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1.
Mol Neurobiol ; 56(2): 1461-1474, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29948947

RESUMO

GABA-B receptors are important for Schwann cell (SC) commitment to a non-myelinating phenotype during development. However, the P0-GABA-B1fl/fl conditional knockout mice, lacking the GABA-B1 receptor specifically in SCs, also presented axon modifications, suggesting SC non-autonomous effects through the neuronal compartment. In this in vitro study, we evaluated whether the specific deletion of the GABA-B1 receptor in SCs may induce autonomous or non-autonomous cross-changes in sensory dorsal root ganglia (DRG) neurons. To this end, we performed an in vitro biomolecular and transcriptomic analysis of SC and DRG neuron primary cultures from P0-GABA-B1fl/fl mice. We found that cells from conditional P0-GABA-B1fl/fl mice exhibited proliferative, migratory and myelinating alterations. Moreover, we found transcriptomic changes in novel molecules that are involved in peripheral neuron-SC interaction.


Assuntos
Axônios/metabolismo , Bainha de Mielina/metabolismo , Receptores de GABA-B/deficiência , Células de Schwann/citologia , Animais , Células Cultivadas , Gânglios Espinais/citologia , Camundongos Transgênicos , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo
2.
J Cell Physiol ; 233(7): 5348-5360, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29227527

RESUMO

Mesenchymal stem cells (MSCs), also known as stromal mesenchymal stem cells, are multipotent cells, which can be found in many tissues and organs as bone marrow, adipose tissue and other tissues. In particular MSCs derived from Adipose tissue (ADSCs) are the most frequently used in regenerative medicine because they are easy to source, rapidly expandable in culture and excellent differentiation potential into adipocytes, chondrocytes, and other cell types. Acetylcholine (ACh), the most important neurotransmitter in Central nervous system (CNS) and peripheral nervous system (PNS), plays important roles also in non-neural tissue, but its functions in MSCs are still not investigated. Although MSCs express muscarinic receptor subtypes, their role is completely unknown. In the present work muscarinic cholinergic effects were characterized in rat ADSCs. Analysis by RT-PCR demonstrates that ADSCs express M1-M4 muscarinic receptor subtypes, whereas M2 is one of the most expressed subtype. For this reason, our attention was focused on M2 subtype. By using the selective M2 against Arecaidine Propargyl Ester (APE) we performed cell proliferation and migration assays demonstrating that APE causes cell growth and migration inhibition without affecting cell survival. Our results indicate that ACh via M2 receptors, may contribute to the maintaining of the ADSCs quiescent status. These data are the first evidence that ACh, via muscarinic receptors, might contribute to control ADSCs physiology.


Assuntos
Acetilcolina/metabolismo , Tecido Adiposo/citologia , Células-Tronco Mesenquimais/citologia , Receptor Muscarínico M2/genética , Acetilcolina/antagonistas & inibidores , Tecido Adiposo/metabolismo , Animais , Arecolina/análogos & derivados , Arecolina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Ratos , Receptor Muscarínico M1/genética , Receptor Muscarínico M2/agonistas , Ativação Transcricional/efeitos dos fármacos
3.
Neural Regen Res ; 12(7): 1013-1023, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28852375

RESUMO

The development, maturation and regeneration of Schwann cells (SCs), the main glial cells of the peripheral nervous system, require the coordinate and complementary interaction among several factors, signals and intracellular pathways. These regulatory molecules consist of integrins, neuregulins, growth factors, hormones, neurotransmitters, as well as entire intracellular pathways including protein-kinase A, C, Akt, Erk/MAPK, Hippo, mTOR, etc. For instance, Hippo pathway is overall involved in proliferation, apoptosis, regeneration and organ size control, being crucial in cancer proliferation process. In SCs, Hippo is linked to merlin and YAP/TAZ signaling and it seems to respond to mechanic/physical challenges. Recently, among factors regulating SCs, also the signaling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) proved relevant for SC fate, participating in the regulation of adhesion, motility, migration and in vitro myelination. In SCs, the factors Src and FAK are regulated by the neuroactive steroid allopregnanolone, thus corroborating the importance of this steroid in the control of SC maturation. In this review, we illustrate some old and novel signaling pathways modulating SC biology and functions during the different developmental, mature and regenerative states.

4.
J Neurochem ; 141(2): 165-178, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28072455

RESUMO

Schwann cells' (SCs) development and maturation require coordinate and complementary activation of several signals and intracellular pathways. Among factors controlling these processes, the signalling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) are relevant for SCs', participating in regulation of their adhesion, motility and migration. Recently, the progesterone metabolite allopregnanolone (ALLO) was proved to be synthesized by SCs, whereas it acts autocrinally on SCs motility and proliferation, which are crucial processes for nerve development, maturation and regeneration. Herein, we investigate the hypothesis that the molecular mechanisms behind the ALLO's action on SCs involve the signalling intermediates Src and FAK. We first demonstrated that ALLO 10-6  M regulates SCs morphology, motility and myelination, also increasing the internode distance in the in vitro myelination model of neuron/SCs co-culture. ALLO's actions were mediated by the modulation of Src/FAK pathway, since they were counteracted by PP2 10-5  M, a selective inhibitor of Src kinase. Then, we proved that Src/FAK activation in SCs involves GABA-A dependent mechanisms and actin re-arrangements. In conclusion, our findings are the first to corroborate the importance of the neuroactive steroid ALLO in regulating SCs development and maturation via the Src and phospho-FAK signalling activation. Cover Image for this issue: doi: 10.1111/jnc.13795.


Assuntos
Movimento Celular/fisiologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Fibras Nervosas Mielinizadas/enzimologia , Pregnanolona/farmacologia , Células de Schwann/enzimologia , Quinases da Família src/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Ratos , Células de Schwann/efeitos dos fármacos
5.
Psychopharmacology (Berl) ; 232(4): 713-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25124315

RESUMO

RATIONALE: During adolescence, the brain is maturing and more sensitive to drugs of abuse that can influence its developmental trajectory. Recently, attention has been focused on basic fibroblast growth factor (FGF-2) given that its administration early in life enhances the acquisition of cocaine self-administration and sensitization at adulthood (Turner et al. (Pharmacol Biochem Behav 92:100-4, 2009), Clinton et al. (Pharmacol Biochem Behav103:6-17, 2012)). Additionally, we found that abstinence from adolescent cocaine exposure long lastingly dysregulates FGF-2 transcription (Giannotti et al. (Psychopharmacology (Berl) 225:553-60, 2013 ). OBJECTIVES: The objectives of the study are to evaluate if (1) a single injection of cocaine (20 mg/kg) at postnatal day 35 alters FGF-2 messenger RNA (mRNA) levels and (2) the first injection influences the trophic response to a second injection (10 mg/kg) provided 24 h or 7 days later. RESULTS: We found regional differences in the FGF-2 expression pattern as either the first or the second injection of cocaine by themselves upregulated FGF-2 mRNA in the medial prefrontal cortex and nucleus accumbens while downregulating it in the hippocampus. The first injection influences the trophic response of the second. Of note, 24 h after the first injection, accumbal and hippocampal FGF-2 changes produced by cocaine in saline-pretreated rats were prevented in cocaine-pretreated rats. Conversely, in the medial prefrontal cortex and hippocampus 7 days after the first injection, the cocaine-induced FGF-2 changes were modified by the subsequent exposure to the psychostimulant. CONCLUSIONS: These findings show that a single cocaine injection is sufficient to produce enduring changes in the adolescent brain and indicate that early cocaine priming alters the mechanisms regulating the trophic response in a brain region-specific fashion.


Assuntos
Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Fator 2 de Crescimento de Fibroblastos/biossíntese , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Expressão Gênica/efeitos dos fármacos , Masculino , Modelos Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Regulação para Cima/efeitos dos fármacos
6.
Glia ; 62(4): 548-65, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24474699

RESUMO

The mechanisms regulating the differentiation into non-myelinating Schwann cells is not completely understood. Recent evidence indicates that GABA-B receptors may regulate myelination and nociception in the peripheral nervous system. GABA-B receptor total knock-out mice exhibit morphological and molecular changes in peripheral myelin. The number of small myelinated fibers is higher and associated with altered pain sensitivity. Herein, we analyzed whether these changes may be produced by a specific deletion of GABA-B receptors in Schwann cells. The conditional mice (P0-GABA-B1(fl/fl)) show a morphological phenotype characterized by a peculiar increase in the number of small unmyelinated fibers and Remak bundles, including nociceptive C-fibers. The P0-GABA-B1(fl/fl) mice are hyperalgesic and allodynic. In these mice, the morphological and behavioral changes are associated with a downregulation of neuregulin 1 expression in nerves. Our findings suggest that the altered pain sensitivity derives from a Schwann cell-specific loss of GABA-B receptor functions, pointing to a role for GABA-B receptors in the regulation of Schwann cell maturation towards the non-myelinating phenotype.


Assuntos
Hiperalgesia/patologia , Fibras Nervosas Amielínicas/fisiologia , Limiar da Dor/fisiologia , Receptores de GABA-B/deficiência , Células de Schwann/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Cultivadas , Marcha/genética , Gânglios Espinais/citologia , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , Proteína P0 da Mielina/genética , Neuregulina-1/metabolismo , Neurônios/fisiologia , Receptores de GABA-B/genética , Células de Schwann/ultraestrutura , Nervo Isquiático/citologia
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