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[PMID]:28747407
[Au] Autor:Roberts ZS; Wolden-Hanson T; Matsen ME; Ryu V; Vaughan CH; Graham JL; Havel PJ; Chukri DW; Schwartz MW; Morton GJ; Blevins JE
[Ad] Endereço:Veterans Affairs Puget Sound Health Care System, Office of Research and Development, Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, Washington.
[Ti] Título:Chronic hindbrain administration of oxytocin is sufficient to elicit weight loss in diet-induced obese rats.
[So] Source:Am J Physiol Regul Integr Comp Physiol;313(4):R357-R371, 2017 Oct 01.
[Is] ISSN:1522-1490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oxytocin (OT) administration elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates, and humans by reducing energy intake and increasing energy expenditure. Although the neurocircuitry underlying these effects remains uncertain, OT neurons in the paraventricular nucleus are positioned to control both energy intake and sympathetic nervous system outflow to interscapular brown adipose tissue (BAT) through projections to the hindbrain nucleus of the solitary tract and spinal cord. The current work was undertaken to examine whether central OT increases BAT thermogenesis, whether this effect involves hindbrain OT receptors (OTRs), and whether such effects are associated with sustained weight loss following chronic administration. To assess OT-elicited changes in BAT thermogenesis, we measured the effects of intracerebroventricular administration of OT on interscapular BAT temperature in rats and mice. Because fourth ventricular (4V) infusion targets hindbrain OTRs, whereas third ventricular (3V) administration targets both forebrain and hindbrain OTRs, we compared responses to OT following chronic 3V infusion in DIO rats and mice and chronic 4V infusion in DIO rats. We report that chronic 4V infusion of OT into two distinct rat models recapitulates the effects of 3V OT to ameliorate DIO by reducing fat mass. While reduced food intake contributes to this effect, our finding that 4V OT also increases BAT thermogenesis suggests that increased energy expenditure may contribute as well. Collectively, these findings support the hypothesis that, in DIO rats, OT action in the hindbrain evokes sustained weight loss by reducing energy intake and increasing BAT thermogenesis.
[Mh] Termos MeSH primário: Tecido Adiposo Marrom/fisiopatologia
Obesidade/tratamento farmacológico
Obesidade/fisiopatologia
Ocitocina/farmacologia
Rombencéfalo/fisiopatologia
Termogênese/efeitos dos fármacos
Perda de Peso/efeitos dos fármacos
[Mh] Termos MeSH secundário: Tecido Adiposo Marrom/efeitos dos fármacos
Animais
Depressores do Apetite/farmacologia
Dieta Hiperlipídica/efeitos adversos
Relação Dose-Resposta a Droga
Infusões Intraventriculares
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Obesidade/etiologia
Ratos
Ratos Long-Evans
Ratos Sprague-Dawley
Rombencéfalo/efeitos dos fármacos
Especificidade da Espécie
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Appetite Depressants); 50-56-6 (Oxytocin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1152/ajpregu.00169.2017


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[PMID]:29190687
[Au] Autor:da Silva AA; Hall JE; do Carmo JM
[Ad] Endereço:Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
[Ti] Título:Leptin reverses hyperglycemia and hyperphagia in insulin deficient diabetic rats by pituitary-independent central nervous system actions.
[So] Source:PLoS One;12(11):e0184805, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The hypothalamic-pituitary-adrenal (HPA) axis has been postulated to play a major role in mediating the antidiabetic effects of leptin. We tested if the pituitary is essential for the chronic central nervous system mediated actions of leptin on metabolic and cardiovascular function in insulin-dependent diabetic and non-diabetic rats. Male 12-week-old hypophysectomized Sprague-Dawley rats (Hypo, n = 5) were instrumented with telemetry probes for determination of mean arterial pressure (MAP) and heart rate (HR) 24-hrs/day and an intracerebroventricular (ICV) cannula was placed into the brain lateral ventricle for continuous leptin infusion. In additional groups of Hypo and control rats (n = 5/group), diabetes was induced by single injection of streptozotocin (50 mg/kg, IP). Hypo rats were lighter, had lower MAP and HR (83±4 and 317±2 vs 105±4 mmHg and 339±4 bpm), with similar caloric intake per kilogram of body weight and fasting plasma glucose levels (84±4 vs 80±4 mg/dl) compared to controls. Chronic ICV leptin infusion (7 days, 0.62 µg/hr) in non-diabetic rats reduced caloric intake and body weight (-10%) in Hypo and control rats and markedly increased HR in control rats (~25 bpm) while causing only modest HR increases in Hypo rats (8 bpm). In diabetic Hypo and control rats, leptin infusion reduced caloric intake, body weight and glucose levels (323±74 to 99±20 and 374±27 to 108±10 mg/dl), respectively; however, the effects of leptin on HR were abolished in Hypo rats. These results indicate that hypophysectomy attenuates leptin's effect on HR regulation without altering leptin's ability to suppress appetite or normalize glucose levels in diabetes.
[Mh] Termos MeSH primário: Sistema Nervoso Central/fisiopatologia
Diabetes Mellitus Experimental/complicações
Hiperglicemia/tratamento farmacológico
Hiperfagia/tratamento farmacológico
Leptina/uso terapêutico
Hipófise/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Glicemia/metabolismo
Pressão Sanguínea
Bradicardia/tratamento farmacológico
Bradicardia/etiologia
Ingestão de Energia
Frequência Cardíaca
Hiperglicemia/complicações
Hiperfagia/complicações
Hipofisectomia
Infusões Intraventriculares
Insulina/sangue
Leptina/administração & dosagem
Masculino
Hipófise/cirurgia
Ratos
Ratos Sprague-Dawley
Estreptozocina
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Insulin); 0 (Leptin); 5W494URQ81 (Streptozocin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180130
[Lr] Data última revisão:
180130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184805


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[PMID]:28923036
[Au] Autor:Huber R; Schlodder D; Effertz C; Rieger S; Tröger W
[Ad] Endereço:Center for Complementary Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Str. 115B, 79106, Freiburg im Breisgau, Germany. roman.huber@uniklinik-freiburg.de.
[Ti] Título:Safety of intravenously applied mistletoe extract - results from a phase I dose escalation study in patients with advanced cancer.
[So] Source:BMC Complement Altern Med;17(1):465, 2017 Sep 18.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mistletoe extracts have anti-tumor properties and are approved for subcutaneous use in cancer patients. Data on Intravenous application are limited. METHODS: An aqueous extract from pine-mistletoe was used to investigate maximum tolerable dose (MTD) and safety of intravenous application. It was infused once weekly for 3 weeks in patients with advanced cancer. Any type of cancer was included; relevant exclusion criteria were concurrent chemo- or radiation therapy. The classical phase I 3 + 3 dose escalation scheme was followed. Predefined dose groups were 200, 400, 700, 1200 and 2000 mg. Maximum planned dose was 2000 mg. With the MTD three more patients should be treated for 9 weeks in order to evaluate intermediate term tolerability. Weekly during the treatment and 1 week later tolerability, clinical status, safety laboratory parameters and adverse events were documented. RESULTS: Twenty-one patients (3 in the dose groups 200, 400, 700 and 1200 mg, respectively, 9 in the dose group 2000 mg) were included. MTD was not reached. Because one dose-limiting toxicity (DLT), an allergic reaction, occurred during infusion of 2000 mg, three more patients had to be included in this dose group and tolerated it, as well as the three patients who received 2000 mg for 9 weeks. Occasionally in the dose group 2000 mg mild to moderate fever occurred. CONCLUSION: Weekly infusions of 2000 mg of the pine-mistletoe extract were tolerated and can be used in further studies but had a risk for allergic reactions and fever. German Clinical Trials Register (Trial registration number DRKS00005028).
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/administração & dosagem
Erva-de-Passarinho/química
Neoplasias/tratamento farmacológico
Extratos Vegetais/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Antineoplásicos Fitogênicos/efeitos adversos
Relação Dose-Resposta a Droga
Feminino
Alemanha
Seres Humanos
Infusões Intraventriculares
Masculino
Meia-Idade
Neoplasias/imunologia
Extratos Vegetais/efeitos adversos
Estudos Prospectivos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Plant Extracts)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-1971-1


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[PMID]:28867578
[Au] Autor:Rostami F; Javan M; Moghimi A; Haddad-Mashadrizeh A; Fereidoni M
[Ad] Endereço:Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
[Ti] Título:Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model.
[So] Source:Life Sci;188:172-185, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS: Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS: STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE: STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage.
[Mh] Termos MeSH primário: Doença de Alzheimer/diagnóstico
Gliose/patologia
Hipocampo/patologia
Resistência à Insulina
Insulina/metabolismo
Sintomas Prodrômicos
Estreptozocina/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Astrócitos/patologia
Colina O-Acetiltransferase/biossíntese
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Comportamento Exploratório/efeitos dos fármacos
Gliose/induzido quimicamente
Infusões Intraventriculares
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Neurônios/patologia
Ratos
Receptor de Insulina/biossíntese
Recognição (Psicologia)/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
Estreptozocina/administração & dosagem
Fatores de Tempo
Proteínas tau/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (tau Proteins); 5W494URQ81 (Streptozocin); EC 2.3.1.6 (Choline O-Acetyltransferase); EC 2.7.10.1 (Receptor, Insulin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28843854
[Au] Autor:Ensho T; Maruyama K; Mori K; Miyazato M; Kangawa K; Nakahara K; Murakami N
[Ad] Endereço:Department of Veterinary Physiology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan.
[Ti] Título:Neuromedin U precursor-related peptide (NURP) exerts neuromedin U-like sympathetic nerve action in the rat.
[So] Source:Biochem Biophys Res Commun;492(3):412-418, 2017 Oct 21.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It has been suggested that novel peptide that is produced from the neuromedin U (NMU) precursor may exist, as this precursor contains multiple consensus sequences for proteolytic processing. Recently, we identified two mature novel peptides comprising 33 and 36 residues in the rat brain, which were designated neuromedin U precursor-related peptide (NURP) 33 and 36. In the present study, we compared the roles of NURP33 and 36 with that of NMU, as neither activates the NMU receptors. Immunoreactivity for NMU and NURPs was widely present in the central nervous system and showed a similar distribution. Intracerebroventricular (icv) injection of NURP33 in rats increased locomotor activity, energy expenditure, heart rate and back surface temperature (BS-T), similarly to NMU or NURP36. NMU treatment reduced food intake, but NURP33 did not. Pretreatment with the ß3 blocker, SR59230A, and the cyclooxygenase blocker, indomethacin, inhibited the NURP33- or NMU-induced increase of BS-T. In addition, icv injection of NURP33 or NMU increased the expression of mRNA for cyclooxygenase 2 in the hypothalamus and for uncoupling protein 1 in the brown adipose tissue. These results suggest that although NURP33 and 36 do not activate the NMU receptors, they might exert NMU-like sympathetic nerve action in the brain.
[Mh] Termos MeSH primário: Neuropeptídeos/química
Neuropeptídeos/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/farmacologia
Sistema Nervoso Simpático/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Ingestão de Alimentos/efeitos dos fármacos
Indometacina/farmacologia
Infusões Intraventriculares
Masculino
Propanolaminas/farmacologia
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate); 0 (Neuropeptides); 0 (Peptide Fragments); 0 (Propanolamines); 117505-80-3 (neuromedin U); XXE1CET956 (Indomethacin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE


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[PMID]:28789474
[Au] Autor:Shepherd DJ; Tsai SY; Cappucci SP; Wu JY; Farrer RG; Kartje GL
[Ad] Endereço:Loyola University Health Sciences Division, Maywood, Illinois (DJS, SPC, GLK); and Edward Hines Jr. Veterans Affairs Hospital, Research Service, Hines, Illinois (DJS, S-YT, SPC, JYW, RGF, GLK).
[Ti] Título:The Subventricular Zone Response to Stroke Is Not a Therapeutic Target of Anti-Nogo-A Immunotherapy.
[So] Source:J Neuropathol Exp Neurol;76(8):683-696, 2017 Aug 01.
[Is] ISSN:1554-6578
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ischemic stroke is a leading cause of adult disability with no pharmacological treatments to promote the recovery of lost function. Neutralizing antibodies against the neurite outgrowth inhibitor Nogo-A have emerged as a promising treatment for subacute and chronic stroke in animal models; however, whether anti-Nogo-A treatment affects poststroke neurogenesis remains poorly understood. In this study, we confirmed expression of Nogo-A by neuroblasts in the adult rat subventricular zone (SVZ), a major neurogenic niche; however, we found no evidence that Nogo-A was expressed at the surface of these cells. In vitro migration assays demonstrated that Nogo-A signaling induced a modest reduction in neuroblast migration speed, while anti-Nogo-A antibodies had no effect on motility properties. Using a permanent distal middle cerebral artery occlusion model of cortical stroke, we found that the number of proliferating cells in the SVZ was unaffected in response to stroke, while neuroblast mobilization from the SVZ toward the stroke lesion correlated positively with lesion size. However, we found no evidence that proliferation or neuroblast mobilization were affected by anti-Nogo-A antibody treatment. Our results suggest that the SVZ is not a therapeutic target of anti-Nogo-A immunotherapy, and contribute to our understanding of the SVZ response to cortical stroke.
[Mh] Termos MeSH primário: Anticorpos/farmacologia
Anticorpos/uso terapêutico
Infarto da Artéria Cerebral Média/tratamento farmacológico
Ventrículos Laterais/efeitos dos fármacos
Proteínas Nogo/imunologia
[Mh] Termos MeSH secundário: Animais
Bromodesoxiuridina/metabolismo
Movimento Celular/efeitos dos fármacos
Ciclosporina/imunologia
Modelos Animais de Doenças
Lateralidade Funcional
Técnicas In Vitro
Infusões Intraventriculares
Ventrículos Laterais/citologia
Masculino
Proteínas do Tecido Nervoso/metabolismo
Proteínas Nogo/metabolismo
Receptor Nogo 1/metabolismo
Técnicas de Cultura de Órgãos
Ratos
Ratos Long-Evans
Receptores de Lisoesfingolipídeo/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Nerve Tissue Proteins); 0 (Nogo Proteins); 0 (Nogo Receptor 1); 0 (Receptors, Lysosphingolipid); 0 (Rtn4r protein, rat); 0 (sphingosine-1-phosphate receptor-2, rat); 83HN0GTJ6D (Cyclosporine); G34N38R2N1 (Bromodeoxyuridine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.1093/jnen/nlx050


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[PMID]:28771575
[Au] Autor:Tillmann S; Pereira VS; Liebenberg N; Christensen AK; Wegener G
[Ad] Endereço:Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark.
[Ti] Título:ZL006, a small molecule inhibitor of PSD-95/nNOS interaction, does not induce antidepressant-like effects in two genetically predisposed rat models of depression and control animals.
[So] Source:PLoS One;12(8):e0182698, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N-methyl-D-aspartate receptor (NMDA-R) antagonists and nitric oxide inhibitors have shown promising efficacy in depression but commonly induce adverse events. To circumvent these, a more indirect disruption of the nitric oxide synthase/postsynaptic density protein 95 kDa complex at the NMDA-R has been proposed. This disruption can be achieved using small molecule inhibitors such as ZL006, which has attracted attention as ischemic stroke therapy in rodents and has been proposed as a potential novel treatment for depression. Based on this, our aim was to translate these findings to animal models of depression to elucidate antidepressant-like properties in more detail. In the present study, we administered ZL006 to two established animal models of depression and control rodents. Following treatment, we measured locomotion in the Open Field and depressive-like behavior in the Forced Swim Test and Tail Suspension Test. Our experimental designs included the use of different species (rats, mice), strains (Flinders Sensitive Line rats, Flinders Resistant Line rats, Wistar Kyoto rats, Wistar Hanover rats, Sprague Dawley rats, B6NTac mice), routes of administration (intraperitoneal, intracerebroventricular), times of administration (single injection, repeated injections), treatment regimens (acute, sustained), and doses (5, 10, 15, 50 mg/kg). ZL006 did not affect behavior in any of the described settings. On a molecular level, ZL006 significantly reduced total nitrate/nitrite concentrations in the cerebellum, supporting that it is capable of reducing nitric oxide metabolites in the brain. Future studies using different experimental parameters are needed to further investigate the behavioral profile of ZL006.
[Mh] Termos MeSH primário: Ácidos Aminossalicílicos/administração & dosagem
Comportamento Animal/efeitos dos fármacos
Benzilaminas/administração & dosagem
Depressão/genética
Depressão/psicologia
[Mh] Termos MeSH secundário: Ácidos Aminossalicílicos/farmacologia
Animais
Benzilaminas/farmacologia
Depressão/tratamento farmacológico
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Predisposição Genética para Doença
Infusões Intraventriculares
Injeções Intraperitoneais
Masculino
Camundongos
Ratos
Ratos Sprague-Dawley
Ratos Wistar
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminosalicylic Acids); 0 (Benzylamines); 0 (ZL006 compound)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182698


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[PMID]:28729445
[Au] Autor:Flores-Barrera E; Thomases DR; Cass DK; Bhandari A; Schwarcz R; Bruno JP; Tseng KY
[Ad] Endereço:Department of Cellular and Molecular Pharmacology, The Chicago Medical School at Rosalind Franklin University, North Chicago, Illinois 60064.
[Ti] Título:Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid.
[So] Source:J Neurosci;37(33):7921-7929, 2017 Aug 16.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of α7-nicotinic acetylcholine receptors (α7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an α7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABA R positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions. Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory-inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.
[Mh] Termos MeSH primário: Neurônios GABAérgicos/fisiologia
Ácido Cinurênico/toxicidade
Córtex Pré-Frontal/fisiologia
Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
Receptor Nicotínico de Acetilcolina alfa7/fisiologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Neurônios GABAérgicos/efeitos dos fármacos
Infusões Intraventriculares
Ácido Cinurênico/administração & dosagem
Masculino
Técnicas de Cultura de Órgãos
Córtex Pré-Frontal/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (alpha7 Nicotinic Acetylcholine Receptor); H030S2S85J (Kynurenic Acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0932-17.2017


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[PMID]:28716964
[Au] Autor:Raybuck JD; Hargus NJ; Thayer SA
[Ad] Endereço:Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.
[Ti] Título:A GluN2B-Selective NMDAR Antagonist Reverses Synapse Loss and Cognitive Impairment Produced by the HIV-1 Protein Tat.
[So] Source:J Neurosci;37(33):7837-7847, 2017 Aug 16.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both and and has been linked to impaired neurocognitive function in humans. studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat. Here, we tested the hypothesis that Tat-induced loss and ifenprodil-mediated rescue of synaptic spines would predict impairment and rescue of cognitive function. Using intracranial multiphoton imaging, we found that infusion of 100 ng of HIV-1 Tat into the lateral ventricle of yellow fluorescent protein-expressing transgenic mice produced a 17 ± 1% loss of dendritic spines in layer 1 of retrosplenial cortex. Repeated imaging of the same dendrites over 3 weeks enabled longitudinal experiments that demonstrated sustained spine loss after Tat infusion and transient rescue after ifenprodil administration (10 mg/kg, i.p.). Parallel trace fear conditioning experiments showed that spine loss predicted learning deficits and that the time course of ifenprodil-induced rescue of spine density correlated with restoration of cognitive function. These results show for the first time that, during exposure to an HIV-1 neurotoxin , alteration of GluN2B-containing NMDAR signaling suppresses spine density and impairs learning. Pharmacological inhibition of these NMDARs rescued spines and restored cognitive function. Drugs that rescue synapses may improve neurocognitive function in HAND. Synaptodendritic damage correlates with cognitive decline in HIV-associated neurocognitive disorder (HAND) patients. We developed an imaging approach for longitudinal tracking of spine density that enabled correlation of synaptic changes with behavioral outcomes in a model of HAND. We show for the first time that spine loss after exposure to an HIV-1 protein can be reversed pharmacologically and that loss and recovery of dendritic spines predict impairment and restoration of cognitive function, respectively. Therefore, synapse loss, the hallmark of cognitive decline in HAND, is reversible. Drugs that restore spine density may have broad application for improving cognitive function during the early phases of neurodegenerative diseases.
[Mh] Termos MeSH primário: Disfunção Cognitiva/prevenção & controle
Antagonistas de Aminoácidos Excitatórios/administração & dosagem
HIV-1
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
Sinapses/efeitos dos fármacos
Produtos do Gene tat do Vírus da Imunodeficiência Humana/toxicidade
[Mh] Termos MeSH secundário: Animais
Disfunção Cognitiva/induzido quimicamente
Disfunção Cognitiva/metabolismo
Infusões Intraventriculares
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos CBA
Camundongos Transgênicos
Piperidinas/administração & dosagem
Receptores de N-Metil-D-Aspartato/metabolismo
Sinapses/metabolismo
Produtos do Gene tat do Vírus da Imunodeficiência Humana/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Excitatory Amino Acid Antagonists); 0 (NR2B NMDA receptor); 0 (Piperidines); 0 (Receptors, N-Methyl-D-Aspartate); 0 (tat Gene Products, Human Immunodeficiency Virus); R8OE3P6O5S (ifenprodil)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0226-17.2017


  10 / 633 MEDLINE  
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[PMID]:28669743
[Au] Autor:Caglayan B; Caglayan AB; Beker MC; Yalcin E; Beker M; Kelestemur T; Sertel E; Ozturk G; Kilic U; Sahin F; Kilic E
[Ad] Endereço:Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey; Istanbul Medipol University, Dept. of Physiology, Istanbul, Turkey; Yeditepe University, Dept. of Genetics and Bioengineering, Istanbul, Turkey.
[Ti] Título:Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice.
[So] Source:Exp Neurol;296:23-31, 2017 Oct.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Conflicting data in the literature about the function of P2X7R in survival following ischemia necessitates the conductance of in-depth studies. To investigate the impacts of activation vs inhibition of the receptor on neuronal survival as well as the downstream signaling cascades, in addition to optic nerve transection (ONT), 30min and 90min of middle cerebral artery occlusion (MCAo) models were performed in mice. Intracellular calcium levels were assessed in primary cortical neuron cultures. Here, we show that P2X7R antagonist Brilliant Blue G (BBG) decreased DNA fragmentation, infarct volume, brain swelling, neurological deficit scores and activation of microglial cells after focal cerebral ischemia. BBG also significantly increased the number of surviving retinal ganglion cells (RGCs) after ONT and the number of surviving neurons following MCAo. Importantly, receptor agonist BzATP resulted in increased activation of microglial cells and induced phosphorylation of ERK, AKT and JNK. These results indicated that inhibition of P2X7R with BBG promoted neuronal survival, not through the activation of survival kinase pathways, but possibly by improved intracellular Ca overload and decreased the levels of Caspase 1, IL-1ß and Bax proteins. On the other hand, BzATP-mediated increased number of activated microglia and increased survival kinase levels in addition to increased caspase-1 and IL-1ß levels indicate the complex nature of the P2X7 receptor-mediated signaling in neuronal injury.
[Mh] Termos MeSH primário: Isquemia Encefálica/metabolismo
Isquemia Encefálica/patologia
Neurônios/patologia
Traumatismos do Nervo Óptico/metabolismo
Traumatismos do Nervo Óptico/patologia
Receptores Purinérgicos P2/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/análogos & derivados
Trifosfato de Adenosina/farmacologia
Trifosfato de Adenosina/uso terapêutico
Animais
Animais Recém-Nascidos
Encéfalo/irrigação sanguínea
Encéfalo/efeitos dos fármacos
Edema Encefálico/etiologia
Isquemia Encefálica/tratamento farmacológico
Proteínas de Ligação ao Cálcio/metabolismo
Células Cultivadas
Córtex Cerebral/citologia
Citocinas/metabolismo
Fragmentação do DNA/efeitos dos fármacos
Modelos Animais de Doenças
Infusões Intraventriculares
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Proteínas dos Microfilamentos/metabolismo
Neurônios/efeitos dos fármacos
Traumatismos do Nervo Óptico/tratamento farmacológico
Inibidores da Agregação de Plaquetas/farmacologia
Inibidores da Agregação de Plaquetas/uso terapêutico
Corantes de Rosanilina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aif1 protein, mouse); 0 (Calcium-Binding Proteins); 0 (Cytokines); 0 (Microfilament Proteins); 0 (Platelet Aggregation Inhibitors); 0 (Receptors, Purinergic P2); 0 (Rosaniline Dyes); 0 (purinergic P2X8 receptor); 4P5DXU1F8Q (3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate); 8L70Q75FXE (Adenosine Triphosphate); M1ZRX790SI (coomassie Brilliant Blue)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE



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