Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
1.
Mol Cell Neurosci ; 126: 103881, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37467904

RESUMEN

BACKGROUND: The pathophysiological mechanism underlying chemotherapy-induced neuropathic pain (CINP) remains unclear. Sensory neuronal hypersensitivity in the dorsal root ganglion (DRG) is essential for the onset and maintenance of chronic pain. Satellite glial cells (SGCs) in the DRG potentially affect the function of sensory neurons, possibly by mediating extracellular or paracrine signaling. Exosomes play an essential role in cell-cell communication. However, the role of SGC-secreted exosomes in glia-neuron communication and CINP remains unclear. METHODS: SGCs and sensory neurons were cultured from the DRG of mice. The SGCs were treated with 4 µM oxaliplatin for 24 h. Glial fibrillary acid protein (GFAP) and connexin-43 (Cx-43) expressions in the SGCs were examined with immunocytochemistry (ICC). Enzyme-linked immunosorbent assay (ELISA) detected cytokine release in the SGCs after oxaliplatin treatment. Subsequently, SGC-secreted exosomes were collected using ultracentrifugation and identified by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Subsequently, DRG neurons were incubated with SGC-secreted exosomes for 24 h. The percentage of reactive oxygen species (ROS)-positive neurons was detected using flow cytometry, and acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) expression were examined by western blotting. SGC-secreted exosomes were intrathecally injected into naïve mice. The mechanical withdrawal threshold was assessed 24, 48, and 72 h following the injection. TRPV1 expression in the DRG was examined 72 h after intrathecal injection. Furthermore, differentially expressed (DE) miRNAs within the SGC-secreted exosomes were detected using RNA sequencing and bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses were performed to predict the function of the target genes of DE miRNAs. Finally, the DE miRNAs with pain regulation potential were identified in silico. RESULTS: After in-vitro oxaliplatin treatment, ICC showed an increase in the immunoreactivity of GFAP and Cx-43 in the SGCs. ELISA results suggested an increased release of tumor necrosis factor-α and interleukin (IL)-1ß, but a decreased release of IL-10. Oxaliplatin treatment increased the secretion of exosomes in the SGCs from 4.34 to 5.99 × 1011 (particles/ml). The exosome-specific markers CD9 and TSG101 were positive, whereas calnexin was negative for the obtained exosomes. Additionally, the SGC-secreted exosomes were endocytosed by DRG neurons after co-incubation. Moreover, after incubation with conditioned SGC-secreted exosomes (after 4 µM oxaliplatin treatment), the percentage of ROS-positive DRG neurons increased and ASIC3 and TRPV1 expressions were upregulated. After the intrathecal injection of the conditioned SGC-secreted exosomes, the mice presented with mechanical hypersensitivity and TRPV1 expression upregulation in the DRG. Notably, 25 and 120 significantly upregulated and downregulated miRNAs, respectively, were identified in the conditioned SGC-secreted exosomes. When predicting the function of target genes of DE miRNAs, certain GO terms, such as synapse organization, neurogenesis regulation, histone modification, and pain-related KEGG or Reactome pathways, including vascular endothelial growth factor A-vascular endothelial growth factor receptor 2, mammalian target of rapamycin, and mitogen-activated protein kinase signaling pathways, related to nervous system function were predicted. Finally, 27 pain regulation-related miRNAs, including miR-324-3p, miR-181a-5p, and miR-122-5p, were identified in silico. CONCLUSION: Our study demonstrates that SGC-secreted exosomes after in-vitro oxaliplatin treatment present a pro-nociceptive effect for DRG neurons and induce mechanical hypersensitivity in naïve mice, possibly via the contained miRNA cargo. Identifying the candidate miRNAs and verifying their functions in vivo are required to elucidate the exosomes mediating 'glia-neuron' communication under CINP condition.


Asunto(s)
Exosomas , MicroARNs , Neuralgia , Ratones , Animales , Oxaliplatino/farmacología , Oxaliplatino/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/farmacología , Ganglios Espinales/metabolismo , Exosomas/metabolismo , Nocicepción , Especies Reactivas de Oxígeno/metabolismo , Neuroglía/metabolismo , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Células Receptoras Sensoriales/metabolismo , MicroARNs/metabolismo , Mamíferos
2.
Brain Behav Immun ; 113: 212-227, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37437817

RESUMEN

Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is hallmarked by the presence of anti-modified protein autoantibodies (AMPA) against post-translationally modified citrullinated, carbamylated and acetylated proteins. It has been suggested that autoantibody-mediated processes represent distinct mechanisms contributing to pain in RA. In this study, we investigated the pronociceptive properties of monoclonal AMPA 1325:01B09 (B09 mAb) derived from the plasma cell of an RA patient. We found that B09 mAb induces pain-like behavior in mice that is not associated with any visual, histological or transcriptional signs of inflammation in the joints, and not alleviated by non-steroidal anti-inflammatory drugs (NSAIDs). Instead, we found that B09 mAb is retained in dorsal root ganglia (DRG) and alters the expression of several satellite glia cell (SGC), neuron and macrophage-related factors in DRGs. Using mice that lack activating FcγRs, we uncovered that FcγRs are critical for the development of B09-induced pain-like behavior, and partially drive the transcriptional changes in the DRGs. Finally, we observed that B09 mAb binds SGC in vitro and in combination with external stimuli like ATP enhances transcriptional changes and protein release of pronociceptive factors from SGCs. We propose that certain RA antibodies bind epitopes in the DRG, here on SGCs, form immune complexes and activate resident macrophages via FcγR cross-linking. Our work supports the growing notion that autoantibodies can alter nociceptor signaling via mechanisms that are at large independent of local inflammatory processes in the joint.


Asunto(s)
Artritis Reumatoide , Autoanticuerpos , Animales , Ratones , Receptores de IgG , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , Dolor
3.
Purinergic Signal ; 18(4): 499-514, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36001278

RESUMEN

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.


Asunto(s)
Hipersensibilidad , Dolor Visceral , Animales , Ratas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Enfermedades del Sistema Nervioso Central , Colon , Hipersensibilidad/metabolismo , Prostaglandinas/metabolismo , Prostaglandinas/farmacología , Ratas Sprague-Dawley , Receptores Purinérgicos P2X7/metabolismo , Dolor Visceral/metabolismo
4.
Glia ; 67(5): 999-1012, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30637823

RESUMEN

Pruritus is a common and disabling symptom in patients with hepatobiliary disorders, particularly in those with cholestatic features. Serum levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in patients suffering from hepatic pruritus, correlated with itch severity and response to treatment. Here we show that in a culture of dorsal root ganglia LPA 18:1 surprisingly activated a large fraction of satellite glia cells, and responses to LPA 18:1 correlated inversely with responses to neuronal expressed transient receptor potential channels. LPA 18:1 caused only a marginal activation of heterologously expressed TRPV1, and responses in dorsal root ganglion cultures from TRPV1-deficient mice were similar to controls. LPA 18:1 desensitized subsequent responsiveness to chloroquine and TGR5 agonist INT-777. The LPA 18:1-induced increase in cytoplasmatic calcium stems from the endoplasmatic reticulum. LPA receptor expression in dorsal root ganglia and Schwann cells, LPAR1 immunohistochemistry, and pharmacological results indicate a signaling pathway through LPA receptor 1. Peripheral rat Schwann cells, which are of glial lineage as the satellite glia cells, were also responsive to LPA 18:1. Summarizing, LPA 18:1 primarily activates rather glial cells than neurons, which may subsequently modulate neuronal responsiveness and sensory sensations such as itch and pain.


Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Lisofosfolípidos/farmacología , Neuroglía/efectos de los fármacos , Células Satélites Perineuronales/efectos de los fármacos , Células de Schwann/efectos de los fármacos , Animales , Calcio/metabolismo , Células Cultivadas , Femenino , Ganglios Espinales/citología , Regulación de la Expresión Génica/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Nervio Ciático/citología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Canal Catiónico TRPA1/deficiencia , Canal Catiónico TRPA1/genética , Canales Catiónicos TRPV/deficiencia , Canales Catiónicos TRPV/genética
5.
Pain Med ; 18(9): 1752-1766, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-28169407

RESUMEN

BACKGROUND: Increasing evidence suggests the potential involvement of metalloproteinase family proteins in the pathogenesis of neuropathic pain, although the underlying mechanisms remain elusive. METHODS: Using the spinal nerve ligation model, we investigated whether ADAM10 proteins participate in pain regulation. By implementing invitro methods, we produced a purified culture of satellite glial cells to study the underlying mechanisms of ADAM10 in regulating neuropathic pain. RESULTS: Results showed that the ADAM10 protein was expressed in calcitonin gene-related peptide (CGRP)-containing neurons of the dorsal root ganglia, and expression was upregulated following spinal nerve ligation surgery invivo. Intrathecal administration of GI254023X, an ADAM10 selective inhibitor, to the rats one to three days after spinal nerve ligation surgery attenuated the spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia. Intrathecal injection of ADAM10 recombinant protein simulated pain behavior in normal rats to a similar extent as those treated by spinal nerve ligation surgery. These results raised a question about the relative contribution of ADAM10 in pain regulation. Further results showed that ADAM10 might act by cleaving E-cadherin, which is mainly expressed in satellite glial cells. GI254023X reversed spinal nerve ligation-induced downregulation of E-cadherin and activation of cyclooxygenase 2 after spinal nerve ligation. ß-catenin, which creates a complex with E-cadherin in the membranes of satellite glial cells, was also downregulated by spinal nerve ligation surgery in satellite glial cells. Finally, knockdown expression of ß-catenin by lentiviral infection in purified satellite glial cells increased expression of inducible nitric oxide synthase and cyclooxygenase 2. CONCLUSION: Our findings indicate that neuron-derived ADAM10 production stimulates peripheral nerve injury-induced neuropathic pain by cleaving E-cadherin in satellite glial cells.


Asunto(s)
Proteína ADAM10/biosíntesis , Cadherinas/metabolismo , Neuralgia/metabolismo , Neuronas/metabolismo , Células Satélites Perineuronales/metabolismo , Animales , Ganglios Espinales/metabolismo , Ligadura , Masculino , Traumatismos de los Nervios Periféricos/metabolismo , Ratas , Ratas Sprague-Dawley , Nervios Espinales
6.
Dev Biol ; 398(1): 97-109, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25433207

RESUMEN

Molecular mechanisms governing the maintenance and proliferation of dorsal root ganglia (DRG) progenitors are largely unknown. Here we reveal that the Hippo pathway regulates the expansion of DRG progenitors and glia during mammalian DRG development. The key effectors of this pathway, transcriptional coactivators Yap and Taz, are expressed in DRG progenitors and glia during DRG development but are at least partially inhibited from activating transcription. Aberrant YAP activation leads to overexpansion of DRG progenitor and glial populations. We further show that the Neurofibromatosis 2 (Nf2) tumor suppressor inhibits Yap during DRG development. Loss of Nf2 leads to similar phenotypes as does YAP hyperactivation, and deleting Yap suppresses these phenotypes. Our study demonstrates that Nf2-Yap signaling plays important roles in controlling the expansion of DRG progenitors and glia during DRG development.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ganglios Espinales/embriología , Regulación del Desarrollo de la Expresión Génica , Neurofibromina 2/metabolismo , Neuroglía/citología , Fosfoproteínas/metabolismo , Transducción de Señal , Células Madre/citología , Aciltransferasas , Animales , Proteínas de Ciclo Celular , Movimiento Celular , Eliminación de Gen , Perfilación de la Expresión Génica , Genes de la Neurofibromatosis 2 , Genes Supresores de Tumor , Vía de Señalización Hippo , Hibridación in Situ , Ratones , Ratones Noqueados , Ratones Transgénicos , Mutación , Neuroglía/metabolismo , Fenotipo , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Tiempo , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP
8.
J Neurosci Methods ; 402: 110034, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38072069

RESUMEN

BACKGROUND: Primary neuronal cultures are used to elucidate cellular and molecular mechanisms involved in disease pathology and modulation by pharmaceuticals and nutraceuticals, and to identify novel therapeutic targets. However, preparation of primary neuronal cultures from rodent embryos is labor-intensive, and it can be difficult to produce high-quality consistent cultures. To overcome these issues, cryopreservation can be used to obtain standardized, high-quality stocks of neuronal cultures. NEW METHOD: In this study, we present a simplified cryopreservation method for rodent primary trigeminal ganglion neurons and glia from Sprague-Dawley neonates, using a 90:10 (v/v) fetal bovine serum/dimethyl sulfoxide cell freezing medium. RESULTS: Cryopreserved trigeminal ganglion cells stored for up to one year in liquid nitrogen exhibited similar neuronal and glial cell morphology to fresh cultures and retained high cell viability. Proteins implicated in inflammation and pain signaling were expressed in agreement with the reported subcellular localization. Additionally, both neurons and glial cells exhibited an increase in intracellular calcium levels in response to a depolarizing stimulus. Cryopreserved cells were also transiently transfected with reporter genes. COMPARISON WITH EXISTING METHODS: Our method is simple, does not require special reagents or equipment, will save time and money, increase flexibility in study design, and produce consistent cultures. CONCLUSIONS: This method for the preparation and cryopreservation of trigeminal ganglia results in primary cultures of neurons and glia similar in viability and morphology to fresh preparations that could be utilized for biochemical, cellular, and molecular studies, increase reproducibility, and save laboratory resources.


Asunto(s)
Neuroglía , Ganglio del Trigémino , Ratas , Animales , Reproducibilidad de los Resultados , Ratas Sprague-Dawley , Neuroglía/fisiología , Neuronas/fisiología , Criopreservación , Células Cultivadas
9.
Int Rev Neurobiol ; 176: 381-450, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38802179

RESUMEN

Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.


Asunto(s)
Esclerosis Amiotrófica Lateral , Neuroglía , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/terapia , Humanos , Neuroglía/fisiología , Animales
10.
Elife ; 112022 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-35997251

RESUMEN

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies. Despite this intimate association, the extent to which sympathetic functions are influenced by satellite glia in vivo remains unclear. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons. However, persisting neurons have elevated activity, and satellite glia-ablated mice show increased pupil dilation and heart rate, indicative of enhanced sympathetic tone. Satellite glia-specific deletion of Kir4.1, an inward-rectifying potassium channel, largely recapitulates the cellular defects observed in glia-ablated mice, suggesting that satellite glia act in part via K+-dependent mechanisms. These findings highlight neuron-satellite glia as functional units in regulating sympathetic output, with implications for disorders linked to sympathetic hyper-activity such as cardiovascular disease and hypertension.


Asunto(s)
Ganglios Simpáticos , Neuroglía , Animales , Supervivencia Celular , Ratones , Neuroglía/fisiología , Neuronas , Transducción de Señal
11.
Cell Rep ; 38(5): 110328, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35108545

RESUMEN

Satellite glia are the major glial type found in sympathetic and sensory ganglia in the peripheral nervous system, and specifically, contact neuronal cell bodies. Sympathetic and sensory neurons differ in morphological, molecular, and electrophysiological properties. However, the molecular diversity of the associated satellite glial cells remains unclear. Here, using single-cell RNA sequencing analysis, we identify five different populations of satellite glia from sympathetic and sensory ganglia. We define three shared populations of satellite glia enriched in immune-response genes, immediate-early genes, and ion channels/ECM-interactors, respectively. Sensory- and sympathetic-specific satellite glia are differentially enriched for modulators of lipid synthesis and metabolism. Sensory glia are also specifically enriched for genes involved in glutamate turnover. Furthermore, satellite glia and Schwann cells can be distinguished by unique transcriptional signatures. This study reveals the remarkable heterogeneity of satellite glia in the peripheral nervous system.


Asunto(s)
Ganglios Sensoriales/metabolismo , Ganglios Espinales/metabolismo , Neuroglía/metabolismo , Células de Schwann/metabolismo , Animales , Ganglios Simpáticos/metabolismo , Humanos , Ratones , Neuronas/metabolismo , Neuronas Aferentes , Sistema Nervioso Periférico/metabolismo
12.
IBRO Neurosci Rep ; 13: 187-197, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36093283

RESUMEN

The trigeminal ganglion is implicated in the underlying pathology of migraine and temporomandibular joint disorders (TMD), which are orofacial pain conditions involving peripheral and central sensitization. The neuropeptide calcitonin gene-related peptide (CGRP) is synthesized in some trigeminal ganglion neurons, and its release promotes inflammation, peripheral and central sensitization, and pain signaling. Recent studies in preclinical migraine and TMD models provide evidence that dietary supplementation with grape seed extract (GSE) inhibits trigeminal pain signaling. The goal of this study was to investigate the cellular mechanisms by which GSE modulates primary trigeminal ganglion cultures. The effect of GSE on CGRP secretion was determined by radioimmunoassay. To determine if GSE effects involved modulation of CGRP or the GABAergic system, expression of CGRP, GAD 65 and 67, GABAA receptor, and GABAB1 and GABAB2 receptor subunits were investigated by immunocytochemistry. GSE significantly inhibited basal CGRP secretion but did not alter neuronal CGRP expression. GAD 65 and 67 expression levels in neurons were significantly increased in response to GSE. While GSE did not cause a change in the neuronal expression of GABAA, GSE significantly increased GABAB1 expression in neurons, satellite glial cells, and Schwann cells. GABAB2 expression was significantly elevated in satellite glia and Schwann cells. These findings support the notion that GSE inhibition of basal CGRP secretion involves increased neuronal GAD 65 and 67 and GABAB receptor expression. GSE repression of CGRP release coupled with increased GABAB1 and GABAB2 glial cell expression would be neuroprotective by suppressing neuronal and glial excitability in the trigeminal ganglion.

13.
Front Pharmacol ; 13: 1038285, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36408236

RESUMEN

Glia are critical players in defining synaptic contacts and maintaining neuronal homeostasis. Both astrocytes as glia of the central nervous system (CNS), as well as satellite glial cells (SGC) as glia of the peripheral nervous system (PNS), intimately interact with microglia, especially under pathological conditions when glia regulate degenerative as well as regenerative processes. The chemotherapeutic agent paclitaxel evokes peripheral neuropathy and cognitive deficits; however, the mechanisms underlying these diverse clinical side effects are unclear. We aimed to elucidate the direct effects of paclitaxel on the function of astrocytes, microglia, and SGCs, and their glia-glia and neuronal-glia interactions. After intravenous application, paclitaxel was present in the dorsal root ganglia of the PNS and the CNS of rodents. In vitro, SGC enhanced the expression of pro-inflammatory factors and reduced the expression of neurotrophic factor NT-3 upon exposure to paclitaxel, resulting in predominantly neurotoxic effects. Likewise, paclitaxel induced a switch towards a pro-inflammatory phenotype in microglia, exerting neurotoxicity. In contrast, astrocytes expressed neuroprotective markers and increasingly expressed S100A10 after paclitaxel exposure. Astrocytes, and to a lesser extent SGCs, had regulatory effects on microglia independent of paclitaxel exposure. Data suggest that paclitaxel differentially modulates glia cells regarding their (neuro-) inflammatory and (neuro-) regenerative properties and also affects their interaction. By elucidating those processes, our data contribute to the understanding of the mechanistic pathways of paclitaxel-induced side effects in CNS and PNS.

14.
Trends Neurosci ; 44(12): 930-932, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34689995

RESUMEN

In a recent study, Tasdemir-Yilmaz and colleagues used single-cell RNA sequencing to reveal how diversity among peripheral glia changes with development and also identified unifying genetic profiles that are shared between mature glia. These data highlight new tools and pathways in which to understand peripheral glial development and function.


Asunto(s)
Neuroglía , Células de Schwann , Humanos , Neurogénesis , Neuroglía/metabolismo , Células de Schwann/metabolismo
15.
J Mol Neurosci ; 71(4): 826-835, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32918240

RESUMEN

Neurotrauma is among the main causes of human disability and mortality. Nerve injury impairs not only neurons but also causes death of satellite glial cells remote from the injury site. We studied the dynamics of expression of different proapoptotic proteins (E2F1, p53, caspase 3) in the dorsal root ganglia (DRG) of a rat after sciatic nerve transection. TUNEL staining and immunoblotting were used for analysis of cell apoptosis and axotomy-induced biochemical changes. Apoptosis of glial cells was observed at 24 h after sciatic nerve transection and increased on day 7, when apoptosis of some neurons only started. The earliest proapoptotic event in the injured DRG was overexpression of transcription factor E2F1 at 4 h after sciatic nerve transection. This preceded the induction of p53 and cleavage of caspase 3 at 24-h post-axotomy. The nerve injury marker amyloid precursor protein and the nerve regeneration marker GAP-43 were overexpressed in DRG on day 7 after sciatic nerve transection. We also developed a novel fluorescence method for differential visualization of the rat DRG and nerves by means of double staining with propidium iodide and Hoechst 33342 that impart red and blue-green fluorescence, respectively. The present experiments showed that glial cells remote from the nerve transection site were more vulnerable to axotomy than DRG neurons. E2F1 and p53 may be considered promising molecular targets for development of potential neuroprotective agents.


Asunto(s)
Ganglios Espinales/metabolismo , Nervio Ciático/lesiones , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Caspasa 3/metabolismo , Factor de Transcripción E2F1/metabolismo , Proteína GAP-43/metabolismo , Masculino , Ratas , Ratas Wistar , Nervio Ciático/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
16.
Biochem Pharmacol ; 187: 114397, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33382970

RESUMEN

Fundamental progresses have been made in pain research with a comprehensive understanding of the neuronal pathways which convey painful sensations from the periphery and viscera to the central nervous system and of the descending modulating pathways. Nevertheless, many patients still suffer from various painful conditions, which are often associated to other primary pathologies, and get no or poor relief from available painkillers. Thus, the interest of many researchers has concentrated on new and promising cellular targets and biochemical pathways. This is the case of glia cells, both in the peripheral and in the central nervous system, and of purinergic receptors. Starting from many intuitions and hypotheses raised by Prof. Geoffrey Burnstock, data have accumulated which clearly highlight the fundamental role exerted by several nucleotide and nucleoside receptors in the modulation of glial cell reaction to pain triggers and of their cross-talk with sensory neurons which significantly contributes to the transition from acute to chronic pain. The purinergic system has therefore become an appealing pharmacological target in pain research, also based on the quite unexpected discovery that purines are involved in ancient analgesic techniques such as acupuncture. A more in-depth understanding of the complex and intricated purine-orchestrated scenario in pain conditions will hopefully lead to the identification and clinical development of new and effective analgesics.


Asunto(s)
Astrocitos/metabolismo , Dolor Crónico/metabolismo , Neuroglía/metabolismo , Receptores Purinérgicos/metabolismo , Analgésicos/administración & dosificación , Animales , Astrocitos/efectos de los fármacos , Dolor Crónico/tratamiento farmacológico , Humanos , Neuroglía/efectos de los fármacos , Agonistas Purinérgicos/administración & dosificación , Antagonistas Purinérgicos/administración & dosificación , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo
17.
Dev Cell ; 56(17): 2516-2535.e8, 2021 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-34469751

RESUMEN

The peripheral nervous system responds to a wide variety of sensory stimuli, a process that requires great neuronal diversity. These diverse neurons are closely associated with glial cells originating from the neural crest. However, the molecular nature and diversity among peripheral glia are not understood. Here, we used single-cell RNA sequencing to profile developing and mature glia from somatosensory dorsal root ganglia and auditory spiral ganglia. We found that glial precursors (GPs) in these two systems differ in their transcriptional profiles. Despite their unique features, somatosensory and auditory GPs undergo convergent differentiation to generate molecularly uniform myelinating and non-myelinating Schwann cells. By contrast, somatosensory and auditory satellite glial cells retain system-specific features. Lastly, we identified a glial signature gene set, providing new insights into commonalities among glia across the nervous system. This survey of gene expression in peripheral glia constitutes a resource for understanding functions of glia across different sensory modalities.


Asunto(s)
Diferenciación Celular/genética , Cresta Neural/citología , Neuroglía/metabolismo , Células de Schwann/metabolismo , Análisis de Secuencia de ARN , Animales , Secuencia de Bases/genética , Diferenciación Celular/fisiología , Ratones Transgénicos , Neuronas/metabolismo , Análisis de Secuencia de ARN/métodos
18.
Brain Neurosci Adv ; 2: 2398212818817495, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-32166166

RESUMEN

The name neuroglia is generally translated as nerve glue. In the recent past, this has been used to describe passive structural cells. Presently, this view has been challenged and the true dynamic and multifunctional nature of neuroglia is beginning to be appreciated. In the central nervous system, the main kinds of neuroglia are astrocytes (the primary homeostatic cells that ensure synaptic transmission), oligodendrocytes (which form the myelin that ensures rapid electrical transmission) and microglia (the main immune cells). In the peripheral nervous system, neuroglia comprise Schwann cells, satellite glia and enteric glia. These functionally diverse and specialised cells are fundamental to function at the molecular, cellular, tissue and system levels. Without nerve glue, the body cannot function and the future will begin to unlock their importance in higher cognitive functions that set humans apart from other animals and their true potential as therapeutic targets in neurodegenerative and other diseases.

19.
Neurosci Bull ; 34(1): 85-97, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28534262

RESUMEN

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.


Asunto(s)
Ganglios Simpáticos/patología , Inflamación Neurogénica/etiología , Dolor/etiología , Dolor/patología , Traumatismos de los Nervios Periféricos/complicaciones , Potenciales de Acción/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Hiperalgesia/etiología , Ligadura/efectos adversos , Macrófagos/patología , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo
20.
Neurochem Int ; 112: 259-266, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28827078

RESUMEN

Human immunodeficiency virus (HIV) envelope glycoprotein (glycoprotein 120, gp120) can induce chronic neuropathic pain by directly stimulating primary sensory afferent neurons. Activation of satellite glial cells (SGCs) in dorsal root ganglia (DRG) plays an important role in the transmission of neuropathic pain. The P2Y12 receptor is expressed in SGCs of DRG. In this study, we investigated the role of the P2Y12 receptor in HIV gp120-induced neuropathic pain. The results showed that peripheral nerve exposure to HIV gp120 increased mechanical and thermal hyperalgesia in gp120-treated model rats. The gp120 treatment increased the expression of P2Y12 mRNA and protein in DRG SGCs. Treatment with P2Y12 short hairpin RNA (shRNA) in DRG SGCs decreased the upregulated expression of P2Y12 mRNA and protein in DRG SGCs as well as relieved mechanical and thermal hyperalgesia in gp120-treated rats. Reduction of P2Y12 receptor decreased co-expression of P2Y12 and glial fibrillary acidic protein (GFAP), expression of GFAP, interleukin (IL)-1ß, tumor necrosis factor (TNF)-receptor 1 (TNF-R1), and phosphorylation of Akt (p-Akt) proteins in DRG of gp120-treated rats. Upregulation of GFAP is a marker of SGC activation. Therefore, P2Y12 shRNA treatment decreased HIV gp120-induced mechanical and thermal hyperalgesia in gp120-treated rats.


Asunto(s)
Proteína gp120 de Envoltorio del VIH/toxicidad , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , ARN Interferente Pequeño/administración & dosificación , Receptores Purinérgicos P2/administración & dosificación , Animales , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Masculino , Neuralgia/metabolismo , ARN Interferente Pequeño/biosíntesis , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2/biosíntesis , Receptores Purinérgicos P2Y12 , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA