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1.
PLoS One ; 15(4): e0231868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320404

RESUMO

BACKGROUND & OBJECTIVE: Deficits in cognitive functions dependent upon the integrity of the prefrontal cortex have been described in Multiple Sclerosis (MS). In a series of studies we have shown that fluid intelligence (g) is a substantial contributor to frontal deficits and that, for some classical "executive" tasks, frontal deficits were entirely explained by g. However, for another group of frontal tasks deficits remained once g was introduced as a covariate. This second set of tests included multitasking and theory of mind tasks. In the present study, we aimed at determining the role of fluid intelligence in frontal deficits seen in patients with MS. METHODS: A group of patients with Relapsing Remitting MS (n = 36) and a group of control subjects (n = 42) were assessed with a battery of classical executive tests (which included the Wisconsin Card Sorting Test, Verbal Fluency, and Trail Making Test B), a multitasking test, a theory of mind test and a fluid intelligence test. RESULTS: MS patients showed significant deficits in the fluid intelligence task. We found differences between patients and control subjects in all tests except for the multitasking test. The differences in the classical executive tests became non-significant once fluid intelligence was introduced as a covariate, but differences in theory of mind remained. CONCLUSIONS: The present results suggest that fluid intelligence can be affected in MS and that this impairment can play a role in the executive deficits described in MS.


Assuntos
Função Executiva , Inteligência , Esclerose Múltipla/psicologia , Adulto , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Adulto Jovem
2.
Transl Brain Rhythm ; 2(1)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28920083

RESUMO

The ventrobasal (VB) thalamus relay nucleus processes information from rodents' whiskers, projecting to somatosensory cortex. Cocaine and methylphenidate (MPH) have been described to differentially alter intrinsic properties of, and spontaneous GABAergic input to, VB neurons. Here we studied using bis-fura 2 ratiometric fluorescence the effects of cocaine and MPH on intracellular [Ca2+] dynamics at the soma and dendrites of VB neurons. Cocaine increased baseline fluorescence in VB somatic and dendritic compartments. Peak and areas of fluorescence amplitudes were reduced by cocaine binge treatment in somas and dendrites at different holding potentials. MPH binge treatment did not alter ratiometric fluorescence at either somatic or dendritic levels. These novel cocaine-mediated blunting effects on intracellular [Ca2+] might account for alterations in the capacity of thalamocortical neurons to maintain gamma band oscillations, as well as their ability to integrate synaptic afferents.

3.
J Neurochem ; 136(3): 526-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26484945

RESUMO

Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 µM) and high (100 µM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 µM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 µM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 µM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre-synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G-protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and thus facilitating GABA release.


Assuntos
Cafeína/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Núcleos Talâmicos/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Cloreto de Cádmio/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Receptor 5-HT2A de Serotonina/genética , Serotonina/farmacologia , Serotoninérgicos/farmacologia , Núcleos Talâmicos/metabolismo , Fosfolipases Tipo C/metabolismo
4.
Biofactors ; 39(4): 476-84, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23361852

RESUMO

Iron, either in its chelated form or as holotransferrin (hTf), prevents the dedifferentiation of Schwann cells (SC), cells responsible for the myelination of the peripheral nervous system (PNS). This dedifferentiation is promoted by serum deprivation through cAMP release, PKA activation, and CREB phosphorylation. Since iron elicits its effect in a transferrin (Tf)-free environment, in this work we postulate that non-transferrin-bound iron (NTBI) uptake must be involved. Divalent metal transporter 1(DMT1) has been widely described in literature as a key player in iron metabolism, but never before in the PNS context. The presence of DMT1 was demonstrated in nerve homogenate, isolated adult-rat myelin, and cultured SC by Western Blot (WB) analysis and confirmed through its colocalization with S-100ß (SC marker) by immunocytochemical and immunohistochemical analyses. Furthermore, the existence of its mRNA was verified in sciatic nerve homogenate by RT-PCR and throughout SC maturational stages. Finally, we describe DMT1's subcellular location in the plasma membrane by confocal microscopy of SC and WB of different subcellular fractions. These data allow us to suggest the participation of DMT1 as part of a Tf independent iron uptake mechanism in SC and lead us to postulate a crucial role for iron in SC maturation and, as a consequence, in PNS myelination.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Ferro/metabolismo , Células de Schwann/metabolismo , Animais , Proteínas de Transporte de Cátions/genética , Membrana Celular/metabolismo , Células Cultivadas , Expressão Gênica , Fibras Nervosas Mielinizadas/metabolismo , Sistema Nervoso Periférico/citologia , Transporte Proteico , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo
5.
J Neurochem ; 124(5): 602-12, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23205768

RESUMO

Methylphenidate (MPH) is widely used to treat children and adolescents diagnosed with attention deficit/hyperactivity disorder. Although MPH shares mechanistic similarities to cocaine, its effects on GABAergic transmission in sensory thalamic nuclei are unknown. Our objective was to compare cocaine and MPH effects on GABAergic projections between thalamic reticular and ventrobasal (VB) nuclei. Mice (P18-30) were subjected to binge-like cocaine and MPH acute and sub-chronic administrations. Cocaine and MPH enhanced hyperlocomotion, although sub-chronic cocaine-mediated effects were stronger than MPH effects. Cocaine and MPH sub-chronic administration altered paired-pulse and spontaneous GABAergic input differently. The effects of cocaine on evoked paired-pulse GABA-mediated currents changed from depression to facilitation with the duration of the protocols used, while MPH induced a constant increase throughout the administration protocols. Thalamic reticular nucleus GAD67 and VB Ca(V) 3.1 protein levels were measured using western blot to better understand their link to increased GABA release. Both proteins were increased by sub-chronic administration of cocaine. MPH showed effects on GABAergic transmission that seems less disruptive than cocaine. Unique effects of cocaine on postsynaptic VB calcium currents might explain deleterious cocaine effects on sensory thalamic nuclei. These results suggest that cocaine and MPH produced distinct presynaptic alterations on GABAergic transmission.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Cocaína/toxicidade , Metilfenidato/toxicidade , Transmissão Sináptica/efeitos dos fármacos , Núcleos Talâmicos/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Western Blotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Núcleos Talâmicos/metabolismo
6.
PLoS One ; 7(10): e46599, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23056363

RESUMO

Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 × 5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2 × 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Corpo Estriado/efeitos dos fármacos , Inflamação/prevenção & controle , Metanfetamina/efeitos adversos , Animais , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Febre/prevenção & controle , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Modafinila , Tirosina 3-Mono-Oxigenase/metabolismo
7.
Synapse ; 65(10): 1087-98, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21590747

RESUMO

Methamphetamine (METH) is a highly addictive drug that might induce neurotoxicity. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders, may have some efficacy for the treatment of psychostimulant addiction. In this study we tested possible neuroprotective effects of modafinil after toxic METH administration in mice. We evaluated the effect of modafinil (two injections of either 90 or 180 mg/kg) and METH binge (3 × 7 mg/kg i.p. injections, 3-h apart) coadministration on DA striatal content, TH immunoreactivity in striatal areas and spontaneous locomotor activity. We also investigated acute locomotor activity and stereotypy profile in mice treated with a single METH dose (2 and 7 mg/kg) pretreated with modafinil (90 and 180 mg/kg). We found that mice treated with a METH binge showed a marked decrease in DA and dopaminergic metabolites as well as lower levels of TH immunoreactivity in the dorsal striatum. Pretreatment with modafinil (both 90 and 180 mg/kg) attenuated these effects but did not prevent METH induced decrease in locomotion. We also found that groups that received the combination of both modafinil and single dose METH showed a decrease in total distance traveled in an open field compared with METH groups. We observed an increment in the time mice expended doing stereotypic movements (continuous sniffing) in the group that received the combination of both METH and modafinil (i.e., decreasing locomotion). Our results suggest a possible protective role of modafinil against METH acute striatal toxicity.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Fármacos Neuroprotetores/farmacologia , Animais , Esquema de Medicação , Interações Medicamentosas , Masculino , Camundongos , Modafinila , Atividade Motora/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos
8.
J Neurosci Res ; 89(8): 1203-17, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21538460

RESUMO

In the present work, we analyzed whether endogenous and/or transplanted bone marrow mononuclear cells (BMMC) migrate spontaneously to the crushed sciatic nerve and whether they transdifferentiate into Schwann cells (SC) in order to help repair the damaged tissue. We also studied both the immunohistochemical evolution of myelin proteins MBP and P(0) and the myelin composition of both the proximal and distal stumps of the crushed sciatic nerve to determine the demyelination-remyelination period. Immunohistochemical analysis of crushed animals showed that the degeneration process consists of loss of nerve fiber integrity accompanied by degradation of myelin basic proteins MBP and P(0) , which is anticipated by protein cluster formation. The remyelination process appears as a recovery in nerve fiber structure as well as in MBP and P(0) immunoreactivity; results obtained studying isolated myelin from the crushed sciatic nerve show a strong correlation between them. As opposed to demyelination, axonal damage is observed for a short period of time and takes place mostly in the crush area and the segments adjacent to the lesion. Evidence of spontaneous migration of endogenous or intravascularly transplanted BMMC (CD34(+) and vimentin(+) ) is found during the demyelination period exclusively to the injured sciatic nerve. Once migration takes place, transdifferentiation to SC is observed. Such migration and transdifferentiation processes might be inferred to constitute a spontaneous repair mechanism after nerve injury.


Assuntos
Células da Medula Óssea/fisiologia , Movimento Celular/fisiologia , Transdiferenciação Celular/fisiologia , Doenças Desmielinizantes/fisiopatologia , Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia , Animais , Feminino , Proteínas da Mielina/metabolismo , Bainha de Mielina/fisiologia , Ratos , Ratos Wistar
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