the PTC group compared with the control group. For 3 mm posterior to the globe, the ONSD/ETD index had 90.5% sensitivity and 92% specificity, and the ONSD/OTD index had 86% sensitivity and 95% specificity. For 10 mm posterior to the globe, the sensitivity and specificity of the ONSD/ETD and ONSD/OTD indices were 86% and 80% and 74% and 82.5%, respectively. CONCLUSIONS: According to our study, the ONSD method and the ONSD/ETD and ONSD/OTD indices are reliable diagnostic markers for PTC. These noninvasive techniques may be useful in monitoring the invasive intracranial catheter and have wide potential clinical applications in district hospitals, emergency departments and intensive care units.
Assuntos
Hipertensão Intracraniana , Pseudotumor Cerebral , Adulto , Humanos , Hipertensão Intracraniana/diagnóstico por imagem , Pressão Intracraniana/fisiologia , Nervo Óptico/diagnóstico por imagem , Pseudotumor Cerebral/diagnóstico por imagem , Estudos Retrospectivos , UltrassonografiaRESUMO
Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.
Assuntos
Sintomas Comportamentais/tratamento farmacológico , Depressão , Ácido Glutâmico/metabolismo , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Riluzol/administração & dosagem , Acetatos/sangue , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Sintomas Comportamentais/etiologia , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Preferências Alimentares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Isótopos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Neuroglia/metabolismo , Neuroglia/patologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , RNA Mensageiro/metabolismo , Cintilografia , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Estresse Psicológico/complicações , Sacarose/administração & dosagem , Edulcorantes/administração & dosagemRESUMO
PURPOSE: To evaluate the effects of metformin alone and combined treatment with metformin and an SGLT2 inhibitor on retinal microvascular morphology using optical coherence tomography angiography (OCTA) in isolated type 2 diabetes mellitus (DM) patients with HbA1c above the expected target (>7%). METHODS: Fifty patients with isolated DM, 7%Assuntos
Diabetes Mellitus Tipo 2
, Retinopatia Diabética
, Inibidores do Transportador 2 de Sódio-Glicose
, Diabetes Mellitus Tipo 2/complicações
, Diabetes Mellitus Tipo 2/tratamento farmacológico
, Retinopatia Diabética/diagnóstico
, Retinopatia Diabética/tratamento farmacológico
, Angiofluoresceinografia
, Humanos
, Estudos Prospectivos
, Vasos Retinianos/diagnóstico por imagem
, Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
, Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
, Tomografia de Coerência Óptica
RESUMO
Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.
Assuntos
Cocaína/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Animais , Cocaína/administração & dosagem , Condicionamento Psicológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Relação Dose-Resposta a Droga , Dinorfinas/genética , Dinorfinas/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neurônios/metabolismo , Mutação Puntual , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Simplexvirus/genéticaRESUMO
Following chronic cocaine treatment, we have found a long-lasting increase in AP-1 binding in the rat nucleus accumbens and striatum, two important targets of the behavioral effects of cocaine. This increase develops gradually over several days and remains at 50% of maximal levels 7 days after the last cocaine exposure. Supershift experiments, along with one- and two-dimensional Western blots, indicate that this chronic AP-1 complex contains at least four Fos-related antigens (FRAs), some of which display delta FosB-like immunoreactivity, that are induced selectively by chronic, but not acute, cocaine treatment. The same chronic FRAs were also induced by several different types of chronic treatments in a region-specific manner in the brain. Thus, the chronic FRAs and associated chronic AP-1 complex could mediate some of the long-term changes in gene expression unique to the chronic-treated state as opposed to the acute-treated and normal states.
Assuntos
Encéfalo/metabolismo , Cocaína/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Western Blotting , Mapeamento Encefálico , Esquema de Medicação , Eletroforese em Gel Bidimensional , Eletrochoque , Ponto Isoelétrico , Masculino , Peso Molecular , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Convulsões/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Fator de Transcrição AP-1/química , Tranilcipromina/administração & dosagemRESUMO
Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.
Assuntos
Antidepressivos/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Antígenos de Diferenciação/metabolismo , Bromodesoxiuridina , Contagem de Células , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Imunofluorescência , Fluoxetina/farmacologia , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Morfolinas/farmacologia , Neurônios/citologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Reboxetina , Tranilcipromina/farmacologiaRESUMO
Neurogenesis continues to occur in the adult hippocampus, although many of the newborn cells degenerate 1-2 weeks after birth. The number and survival of newborn cells are regulated by a variety of environmental stimuli, but very little is known about the intracellular signal transduction pathways that control adult neurogenesis. In the present study, we examine the expression of the phosphorylated cAMP response element-binding protein (pCREB) in immature neurons in adult hippocampus and the role of the cAMP cascade in the survival of new neurons. The results demonstrate that virtually all immature neurons, identified by triple immunohistochemistry for bromodeoxyuridine (BrdU) and polysialic acid-neural cell adhesion molecule (PSA-NCAM), are also positive for pCREB. In addition, upregulation of cAMP (via pharmacological inhibition of cAMP breakdown or by antidepressant treatment) increases the survival of BrdU-positive cells. A possible role for pCREB in the regulation of PSA-NCAM, a marker of immature neurons involved in neuronal remodeling and neurite outgrowth, is supported by cell culture studies demonstrating that the cAMP-CREB pathway regulates the expression of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM. These findings indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation and function, of newborn neurons.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Animais , Antidepressivos/farmacologia , Antígenos de Diferenciação/biossíntese , Bromodesoxiuridina , Divisão Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Colforsina/farmacologia , AMP Cíclico/metabolismo , Fluoxetina/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Molécula L1 de Adesão de Célula Nervosa/biossíntese , Neurônios/citologia , Neurônios/efeitos dos fármacos , Células PC12 , Fosforilação , Ratos , Rolipram/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Ácidos Siálicos/biossíntese , Sialiltransferases/genética , Sialiltransferases/metabolismoRESUMO
Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents.
Assuntos
Antidepressivos/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação para Cima/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/farmacologia , Antipsicóticos/farmacologia , Química Encefálica/efeitos dos fármacos , Cocaína/farmacologia , Corantes , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Desipramina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Fluoxetina/farmacologia , Haloperidol/farmacologia , Óperon Lac/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Inibidores da Monoaminoxidase/farmacologia , Fosforilação , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Tranilcipromina/farmacologia , beta-Galactosidase/biossíntese , beta-Galactosidase/genéticaRESUMO
The present study demonstrates that the regulator of G-protein-signaling protein type 4 (RGS4) is differentially regulated in the locus coeruleus (LC) and the paraventricular nucleus (PVN) of the hypothalamus by chronic stress and glucocorticoid treatments. Acute or chronic administration of corticosterone to adult rats decreased RGS4 mRNA levels in the PVN but increased these levels in the LC. Similarly, chronic unpredictable stress decreased RGS4 mRNA levels in the PVN but had a strong trend to increase these levels in the LC. Chronic stress also decreased RGS4 mRNA levels in the pituitary. The molecular mechanisms of RGS4 mRNA regulation were further investigated in vitro in the LC-like CATH.a cell line and the neuroendocrine AtT20 cell line using the synthetic corticosterone analog dexamethasone. Consistent with the findings in vivo, dexamethasone treatment caused a dose- and time-dependent decrease in RGS4 mRNA levels in AtT20 cells but a dose- and time-dependent increase in CATH.a cells. RGS4 mRNA regulation seen in these two cell lines seems to be attributable, at least in part, to opposite changes in mRNA stability. The differential regulation of RGS4 expression in the LC and in key relays of the hypothalamic-pituitary-adrenal axis could contribute to the brain's region-specific and long-term adaptations to stress.
Assuntos
Encéfalo/fisiologia , Glucocorticoides/farmacologia , Proteínas do Tecido Nervoso/fisiologia , Proteínas/fisiologia , Proteínas RGS , Estresse Fisiológico/fisiopatologia , Animais , Células Cultivadas , Doença Crônica , Corticosterona/farmacologia , AMP Cíclico/fisiologia , Dexametasona/farmacologia , Retroalimentação , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Transtorno Depressivo/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Desenho de Fármacos , Hipocampo/fisiopatologia , Humanos , Zíper de Leucina/fisiologia , Receptores de AMP Cíclico/efeitos dos fármacos , Receptores de AMP Cíclico/fisiologia , Receptores de Neurotransmissores/efeitos dos fármacos , Receptores de Neurotransmissores/fisiologia , Restrição Física , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Psicológico/fisiopatologiaRESUMO
The stress-dependence and chronic nature of anxiety disorders along with the anxiolytic effectiveness of antidepressant drugs suggests that neuronal plasticity may play a role in the pathophysiology of anxiety. Intracellular signaling pathways are known in many systems to be critical links in the cascades from surface signals to the molecular alterations that result in functional plasticity. Chronic antidepressant treatments can regulate intracellular signaling pathways and can induce molecular, cellular, and structural changes over time. These changes may be important to the anxiolytic effectiveness of these drugs. In addition, the signaling proteins implicated in the actions of chronic antidepressant action, such as cAMP response element binding protein (CREB), have also been implicated in conditioned fear and in anxiety. The cellular mechanisms underlying conditioned fear indicate roles for additional signaling pathways; however, less is known about such mechanisms in anxiety. The challenge to identify intracellular signaling pathways and related molecular and structural changes that are critical to the etiology and treatment of anxiety will further establish the importance of mechanisms of neuronal plasticity in functional outcome and improve treatment strategies.