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1.
J Mol Neurosci ; 70(3): 433-448, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31749125

RESUMO

Several studies in the last decade demonstrated that progestogens play an important role in the biology of Schwann cells, the main neuroglial cells of the peripheral nervous system. Since a recent study showed that the S42 rat Schwann cell line expressed membrane progesterone receptors (mPRs), members of the PAQR family, in this study, we examined mPR expression in a more physiological model, primary rat Schwann cells. We demonstrated that primary rat Schwann cells show a different pattern of mPR expression compared to the previously studied model; mPRα (PAQR7) and ß (PAQR8) isoforms were the major mPR members identified, with different sub-cellular localizations. Activation of the nuclear progesterone receptor (PR) with the specific agonist R5020 upregulated mPR expression, while activation of mPRs with the specific agonist Org OD 02-0 changed their sub-cellular localization. An in-depth analysis revealed additional effects of mPR activation, such as AKT activation, reduced expression of the myelin-associated glycoprotein (MAG), morphological changes, altered expression of several Schwann cell differentiation markers, and increased Schwann cell migration and proliferation. In conclusion, we identified mPRα and mPRß in primary rat Schwann cells, and our findings suggest a putative role for mPRs in the regulation of Schwann cell migration, proliferation, and differentiation. Therefore, mPRs are a potential pharmacological target for Schwann cell-related disorders and neurodegenerative diseases, especially those in which Schwann cell-mediated axon remyelination is desirable.

2.
Cell Death Discov ; 5: 92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069117

RESUMO

Schwann cells (SCs) play a central role in peripheral nervous system physiology and in the response to axon injury. The ability of SCs to proliferate, secrete growth factors, modulate immune response, migrate and re-myelinate regenerating axons has been largely documented. However, there are several restrictions hindering their clinical application, such as the difficulty in collection and a slow in vitro expansion. Adipose-derived stem cells (ASCs) present good properties for peripheral nerve regenerative medicine. When exposed to specific growth factors in vitro, they can acquire a SC-like phenotype (dASCs) expressing key SCs markers and assuming spindle-shaped morphology. Nevertheless, the differentiated phenotype is unstable and several strategies, including pharmacological stimulation, are being studied to improve differentiation outcomes. Cholinergic receptors are potential pharmacological targets expressed in glial cells. Our previous work demonstrated that muscarinic cholinergic receptors, in particular M2 subtype, are present in SCs and are able to modulate several physiological processes. In the present work, muscarinic receptors expression was characterised and the effects mediated by M2 muscarinic receptor were evaluated in rat dASCs. M2 receptor activation, by the preferred agonist arecaidine propargyl ester (APE), caused a reversible arrest of dASCs cell growth, supported by the downregulation of proteins involved in the maintenance of cell proliferation and upregulation of proteins involved in the differentiation (i.e., c-Jun and Egr-2), without affecting cell survival. Moreover, M2 receptor activation in dASCs enhances a pronounced spindle-shaped morphology, supported by Egr2 upregulation, and inhibits cell migration. Our data clearly demonstrate that rat dASCs express functional muscarinic receptors, in particular M2 subtype, which is able to modulate their physiological and morphological processes, as well as SCs differentiation. These novel findings could open new opportunities for the development of combined cell and pharmacological therapies for peripheral nerve regeneration, harnessing the potential of dASCs and M2 receptors.

3.
Neural Regen Res ; 14(6): 939-947, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30761997

RESUMO

Subsequent to a peripheral nerve injury, there are changes in gene expression within the dorsal root ganglia in response to the damage. This review selects factors which are well-known to be vital for inflammation, cell death and nociception, and highlights how alterations in their gene expression within the dorsal root ganglia can affect functional recovery. The majority of studies used polymerase chain reaction within animal models to analyse the dynamic changes following peripheral nerve injuries. This review aims to highlight the factors at the gene expression level that impede functional recovery and are hence are potential targets for therapeutic approaches. Where possible the experimental model, specific time-points and cellular location of expression levels are reported.

4.
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
5.
Steroids ; 142: 6-13, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-28962850

RESUMO

The role played by progestogens in modulating Schwann cell pathophysiology is well established. Progestogens exert their effects in these cells through both classical genomic and non-genomic mechanisms, the latter mediated by the GABA-A receptor. However, there is evidence that other receptors may be involved. Membrane progesterone receptors (mPRs) are novel 7-transmembrane receptors coupled to G proteins that have been characterized in different tissues and cells, including the central nervous system (CNS). The mPRs were shown to mediate some of progestogens' neuroprotective effects in the CNS, and to be upregulated in glial cells after traumatic brain injury. Based on this evidence, this paper investigated the possible involvement of mPRs in mediating progestogen actions in S42 Schwann cells. All five mPR isoforms and progesterone receptor membrane component 1 (PGRMC1) were detected in Schwann cells, and were present on the cell membrane. Progesterone and the mPR-specific agonist, Org-OD-02-0 (02) bound to these membranes, indicating the presence of functional mPRs. The mPR agonist 02 rapidly increased cell migration in an in vitro assay, suggesting a putative role of mPRs in the nerve regeneration process. Treatment with pertussis toxin and 8-Br-cAMP blocked 02-induced cell migration, suggesting this progestogen action is mediated by activation of an inhibitory G protein, leading to a decrease in intracellular cAMP levels. In contrast, long-term mPR activation led to increased expression levels of myelin associated glycoprotein (MAG). Taken together, these findings show that mPRs are present and active in Schwann cells and have a role in modulating their physiological processes.


Assuntos
Membrana Celular/metabolismo , Movimento Celular , Glicoproteína Associada a Mielina/biossíntese , Neuroglia/citologia , Neuroglia/metabolismo , Receptores de Progesterona/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Neuroglia/efeitos dos fármacos , Toxina Pertussis/farmacologia , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/análise , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Progesterona/agonistas , Receptores de Progesterona/análise , Tionucleotídeos/farmacologia , Células Tumorais Cultivadas
6.
PLoS One ; 13(12): e0208596, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532260

RESUMO

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Restrição Calórica , Inflamação/prevenção & controle , Degeneração Neural/prevenção & controle , Neuralgia/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Aminoácidos/sangue , Animais , Carnitina/análogos & derivados , Carnitina/sangue , Citocinas/análise , Metabolismo Energético , Glucose/metabolismo , Heterozigoto , Resistência à Insulina , Masculino , Camundongos , Camundongos Transgênicos , Estado Pré-Diabético/dietoterapia , Estado Pré-Diabético/patologia , Células de Schwann/citologia , Células de Schwann/metabolismo
7.
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
8.
Regen Med ; 13(2): 141-157, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29160149

RESUMO

AIM: This in vitro and in vivo study reports on silk fibroin (SF) scaffold, functionalized for in situ delivery of GABA and/or allopregnanolone (ALLO), as biomaterial for potential application in tissue engineering and nerve regeneration. MATERIALS & METHODS: We evaluated the feasibility to design 2D scaffolds (films) made of regenerated Bombyx mori SF, functionalized with GABA and/or ALLO to enhance in vitro biological functions, health, survival and growth of Schwann cells and sensitive neurons of the dorsal root ganglia. RESULTS & CONCLUSION: Our 2D-SF film showed an efficient loading and controllable release of drugs promoting nerve regeneration. SF functionalized film may be helpful for the development of bioengineered conduits and, in principle, have great potential for long-gap nerve injury repair.


Assuntos
Fibroínas/fisiologia , Neurônios/citologia , Células de Schwann/citologia , Seda , Engenharia Tecidual/métodos , Animais , Materiais Biocompatíveis , Bombyx , Fibroínas/química , Teste de Materiais , Regeneração Nervosa , Pregnanolona/química , Pregnanolona/fisiologia , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/fisiologia
9.
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.

10.
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
11.
Neural Plast ; 2016: 5985021, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28090360

RESUMO

Memory is our ability to store and remember past experiences; it is the result of changes in neuronal circuits of specific brain areas as the hippocampus. During memory formation, neurons integrate their functions and increase the strength of their connections, so that synaptic plasticity is improved and consolidated. All these processes recruit several proteins at the synapses, whose expression is highly regulated by DNA methylation and histone tails posttranslational modifications. Steroids are known to influence memory process, and, among them, neurosteroids are implicated in neurodegenerative disease related to memory loss and cognitive impairment. The epigenetic control of neurosteroids involvement in memory formation and maintenance could represent the basis for neuroregenerative therapies.


Assuntos
Epigênese Genética/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Neurotransmissores/fisiologia , Animais , Epigênese Genética/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurotransmissores/farmacologia
12.
Proteomics ; 16(4): 645-56, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26698593

RESUMO

In the skeletal muscle, the ageing process is characterized by a loss of muscle mass and strength, coupled with a decline of mitochondrial function and a decrease of satellite cells. This profile is more pronounced in hindlimb than in forelimb muscles, both in humans and in rodents. Utilizing light and electron microscopy, myosin heavy chain isoform distribution, proteomic analysis by 2D-DIGE, MALDI-TOF MS and quantitative immunoblotting, this study analyzes the protein levels and the nuclear localization of specific molecules, which can contribute to a preferential muscle loss. Our results identify the molecular changes in the hindlimb (gastrocnemius) and forelimb (triceps) muscles during ageing in rats (3- and 22-month-old). Specifically, the oxidative metabolism contributes to tissue homeostasis in triceps, whereas respiratory chain disruption and oxidative-stress-induced damage imbalance the homeostasis in gastrocnemius muscle. High levels of dihydrolipoyllysine-residue acetyltransferase (Dlat) and ATP synthase subunit alpha (Atp5a1) are detected in triceps and gastrocnemius, respectively. Interestingly, in triceps, both molecules are increased in the nucleus in aged rats and are associated to an increased protein acetylation and myoglobin availability. Furthermore, autophagy is retained in triceps whereas an enhanced fusion, decrement of mitophagy and of regenerative potential is observed in aged gastrocnemius muscle.


Assuntos
Envelhecimento , Proteínas Musculares/análise , Músculo Esquelético/patologia , Doenças Musculares/patologia , Animais , Autofagia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiologia , Doenças Musculares/metabolismo , Cadeias Pesadas de Miosina/análise , Cadeias Pesadas de Miosina/metabolismo , Proteômica , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Eletroforese em Gel Diferencial Bidimensional
14.
Front Cell Neurosci ; 9: 83, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25852476

RESUMO

Changes in GABAergic inhibition occur during physiological processes, during response to drugs and in various pathologies. These changes can be achieved through direct allosteric modifications at the γ-amino butyric acid (GABA) type A (GABAA) receptor protein level, or by altering the synthesis, trafficking and stability of the receptor. Neurosteroids (NSs) and protein kinase C (PKC) are potent modulators of GABAA receptors and their effects are presumably intermingled, even though evidence for this hypothesis is only partially explored. However, several PKC isoforms are able to phosphorylate the GABAA receptor, producing different functional effects. We focused on the ε isoform, that has been correlated to the sensitivity of the GABAA receptor to allosteric modulators and whose expression may be regulated in peripheral sensory neurons by NSs. The cross-talk between PKC-ε and NSs, leading to changes in GABAA receptor functionality, is considered and discussed in this perspective.

15.
J Neurosci Res ; 93(2): 285-95, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25327365

RESUMO

The γ-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury.


Assuntos
Bainha de Mielina/metabolismo , Nós Neurofibrosos/metabolismo , Receptores de GABA-B/metabolismo , Nervo Isquiático , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Embrião de Mamíferos , GABAérgicos/farmacologia , Gânglios Espinais/citologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Glicoproteína Associada a Mielina/genética , Glicoproteína Associada a Mielina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-B/genética , Nervo Isquiático/citologia , Nervo Isquiático/embriologia , Nervo Isquiático/crescimento & desenvolvimento , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia
16.
Neural Regen Res ; 9(1): 10-5, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25206738

RESUMO

Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-derived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events (e.g., DNA damage) or environmental cues (e.g., stressful stimuli or diseases), which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can influence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.

17.
Biomed Res Int ; 2014: 368678, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25165701

RESUMO

Neuropathic pain arises as a direct consequence of a lesion or disease affecting the peripheral somatosensory system. It may be associated with allodynia and increased pain sensitivity. Few studies correlated neuropathic pain with nerve morphology and myelin proteins expression. Our aim was to test if neuropathic pain is related to nerve degeneration, speculating whether the modulation of peripheral GABA-B receptors may promote nerve regeneration and decrease neuropathic pain. We used the partial sciatic ligation- (PSL-) induced neuropathic model. The biochemical, morphological, and behavioural outcomes of sciatic nerve were analysed following GABA-B ligands treatments. Simultaneous 7-days coadministration of baclofen (10 mg/kg) and CGP56433 (3 mg/kg) alters tactile hypersensitivity. Concomitantly, specific changes of peripheral nerve morphology, nerve structure, and myelin proteins (P0 and PMP22) expression were observed. Nerve macrophage recruitment decreased and step coordination was improved. The PSL-induced changes in nociception correlate with altered nerve morphology and myelin protein expression. Peripheral synergic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain.


Assuntos
Regeneração Nervosa , Neuralgia/tratamento farmacológico , Neuropatia Ciática/tratamento farmacológico , Ácido gama-Aminobutírico/metabolismo , Animais , Baclofeno/administração & dosagem , Expressão Gênica , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Ligantes , Proteínas da Mielina/biossíntese , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Neuralgia/fisiopatologia , Ratos , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/fisiopatologia
18.
Dev Neurobiol ; 74(7): 676-91, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24403178

RESUMO

Glial cells express acetylcholine receptors. In particular, rat Schwann cells express different muscarinic receptor subtypes, the most abundant of which is the M2 subtype. M2 receptor activation causes a reversible arrest of the cell cycle. This negative effect on Schwann cell proliferation suggests that these cells may possibly progress into a differentiating program. In this study we analyzed the in vitro modulation, by the M2 agonist arecaidine, of transcription factors and specific signaling pathways involved in Schwann cell differentiation. The arecaidine-induced M2 receptor activation significantly upregulates transcription factors involved in the promyelinating phase (e.g., Sox10 and Krox20) and downregulates proteins involved in the maintenance of the undifferentiated state (e.g., c-jun, Notch-1, and Jagged-1). Furthermore, arecaidine stimulation significantly increases the expression of myelin proteins, which is accompanied by evident changes in cell morphology, as indicated by electron microscopy analysis, and by substantial cellular re-distribution of actin and cell adhesion molecules. Moreover, ultrastructural and morphometric analyses on sciatic nerves of M2/M4 knockout mice show numerous degenerating axons and clear alterations in myelin organization compared with wild-type mice. Therefore, our data demonstrate that acetylcholine mediates axon-glia cross talk, favoring Schwann cell progression into a differentiated myelinating phenotype and contributing to compact myelin organization.


Assuntos
Bainha de Mielina/fisiologia , Neurogênese , Receptor Muscarínico M2/metabolismo , Células de Schwann/fisiologia , Animais , Arecolina/análogos & derivados , Arecolina/farmacologia , Axônios/efeitos dos fármacos , Axônios/fisiologia , Axônios/ultraestrutura , Células Cultivadas , Camundongos Knockout , Proteínas da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestrutura , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurogênese/efeitos dos fármacos , Fármacos do Sistema Nervoso Periférico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/genética , Receptor Muscarínico M4/genética , Receptor Muscarínico M4/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/ultraestrutura , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , Nervo Isquiático/fisiopatologia , Nervo Isquiático/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
19.
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
20.
J Neuroimmune Pharmacol ; 8(1): 202-11, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23242694

RESUMO

Neuropathic pain originates from a damage or disease affecting the somatosensory system. Its treatment is unsatisfactory as it appears refractory to most analgesics. Animal models of neuropathic pain are now available that help to clarify the underlying mechanisms. Recently it has been recognized that inflammatory and immune mechanisms in the peripheral and in the central nervous system play a role in the onset and the maintenance of pain. In response to nervous tissue damage, activation of resident or recruited immune cells leads to the production of inflammatory mediators, as cytokines. In models of neuropathic pain, such as nerve injury and diabetes induced neuropathy, the time course of the expression of the proinflammatory cytokines TNF-α,IL-1ß and IL-6 and of the antiinflammatory cytokine IL-10 has been well characterized both in the peripheral (sciatic nerve, dorsal root ganglia) and the central (spinal cord) nervous system. These cytokines appear activated/modulated in the nervous tissue in parallel with the occurrence of painful behaviour, i.e. allodynia and hyperalgesia. Novel therapeutic approaches efficacious to reduce painful symptoms, for example treatments with the non specific purinergic antagonist PPADS, the phytoestrogen genistein and a cell stem therapy with murine adult neural stem cells also re-established a balance between pro and antinflammatory mediators in the peripheral and central nervous system. These data suggest a pivotal role of immune system and inflammation in neuropathic pain. The modulation of inflammatory molecules appears to be a common trait accomplished throughout different mechanisms by different drugs that might converge in neuropathic pain modulation.


Assuntos
Citocinas/fisiologia , Neuralgia/patologia , Animais , Comportamento Animal/fisiologia , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/psicologia , Neuralgia/terapia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Doenças da Medula Espinal/metabolismo , Doenças da Medula Espinal/patologia , Transplante de Células-Tronco
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