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1.
Neuropsychopharmacology ; 45(13): 2278-2288, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32842137

RESUMO

Major depressive disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABAA agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism.


Assuntos
Transtorno Depressivo Maior , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Viés , Transtorno Depressivo Maior/tratamento farmacológico , Córtex Pré-Frontal , Roedores
2.
Genes Brain Behav ; 18(1): e12475, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29566304

RESUMO

Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/- ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/- mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/- and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders.


Assuntos
Oligodendroglia/metabolismo , Comportamento Social , Estresse Psicológico/genética , Transcriptoma , Tonsila do Cerebelo/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo
3.
Transl Psychiatry ; 7(8): e1189, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28763063

RESUMO

Attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS) as well as obsessive compulsive disorder (OCD) are co-occurring neurodevelopmental diseases that share alterations of frontocortical neurometabolites. In this longitudinal study we investigated the behavioral and neurochemical effects of aripiprazole and riluzole treatment in juvenile spontaneously hypertensive rats (SHR), a model for ADHD. For neurochemical analysis we employed in vivo magnetic resonance spectroscopy (MRS). Spectra from voxels located at the central striatum and prefrontal cortex were acquired postnatally from day 35 to 50. In the SHR strain only, treatments reduced repetitive grooming and climbing behavior. The absolute quantification of cerebral metabolites in vivo using localized 1H-MRS at 11.7T showed significant alterations in SHR rats compared to controls (including glutamine, aspartate and total NAA). In addition, drug treatment reduced the majority of the detected metabolites (glutamate and glutamine) in the SHR brain. Our results indicate that the drug treatments might influence the hypothesized 'hyperactive' state of the cortico-striatal-thalamo-cortical circuitries of the SHR strain. Furthermore, we could show that behavioral changes correlate with brain region-specific alterations in neurometabolite levels in vivo. These findings should serve as reference for animal studies and for the analysis of neurometabolites in selected human brain regions to further define neurochemical alterations in neuropsychiatric diseases.


Assuntos
Aripiprazol/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Riluzol/farmacologia , Animais , Antipsicóticos/farmacologia , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Endogâmicos WKY
4.
Neuroscience ; 154(4): 1450-7, 2008 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-18541383

RESUMO

Aggregation of alpha-synuclein may contribute to neuropathology in Parkinson's disease patients and in transgenic animal models. Natively unfolded alpha-synuclein binds to various proteins and conformational changes due to alpha-synuclein misfolding may alter physiological interactions. In the present study, we used protein arrays spotted with 5000 recombinant human proteins for a large scale interaction analysis of monomeric versus oligomeric alpha-synuclein. Monomeric alpha-synuclein bound to arrayed cAMP regulated phosphoprotein 19 and binding appears to be disrupted by alpha-synuclein oligomerization. Incubation with recombinant alpha-synuclein oligomers lead to the identification of several GTPase activating proteins and Cdc42 effector proteins as binding partners. Protein database searches revealed a Cdc42/Rac interactive binding domain in some interactors. To demonstrate in vivo relevance, we analyzed brainstem protein extracts from alpha-synuclein(A30P) transgenic mice. Pull-down assays using beads conjugated with a Cdc42/Rac interactive binding domain lead to an enrichment of endogenous alpha-synuclein oligomers. Cdc42 effector proteins were also co-immunoprecipitated with alpha-synuclein from brainstem lysates and were colocalized with alpha-synuclein aggregates in brain sections by double immunostaining. By two-dimensional gel electrophoretic analysis of synaptosomal fractions from transgenic mouse brains we detected additional isoforms of septin 6, a downstream target of Cdc42 effector proteins. Small GTPases have recently been identified in a genetic modifier screen to suppress alpha-synuclein toxicity in yeast. Our data indicate that components of small GTPase signal transduction pathways may be directly targeted by alpha-synuclein oligomers which potentially leads to signaling deficits and neurodegeneration.


Assuntos
Encéfalo/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Western Blotting , Encéfalo/patologia , Eletroforese em Gel Bidimensional , Humanos , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Transgênicos , Microscopia de Força Atômica , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Análise Serial de Proteínas , Conformação Proteica , Dobramento de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteína cdc42 de Ligação ao GTP/química
5.
Cell Mol Neurobiol ; 27(4): 505-15, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17380380

RESUMO

1. Alpha-synuclein is known to play an important role in the pathogenesis of Parkinson's disease (PD). The pathogenicity of alpha-synuclein is related to its ability to form intraneuronal inclusions. The inclusions, which are found in brains of patients with PD and diffuse Lewy body disease consist partially of C-terminally truncated alpha-synuclein. This alpha-synuclein species has an increased ability to form aggregates compared to full length alpha-synuclein.2. We have used an adeno-associated virus (AAV) vector system to overexpress either C-terminally truncated or full length alpha-synuclein containing the A53T mutation, which have both been identified in brains of familial PD patients and transgenic mouse models. Dissociated mesencephalic neurons, cerebellar granule neurons, and organotypic midbrain slice cultures were infected with AAV containing the transgene under the control of the cytomegalovirus promoter.3. We demonstrate that viral overexpression of alpha-synuclein(A53T) leads to the formation of distorted neurites, intraneuritic swellings, and granular perikaryal deposits in cultured neurons. Our results indicate that these cell culture models may represent an early phase of PD reflecting pathologic neuritic alterations before significant neuronal cell loss occurs.


Assuntos
Placa Amiloide/genética , Transdução Genética , alfa-Sinucleína/genética , Animais , Animais Recém-Nascidos , Células Cultivadas , Dependovirus/genética , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Modelos Biológicos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/genética
6.
J Pharmacol Exp Ther ; 316(1): 189-99, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16188953

RESUMO

Pramipexole has been shown to possess neuroprotective properties in vitro that are partly independent of its dopaminergic agonism. The site of neuroprotective action is still unknown. Using [(3)H]pramipexole, we show that the drug enters and accumulates in cells and mitochondria. Detoxification of reactive oxygen species (ROS) by pramipexole is shown in vitro and in vivo by evaluating mitochondrial ROS release and aconitase-2 activity, respectively. Pramipexole and its (+)-enantiomer SND919CL2X [low-affinity dopamine agonist; (+)2-amino-4,5,6,7-tetrahydro-6-l-propylamino-benzathiazole dihydrochloride] possess equipotent efficacy toward hydrogen peroxide and nitric oxide generated in vitro and inhibit cell death in glutathione-depleted neuroblastoma cells. IC(50) values ranged from 15 to 1000 microM, consistent with the reactivity of the respective radical and the compartmentalization of ROS generation and ROS detoxification. Finally, both compounds were tested in superoxide dismutase 1-G93A mice, a model of familial amyotrophic lateral sclerosis. SND919CL2X (100 mg/kg) prolongs survival time and preserves motor function in contrast to pramipexole (3 mg/kg), which shows an increase in running wheel activity before disease onset, presumably caused by the dopaminergic agonism. We conclude that both enantiomers, in addition to their dopaminergic activity, are able to confer neuroprotective effects by their ability to accumulate in brain, cells, and mitochondria where they detoxify ROS. However, a clinical use of pramipexole as a mitochondria-targeted antioxidant is unlikely, because the high doses needed for antioxidative action in vitro are not accessible in vivo due to dopaminergic side effects. In contrast, SND919CL2X may represent the prototype of a mitochondria-targeted neuroprotectant because it has the same antioxidative properties without causing adverse effects.


Assuntos
Antioxidantes , Agonistas de Dopamina/farmacologia , Fármacos Neuroprotetores , Tiazóis/farmacologia , Aconitato Hidratase/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzotiazóis , Química Encefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Meios de Cultura , Agonistas de Dopamina/farmacocinética , Peróxido de Hidrogênio/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/psicologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Oxidantes/farmacologia , Pramipexol , Estereoisomerismo , Superóxido Dismutase/genética , Superóxido Dismutase/fisiologia , Superóxido Dismutase-1 , Tiazóis/farmacocinética
7.
Transplantation ; 72(12): 1881-9, 2001 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-11773884

RESUMO

BACKGROUND: Clinical evidence indicates that vascular endothelial cell (EC) dysfunction occurs early after transplantation (Tx) and initiates chronic graft vasculopathy. This study explored this phenomenon in rat aorta Tx using the stringent Dark Agouti (DA)-to-Lewis (LEW) and the weak Fischer 344 (F344)-to-LEW strain combinations. METHODS: Donor abdominal aortae were orthotopically grafted into LEW rats. At post-Tx days 7, 14, 28, and 56, grafts were collected to assess changes in EC morphology (en face silver staining) and EC function, i.e., vasodilatory response to acetylcholine (ACH) after phenylephrine (PHE) precontraction; changes in vascular smooth muscle cell (VSMC) alpha-actin (western blotting), degree of apoptosis (caspase-3 activity), and morphology. RESULTS: In DA allografts, VSMC and EC dysfunctions developed concomitantly and were completed at 14 days post-Tx, most likely due to the EC and alpha-actin-positive VSMC loss. Meanwhile, allografts revealed markedly increased caspase-3 activity. Neointima formation, restricted to the edges of allografts at day 28, covered the entire allografts by day 56 post-Tx. In F344-allografts, VSMC function was maintained up to day 14 post-Tx, whereas ACH-induced relaxation was reduced by 50% at day 7 and abolished at day 14. EC denudation was not seen up to 56 days post-Tx, despite prominent leukocyte adhesion. Neointima formation was not detected at day 28 post-Tx but appeared along the entire allografts at day 56 post-Tx. CONCLUSIONS: These results confirm that Tx-induced EC dysfunction precedes the development of vasculopathy in rat aorta allografts and suggest that this early phenomenon can be best studied in the F344-to-LEW strain combination.


Assuntos
Aorta/fisiopatologia , Aorta/transplante , Endotélio Vascular/fisiopatologia , Actinas/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Caspase 3 , Caspases/metabolismo , Adesão Celular , Ciclosporina/farmacologia , Ativação Enzimática , Leucócitos/fisiologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Endogâmicos , Transplante/efeitos adversos , Transplante Homólogo , Vasoconstrição , Vasodilatação
8.
FASEB J ; 14(15): 2549-58, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11099474

RESUMO

Angiogenesis is crucial for many biological and pathological processes including the ovarian cycle and tumor growth. To identify molecules relevant for angiogenesis, we performed mRNA fingerprinting and subsequent Northern blot analysis using bovine cord-forming vs. monolayer-forming endothelial cells (EC) in vitro and staged bovine corpora lutea in vivo. We detected the receptor for activated C kinase 1 (RACK1), the specific receptor for activated protein kinase C beta (PKC beta), to be up-regulated in bovine cord-forming EC in vitro and in angiogenically active stages of bovine corpora lutea in vivo. Thereafter we established and determined the complete bovine RACK1 cDNA sequence. RACK1 was massively induced in subconfluent vs. contact-inhibited bovine EC, during angiogenesis in vitro, active phases of the murine ovarian cycle, human tumor angiogenesis, and in cancer cells in vivo as assessed by quantitative PCR and in situ hybridization. RACK1 transcripts were localized to proliferating EC in vitro and the endothelium of tumor neovascularizations in vivo by in situ hybridization. PKC beta plays an important role in angiogenesis and cancer growth. Our data suggest that downstream signaling of PKC beta in angiogenically active vs. inactive tissues and endothelium is affected by the availability of RACK1.


Assuntos
Carcinoma/genética , Proteínas de Neoplasias/genética , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Receptores de Superfície Celular/genética , Animais , Sequência de Bases , Bovinos , Clonagem Molecular , DNA Complementar/genética , Endotélio Vascular/metabolismo , Estro/fisiologia , Feminino , Proteínas de Ligação ao GTP , Humanos , Dados de Sequência Molecular , RNA Mensageiro/isolamento & purificação , RNA Neoplásico/isolamento & purificação , Receptores de Quinase C Ativada , Homologia de Sequência do Ácido Nucleico , Regulação para Cima
9.
Cell Mol Biol (Noisy-le-grand) ; 46(1): 63-9, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10726972

RESUMO

Transgenic mice with several copies of a mutated human superoxide dismutase 1 (Gly93-Ala substitution) gene, i.e. a mutation responsible for the development of familial amyotrophic lateral sclerosis (ALS), integrated into the mouse genome, develop a slowly progressive paralysis of the hind-limbs accompanied by a corresponding degeneration of spinal cord neuronal tissue. We have used two different lines of these transgenic mice [a low (approximately 12 copies) or a high (approximately 24) copy number of the mutated human superoxide dismutase 1 gene] to find evidence of programmed cell death in affected spinal cord tissue at distinct age groups. Hallmarks of programmed cell death, i.e. DNA laddering and an increase in caspase 3-like activity, were found in the spinal cord of both lines of mice. Behavioural evaluation of the mice indicated that the hallmarks of programmed cell death were mainly, but not exclusively found in symptomatic animals just before or at end-stage. These data suggest that programmed cell death may play a role in the disease process of familial ALS particularly in its terminal phase.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Apoptose , Caspases/metabolismo , Superóxido Dismutase/genética , Fatores Etários , Esclerose Lateral Amiotrófica/enzimologia , Animais , Caspase 3 , Fragmentação do DNA/genética , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Mutação , Medula Espinal/patologia , Superóxido Dismutase-1
10.
Naunyn Schmiedebergs Arch Pharmacol ; 362(6): 526-37, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11138845

RESUMO

The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing and antiapoptotic properties in several in vitro and in vivo paradigms. After showing that this compound does not inhibit monoamine oxidase B and only marginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated it in models considered relevant for Parkinson's disease. CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10(-7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Treatment of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2x30 mg/kg s.c. at a 72-h interval) with CGP 3466 (0.1 mg/kg s.c.) or CGP 3466B (0.014 mg/kg and 0.14 mg/kg p.o.) b.i.d. for 18 days partially prevented the loss of tyrosine hydroxylase-positive cells in the substantia nigra; a lower dose of CGP 3466B (0.0014 mg/kg p.o.) showed a marginal effect, whereas a high dose, i.e. 1.4 mg/kg p.o., was ineffective, suggesting a bell-shaped dose-response relationship which has also been observed in other paradigms. The effect of CGP 3466 on motor function was evaluated in rats that received intrastriatal injections of 6-OHDA unilaterally, according to a four-site injection protocol, and that were subsequently treated b.i.d. with 0.014 mg/kg i.p. CGP 3466B for 3 weeks. After another 3 weeks without treatment, skilled paw use was assessed by means of the staircase test. The results indicated a significant improvement of skilled motor performance as measured by means of the number of eaten pellets. Since due to the long wash-out period a symptomatic effect of CGP 3466B can be ruled out, it is likely that this improvement was related to interference with the course of the degeneration of the dopaminergic neurons. In conclusion, our results indicate that CGP 3466 is able to prevent death of dopaminergic cells in in vitro and in vivo models of Parkinson's disease. In addition, treatment with CGP 3466 resulted in improved skilled motor performance in 6-OHDA-lesioned rats.


Assuntos
Antiparkinsonianos/farmacologia , Dopamina/metabolismo , Neurônios/efeitos dos fármacos , Oxepinas/farmacologia , Transtornos Parkinsonianos/patologia , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Técnicas de Cultura de Células , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/farmacocinética , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Neurônios/enzimologia , Neurônios/patologia , Oxidopamina , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/enzimologia , Gravidez , Ratos , Selegilina/farmacologia , Substância Negra/enzimologia , Trítio , Tirosina 3-Mono-Oxigenase/metabolismo
11.
J Cell Biol ; 151(7): 1537-48, 2000 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-11134081

RESUMO

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.


Assuntos
Hipertrofia/patologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-fenilpiridínio/farmacologia , Animais , Axotomia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/patologia , Contagem de Células , Tamanho Celular , Células Cultivadas , Colina O-Acetiltransferase/metabolismo , Ativação Enzimática , Hipertrofia/enzimologia , Camundongos , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/enzimologia , Mutação/genética , Doenças Neurodegenerativas/enzimologia , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Oxidopamina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
12.
Nucleic Acids Res ; 26(7): 1826-33, 1998 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-9512559

RESUMO

Two yeast artificial chromosomes containing the entire human nerve growth factor gene were isolated and mapped. By homologous recombination a luciferase gene was precisely engineered into the coding portion of the NGF gene and a neomycin selection marker was placed adjacent to one of the YAC telomeres. Expression of the YAC-based NGF reporter gene and a plasmid-based NGF reporter gene were compared with the regulation of endogenous mouse NGF protein in mouse L929 fibroblasts. In contrast to the plasmid-based reporter gene, expression and regulation of the YAC-based reporter gene was independent of the site of integration of the transgene. Basic fibroblast growth factor and okadaic acid stimulated expression of the YAC transgene, whereas transforming growth factor-beta and dexamethasone inhibited it. Although cyclic AMP strongly stimulated production of the endogenous mouse NGF, no effect was seen on the human NGF reporter genes. Downregulation of the secretion of endogenous mouse NGF already occurred at an EC50 of 1-2 nM dexamethasone, but downregulation of the expression of NGF reporter genes occurred only at EC50 of 10 nM. This higher concentration was also required for upregulation of luciferase genes driven by the dexamethasone-inducible promoter of the mouse mammary tumor virus in L929 fibroblasts.


Assuntos
Fatores de Crescimento Neural/biossíntese , Fatores de Crescimento Neural/genética , Animais , Sequência de Bases , Cromossomos Artificiais de Levedura , Clonagem Molecular/métodos , Primers do DNA , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Cinética , Células L , Luciferases/biossíntese , Mamíferos , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Proteínas Recombinantes de Fusão/biossíntese , Mapeamento por Restrição , Transfecção/métodos
16.
Proc Natl Acad Sci U S A ; 91(6): 2041-5, 1994 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-8134347

RESUMO

Many theories of memory postulate that processing of information outlasts the learning situation and involves several different physiological substrates. If such physiologically distinct mechanisms or stages of memory do in fact exist, they should be differentially affected by particular experimental manipulations. Accordingly, a selective improvement of the processes underlying short-term memory should be detectable only while the information is encoded in the short-term mode, and a selective influence on long-term memory should be detectable only from the moment when memory is based on the long-term trace. Our comparative study of the time course of the effects of the cholinergic agonist arecoline, the gamma-aminobutyric acid type B receptor antagonist CGP 36742, the angiotensin-converting enzyme inhibitor captopril, and the nootropic oxiracetam, four substances with completely different primary sites of action, show that the memory-enhancing effects consistently come into evidence no sooner than 16-24 h after the learning trial. On the one hand, this finding suggests that all these substances act by way of the same type of mechanism; on the other hand, it demonstrates that the substrate modulated by the compounds forms the basis of memory only after 16-24 h. From the observation that animals also show clear signs of retention during the first 16 h--i.e., before the effects of the substances are measurable--it can be inferred that retention during this time is mediated by other mechanisms that are not influenced by any of the substances.


Assuntos
Arecolina/farmacologia , Captopril/farmacologia , Memória/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Pirrolidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Antagonistas de Receptores de GABA-A , Masculino , Camundongos , Psicotrópicos/farmacologia , Fatores de Tempo
18.
Psychopharmacology (Berl) ; 109(4): 383-9, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1365851

RESUMO

Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.


Assuntos
Aldosterona/farmacologia , Corticosterona/farmacologia , Memória/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/antagonistas & inibidores , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Captopril/antagonistas & inibidores , Captopril/farmacologia , Escuridão , Masculino , Camundongos , Nimodipina/antagonistas & inibidores , Nimodipina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estricnina/antagonistas & inibidores , Estricnina/farmacologia
20.
Ann N Y Acad Sci ; 640: 86-90, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1776765

RESUMO

Both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) exert neurotrophic actions on the cholinergic neurons of the basal forebrain nuclei. These neurotrophic factors are synthesized by hippocampal and cortical neurons that are located in the projection field of the basal forebrain cholinergic neurons. Both in vivo and in vitro the levels of NGF- and BDNF-mRNAs are increased up to 20-fold by kainic acid via non-NMDA glutamate receptors. Enhancement of the effectiveness of the GABAergic system by benzodiazepam or direct GABA agonists blocks the effect of kainic acid and reduces the basic levels of NGF- and BDNF-mRNAs. Whereas the increases in both NGF- and BDNF-mRNAs above normal levels are mediated by non-NMDA receptors, maintenance of the normal levels of NGF- and BDNF-mRNAs seems to be mediated predominantly by NMDA receptors. The regulation of NGF and BDNF synthesis via specific transmitter systems is discussed in the context of the refined tuning of synaptic functions, the potential implications for memory functions, and the possible therapeutic consequences for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Fatores de Crescimento Neural/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Neurônios/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Fator Neurotrófico Derivado do Encéfalo , Fatores de Crescimento Neural/uso terapêutico , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/metabolismo
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