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1.
Sci Rep ; 13(1): 282, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609414

RESUMO

Neuroinflammation is a hallmark of hypoxic-ischemic injury and can be characterized by the activation of glial cells and the expression of inflammatory cytokines and chemokines. Interleukin (IL)-1ß and tumor necrosis factor (TNF)α are among the best-characterized early response cytokines and are often expressed concurrently. Several types of central nervous system cells secrete IL-1ß and TNFα, including microglia, astrocytes, and neurons, and these cytokines convey potent pro-inflammatory actions. Chemokines also play a central role in neuroinflammation by controlling inflammatory cell trafficking. Our aim was to characterise the evolution of early neuroinflammation in the neonatal piglet model of hypoxic-ischemic encephalopathy (HIE). Piglets (< 24 h old) were exposed to HI insult, and recovered to 2, 4, 8, 12 or 24H post-insult. Brain tissue from the frontal cortex and basal ganglia was harvested for assessment of glial cell activation profiles and transcription levels of inflammatory markers in HI piglets with comparison to a control group of newborn piglets. Fluorescence microscopy was used to observe microglia, astrocytes, neurons, degenerating neurons and possibly apoptotic cells, and quantitative polymerase chain reaction was used to measure gene expression of several cytokines and chemokines. HI injury was associated with microglial activation and morphological changes to astrocytes at all time points examined. Gene expression analyses of inflammation-related markers revealed significantly higher expression of pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin 1 beta (IL-1ß), chemokines cxc-chemokine motif ligand (CXCL)8 and CXCL10, and anti-inflammatory cytokine transforming growth factor (TGF)ß in every HI group, with some region-specific differences noted. No significant difference was observed in the level of C-X-C chemokine receptor (CCR)5 over time. This high degree of neuroinflammation was associated with a reduction in the number of neurons in piglets at 12H and 24H in the frontal cortex, and the putamen at 12H. This reduction of neurons was not associated with increased numbers of degenerating neurons or potentially apoptotic cells. HI injury triggered a robust early neuroinflammatory response associated with a reduction in neurons in cortical and subcortical regions in our piglet model of HIE. This neuroinflammatory response may be targeted using novel therapeutics to reduce neuropathology in our piglet model of neonatal HIE.


Assuntos
Citocinas , Hipóxia-Isquemia Encefálica , Animais , Suínos , Citocinas/metabolismo , Animais Recém-Nascidos , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Neuroglia/metabolismo , Encéfalo/metabolismo , Hipóxia/metabolismo , Microglia/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Fator de Crescimento Transformador beta/metabolismo , Inflamação/patologia
2.
Commun Biol ; 6(1): 40, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639529

RESUMO

Astrocytes are resident glial cells of the central nervous system (CNS) that play complex and heterogeneous roles in brain development, homeostasis and disease. Since their vast involvement in health and disease is becoming increasingly recognized, suitable and reliable tools for studying these cells in vivo and in vitro are of utmost importance. One of the key challenges hereby is to adequately mimic their context-dependent in vivo phenotypes and functions in vitro. To better understand the spectrum of astrocytic variations in defined settings we performed a side-by-side-comparison of murine embryonic stem cell (ESC)-derived astrocytes as well as primary neonatal and adult astrocytes, revealing major differences on a functional and transcriptomic level, specifically on proliferation, migration, calcium signaling and cilium activity. Our results highlight the need to carefully consider the choice of astrocyte origin and phenotype with respect to age, isolation and culture protocols based on the respective biological question.


Assuntos
Astrócitos , Neuroglia , Animais , Camundongos , Astrócitos/fisiologia , Diferenciação Celular , Sistema Nervoso Central , Células-Tronco Embrionárias
3.
Curr Protoc ; 3(1): e654, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36688682

RESUMO

Glial cells are the support cells of the nervous system. Glial cells typically have elaborate morphologies that facilitate close contacts with neighboring neurons, synapses, and the vasculature. In the retina, Müller glia (MG) are the principal glial cell type that supports neuronal function by providing a myriad of supportive functions via intricate cell morphologies and precise contacts. Thus, complex glial morphology is critical for glial function, but remains challenging to resolve at a sub-cellular level or reproducibly quantify in complex tissues. To address this issue, we developed GliaMorph as a Fiji-based macro toolkit that allows 3D glial cell morphology analysis in the developing and mature retina. As GliaMorph is implemented in a modular fashion, here we present guides to (a) setup of GliaMorph, (b) data understanding in 3D, including z-axis intensity decay and signal-to-noise ratio, (c) pre-processing data to enhance image quality, (d) performing and examining image segmentation, and (e) 3D quantification of MG features, including apicobasal texture analysis. To allow easier application, GliaMorph tools are supported with graphical user interfaces where appropriate, and example data are publicly available to facilitate adoption. Further, GliaMorph can be modified to meet users' morphological analysis needs for other glial or neuronal shapes. Finally, this article provides users with an in-depth understanding of data requirements and the workflow of GliaMorph. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Download and installation of GliaMorph components including example data Basic Protocol 2: Understanding data properties and quality 3D-essential for subsequent analysis and capturing data property issues early Basic Protocol 3: Pre-processing AiryScan microscopy data for analysis Alternate Protocol: Pre-processing confocal microscopy data for analysis Basic Protocol 4: Segmentation of glial cells Basic Protocol 5: 3D quantification of glial cell morphology.


Assuntos
Neuroglia , Retina , Fiji , Neuroglia/fisiologia , Neurônios
4.
Biol Pharm Bull ; 46(1): 102-110, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36596518

RESUMO

Peripheral neuropathy is one of the major adverse effects that limit the clinical application of bortezomib (BTZ). However, the underlying mechanisms of BTZ-induced peripheral neuropathy (BIPN) remain elusive. To examine cell types potentially involved in the development of BIPN, we used four purified cultures of cells of the peripheral nervous system: Schwann cells (SCs), satellite glial cells (SGCs), macrophages, and dorsal root ganglion (DRG) neurons. Administration of a low BTZ concentration (5 nM; similar to concentrations in clinical use) caused dedifferentiation of cultured SCs, returning mature SCs to an immature state. In cultured SGCs, BTZ increased glial fibrillary acidic protein (GFAP) levels without inducing the release of inflammatory cytokines or chemokines. In macrophages, BTZ caused little inflammatory response. Finally, in DRG neurons, BTZ strongly suppressed the expression levels of sensor and transducer ion channels without affecting cell morphology. Taken together, low concentrations of BTZ can cause SC dedifferentiation (i.e., demyelination), increased GFAP level in SGC, and decreased expression levels of sensor and transducer ion channels in DRG neurons (i.e., numbness feeling). Thus, we have reported, for the first time, specific effects of BTZ on peripheral nervous system cells, thereby contributing to a better understanding of the initiating mechanism of BIPN.


Assuntos
Gânglios Espinais , Doenças do Sistema Nervoso Periférico , Humanos , Bortezomib/efeitos adversos , Gânglios Espinais/metabolismo , Neurônios , Neuroglia/metabolismo , Células de Schwann/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Macrófagos/metabolismo , Canais Iônicos
5.
Sci Rep ; 13(1): 633, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635325

RESUMO

Microglial cells are the primary resident immune cells in the retina. In healthy adults, they are ramified; that is, they have extensive processes that move continually. In adult retinas, microglia maintain the normal structure and function of neurons and other glial cells, but the mechanism underlying this process is not well-understood. In the mouse hippocampus, microglia engulf small pieces of axons and presynaptic terminals via a process called trogocytosis. Here we report that microglia in the adult macaque retina also engulf pieces of neurons and glial cells, but not at sites of synapses. We analyzed microglia in a volume of serial, ultrathin sections of central macaque retina in which many neurons that ramify in the inner plexiform layer (IPL) had been reconstructed previously. We surveyed the IPL and identified the somas of microglia by their small size and scant cytoplasm. We then reconstructed the microglia and studied their interactions with other cells. We found that ramified microglia frequently ingested small pieces of each major type of inner retinal neuron and Müller glial cells via trogocytosis. There were a few instances where the interactions took place near synapses, but the synapses, themselves, were never engulfed. If trogocytosis by retinal microglia plays a role in synaptic remodeling, it was not apparent from the ultrastructure. Instead, we propose that trogocytosis enables these microglia to present antigens derived from normal inner retinal cells and, when activated, they would promote antigen-specific tolerance.


Assuntos
Microglia , Neurônios Retinianos , Animais , Camundongos , Microglia/fisiologia , Trogocitose , Retina , Neuroglia
6.
J Neural Eng ; 20(1)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36608343

RESUMO

Objective. Regeneration of damaged nerves is required for recovery following nervous system injury. While neural cell behavior may be modified by neuromodulation techniques, the impact of static direct current (DC) magnetic stimulation remains unclear.Approach. This study quantifies the effects of DC magnetostimulation on primary neuronal outgrowthin vitro. The extension of neurites of dorsal root ganglia (DRG) subjected to two different low-strength (mT) static magnetic flux configurations was investigated.Main results. After 3 d of 1 h in-plane (IP) magnetic field stimulation, a 62.5% increase in neurite outgrowth area was seen relative to unstimulated controls. The combined action of in-plane + out-of-plane (IP + OOP) magnetic field application produced a directional outgrowth bias parallel to the IP field direction. At the same time, the diverse magnetic field conditions produced no changes in two soluble neurotrophic factors, nerve growth factor and brain-derived neurotrophic factor, released from resident glia.Significance. These results demonstrate the potential for DC magnetostimulation to enhance neuronal regrowth and improve clinical outcomes.


Assuntos
Neuritos , Neurônios , Neuritos/fisiologia , Neuroglia , Campos Magnéticos , Crescimento Neuronal/fisiologia , Gânglios Espinais/fisiologia , Células Cultivadas , Regeneração Nervosa
7.
Biol Open ; 12(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36625299

RESUMO

Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2α (HIF2α) are both essential for retinal astrocyte and vascular development. Tlx-/- mutation and astrocyte specific Hif2α disruption in Hif2αf/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2α support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states. While Tlx+/- and Hif2αf/+/GFAPCre mice are phenotypically normal, Tlx+/-/Hif2αf/+/GFAPCre mice display precocious retinal astrocyte differentiation towards non-angiogenic states, along with significantly reduced retinal angiogenesis. In wild-type mice, TLX and HIF2α coexist in the same protein complex, suggesting a cooperative function under physiological conditions. Furthermore, astrocyte specific disruption of Phd2 (prolyl hydroxylase domain protein 2), a manipulation previously shown to cause HIF2α accumulation, did not rescue retinal angiogenesis in Tlx-/- background, which suggests functional dependence of HIF2α on TLX. Finally, the expression of fibronectin and VEGF-A is significantly reduced in retinal astrocytes of neonatal Tlx+/-/Hif2αf/+/GFAPCre mice. Overall, these data indicate that TLX and HIF2α cooperatively support retinal angiogenesis by maintaining angiogenic potential of retinal astrocytes.


Assuntos
Astrócitos , Neuroglia , Animais , Camundongos , Astrócitos/metabolismo , Animais Recém-Nascidos , Retina/metabolismo , Hipóxia/metabolismo
8.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675113

RESUMO

Both astrocytic and microglial functions have been extensively investigated in healthy subjects and neurodegenerative diseases. For astrocytes, not only various sub-types were identified but phagocytic activity was also clarified recently and is making dramatic progress. In this review paper, we mostly focus on the functional role of astrocytes in the extracellular matrix and on interactions between reactive astrocytes and reactive microglia in normal states and in neurodegenerative diseases, because the authors feel it is necessary to elucidate the mechanisms among activated glial cells in the pathology of neurological diseases in order to pave the way for drug discovery. Finally, we will review cyclic phosphatidic acid (cPA), a naturally occurring phospholipid mediator that induces a variety of biological activities in the brain both in vivo and in vitro. We propose that cPA may serve as a novel therapeutic molecule for the treatment of brain injury and neuroinflammation.


Assuntos
Microglia , Doenças Neurodegenerativas , Humanos , Microglia/patologia , Astrócitos/patologia , Doenças Neurodegenerativas/patologia , Sistema Nervoso Central , Neuroglia , Ácidos Fosfatídicos
9.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675275

RESUMO

Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.


Assuntos
Neuralgia , Traumatismos da Medula Espinal , Feminino , Camundongos , Animais , Doenças Neuroinflamatórias , Medula Espinal , Neuralgia/complicações , Neuroglia , Traumatismos da Medula Espinal/complicações
10.
Medicine (Baltimore) ; 102(1): e32653, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607875

RESUMO

Diabetic peripheral neuropathy (DPN) is the most common neuropathy in the world, mainly manifested as bilateral symmetry numbness, pain or paresthesia, with a high rate of disability and mortality. Schwann cells (SCs), derived from neural ridge cells, are the largest number of glial cells in the peripheral nervous system, and play an important role in DPN. Studies have found that SCs are closely related to the pathogenesis of DPN, such as oxidative stress, endoplasmic reticulum stress, inflammation, impaired neurotrophic support and dyslipidemia. This article reviews the mechanism of SCs in DPN.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Humanos , Estresse Oxidativo , Células de Schwann/patologia , Neuroglia/patologia , Diabetes Mellitus/patologia
11.
PLoS Genet ; 19(1): e1010581, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36626385

RESUMO

Glial cells play a critical role in maintaining homeostatic ion concentration gradients. Salt-inducible kinase 3 (SIK3) regulates a gene expression program that controls K+ buffering in glia, and upregulation of this pathway suppresses seizure behavior in the eag, Shaker hyperexcitability mutant. Here we show that boosting the glial SIK3 K+ buffering pathway suppresses seizures in three additional molecularly diverse hyperexcitable mutants, highlighting the therapeutic potential of upregulating glial K+ buffering. We then explore additional mechanisms regulating glial K+ buffering. Fray, a transcriptional target of the SIK3 K+ buffering program, is a kinase that promotes K+ uptake by activating the Na+/K+/Cl- co-transporter, Ncc69. We show that the Wnk kinase phosphorylates Fray in Drosophila glia and that this activity is required to promote K+ buffering. This identifies Fray as a convergence point between the SIK3-dependent transcriptional program and Wnk-dependent post-translational regulation. Bypassing both regulatory mechanisms via overexpression of a constitutively active Fray in glia is sufficient to robustly suppress seizure behavior in multiple Drosophila models of hyperexcitability. Finally, we identify cortex glia as a critical cell type for regulation of seizure susceptibility, as boosting K+ buffering via expression of activated Fray exclusively in these cells is sufficient to suppress seizure behavior. These findings highlight Fray as a key convergence point for distinct K+ buffering regulatory mechanisms and cortex glia as an important locus for control of neuronal excitability.


Assuntos
Proteínas de Drosophila , Animais , Proteínas de Drosophila/genética , Neuroglia/metabolismo , Neurônios/metabolismo , Drosophila/metabolismo , Convulsões/genética , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Proteínas Serina-Treonina Quinases/genética
12.
Methods Mol Biol ; 2593: 283-305, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36513939

RESUMO

There is a growing interest in expanding the multiplexing capability of immunohistochemistry to achieve a deeper phenotyping of various cell types in health and disease. Here, we describe a protocol of cyclic multiplex fluorescent immunohistochemistry that enables the labeling of up to 16 antigens on the same formalin-fixed paraffin-embedded section using "off-the-shelf," commercially available, primary antibodies as well as fluorescently conjugated secondary antibodies. Key steps include the denaturing/stripping of the antibodies by microwaving and the quenching of any remaining fluorescent signal between the cycles of otherwise traditional multiplexed fluorescent immunohistochemistry. We have successfully applied this protocol to characterize astrocytic and microglial responses to Aß plaques and neurofibrillary tangles in Alzheimer's disease brains, but it could be easily adapted to other user's needs regarding cell types, disease, and organ.


Assuntos
Doença de Alzheimer , Humanos , Imuno-Histoquímica , Inclusão em Parafina , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Neuroglia/metabolismo , Formaldeído/metabolismo , Fenótipo
13.
Methods Mol Biol ; 2561: 105-133, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36399267

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disorder and a mechanistically complex disease. For the last decade, human models of AD using induced pluripotent stem cells (iPSCs) have emerged as a powerful way to understand disease pathogenesis in relevant human cell types. In this review, we summarize the state of the field and how this technology can apply to studies of both familial and sporadic studies of AD. We discuss patient-derived iPSCs, genome editing, differentiation of neural cell types, and three-dimensional organoids, and speculate on the future of this type of work for increasing our understanding of, and improving therapeutic development for, this devastating disease.


Assuntos
Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Neurônios/patologia , Neuroglia/patologia , Organoides/patologia
14.
Am J Physiol Gastrointest Liver Physiol ; 324(2): G115-G130, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36511517

RESUMO

Proteolipid protein 1 (Plp1) is highly expressed in enteric glia, labeling cells throughout the mucosa, muscularis, and the extrinsic innervation. Plp1 is a major constituent of myelin in the central and peripheral nervous systems, but the absence of myelin in the enteric nervous system (ENS) suggests another role for Plp1 in the gut. Although the functions of enteric glia are still being established, there is strong evidence that they regulate intestinal motility and permeability. To interrogate the role of Plp1 in enteric glia, we investigated gut motility, secretomotor function and permeability, and evaluated the ENS in mice lacking Plp1. We studied two time points: ∼3 mo (young) and >1 yr (old). Old Plp1 null mice exhibited increased fecal output, decreased fecal water content, faster whole gut transit times, reduced intestinal permeability, and faster colonic migrating motor complexes. Interestingly, in both young and old mice, the ENS exhibited normal glial and neuronal numbers as well as glial arborization density in the absence of Plp1. As Plp1-associated functions involve mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mapk/Erk1/2) signaling and Mapk/Erk1/2 are reported to have a regulatory role in intestinal motility, we measured protein expression of Erk1/2 and its active form in the small intestine. Old Plp1 null mice had reduced levels of phosphorylated-Erk1/2. Although Plp1 is not required for the normal appearance of enteric glial cells, it has a regulatory role in intestinal motility and barrier function. Our results suggest that functional changes mediated by Plp1-expressing enteric glia may involve Erk1/2 activation.NEW & NOTEWORTHY Here, we describe that Plp1 regulates gut motility and barrier function. The functional effects of Plp1 eradication are only seen in old mice, not young. The effects of Plp1 appear to be mediated through the Erk1/2 pathway.


Assuntos
Sistema Nervoso Entérico , Neurônios , Camundongos , Animais , Neurônios/metabolismo , Neuroglia/metabolismo , Sistema Nervoso Entérico/fisiologia , Motilidade Gastrointestinal/fisiologia , Camundongos Knockout , Proteolipídeos/metabolismo , Proteolipídeos/farmacologia
15.
Dis Model Mech ; 16(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36518009

RESUMO

Bone morphogenetic protein (BMP)4 plays a critical role in regulating neuronal and glial activity in the course of spinal cord injury (SCI). The underlying cause and cellular source of BMP4 accumulation at the injured spinal cord remain unclear. Here, we observed that plasma BMP4 levels are statistically higher in SCI patients than in healthy donors. When comparing rats in the sham group (T9 laminectomy without SCI) with rats in the SCI group, we found a persistent decline in BBB scores, together with necrosis and mononuclear cell accumulation at the contusion site. Moreover, during 2 weeks after SCI both plasma and cerebrospinal fluid levels of BMP4 displayed notable elevation, and a positive correlation. Importantly, percentages of circulating BMP4-positive (BMP4+) monocytes and infiltrating MDMs were higher in the SCI group than in the sham group. Finally, in the SCI+clodronate liposome group, depletion of monocytes effectively attenuated the accumulation of both BMP4+ MDMs and BMP4 in the injured spinal cord. Our results indicated that, following SCI, infiltrating MDMs provide an important source of BMP4 in the injured spinal cord and, therefore, might serve as a potential therapeutic target.


Assuntos
Monócitos , Traumatismos da Medula Espinal , Ratos , Animais , Monócitos/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/metabolismo , Neurônios/metabolismo , Neuroglia/metabolismo , Proteína Morfogenética Óssea 4/metabolismo
16.
Acta Histochem ; 125(1): 151985, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36495673

RESUMO

The P2X7 receptor participates in several intracellular events and acts with the pannexin-1 channel. This study examined the effects of probenecid (PB) and brilliant blue G (BBG), which are antagonists of the pannexin-1 channel and P2X7 receptor, respectively, on rat ileum enteric glial cells after on ischemia and reperfusion. The ileal vessels were occluded for 45 min with nontraumatic vascular tweezers, and reperfusion was performed for periods of 24 h and 14 and 28 days. After ischemia (IR groups), the animals were treated with BBG (BG group) or PB (PB group). The double-labeling results demonstrated the following: the P2X7 receptor was present in enteric glial cells (S100ß) and enteric neurons positive for HuC/D; enteric glial cells exhibited different phenotypes; some enteric glial cells were immunoreactive to only S100ß or GFAP; and the pannexin-1 channel was present in enteric glial cells (GFAP). Density (in cells/cm2) analyses showed that the IR group exhibited a decrease in the number of cells immunoreactive for the P2X7 receptor, pannexin-1, and HuC/D and that treatment with BBG or PB resulted in the recovery of the numbers of these cells. The number of glial cells (S100ß and GFAP) was higher in the IR group, and the treatments decreased the number of these cells to the normal value. However, the PB group did not exhibit recovery of S100ß-positive glia. The cell profile area (µm2) of S100ß-positive enteric glial cells decreased to the normal value after BBG treatment, whereas no recovery was observed in the PB group. The ileum contractile activity was decreased in the IR group and returned to baseline in the BG and PB groups. BBG and PB can effectively induce the recovery of neurons and glia cells and are thus potential therapeutic agents in the treatment of gastrointestinal tract diseases.


Assuntos
Probenecid , Receptores Purinérgicos P2X7 , Ratos , Animais , Probenecid/farmacologia , Ratos Wistar , Neuroglia , Reperfusão , Isquemia
17.
Proc Natl Acad Sci U S A ; 120(1): e2210967120, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36574666

RESUMO

The convolutions of the mammalian cerebral cortex allow the enlargement of its surface and addition of novel functional areas during evolution while minimizing expansion of the cranium. Cognitive neurodevelopmental disorders in humans, including microcephaly and lissencephaly, are often associated with impaired gyrification. In the classical model of gyrification, surface area is initially set by the number of radial units, and the forces driving cortical folding include neuronal growth, formation of neuropil, glial cell intercalation, and the patterned growth of subcortical white matter. An alternative model proposes that specified neurogenic hotspots in the outer subventricular zone (oSVZ) produce larger numbers of neurons that generate convexities in the cortex. This directly contradicts reports showing that cortical neurogenesis and settling of neurons into the cortical plate in primates, including humans, are completed well prior to the formation of secondary and tertiary gyri and indeed most primary gyri. In addition, during the main period of gyrification, the oSVZ produces mainly astrocytes and oligodendrocytes. Here we describe how rapid growth of intracortical neuropil, addition of glial cells, and enlargement of subcortical white matter in primates are the primary forces responsible for the post-neurogenic expansion of the cortical surface and formation of gyri during fetal development. Using immunohistochemistry for markers of proliferation and glial and neuronal progenitors combined with transcriptomic analysis, we show that neurogenesis in the ventricular zone and oSVZ is phased out and transitions to gliogenesis prior to gyral development. In summary, our data support the classical model of gyrification and provide insight into the pathogenesis of congenital cortical malformations.


Assuntos
Córtex Cerebral , Primatas , Humanos , Animais , Córtex Cerebral/metabolismo , Neurônios , Neuroglia , Neurópilo , Mamíferos
18.
Nanoscale ; 15(2): 687-706, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36515425

RESUMO

Graphene-based materials (GBMs) have been investigated in recent years with the aim of developing flexible interfaces to address a range of neurological disorders, where electrical stimulation may improve brain function and tissue regeneration. The recent discovery that GBM electrodes can generate an electrical response upon light exposure has inspired the development of non-genetic approaches capable of selectively modulating brain cells without genetic manipulation (i.e., optogenetics). Here, we propose the conjugation of graphene with upconversion nanoparticles (UCNPs), which enable wireless transcranial activation using tissue-penetrating near-infrared (NIR) radiation. Following a design of experiments approach, we first investigated the influence of different host matrices and dopants commonly used to synthesize UCNPs in the electrical response of graphene. Two UCNP formulations achieving optimal enhancement of electrical conductivity upon NIR activation at λ = 780 or 980 nm were identified. These formulations were then covalently attached to graphene nanoplatelets following selective hydroxyl derivatization. The resulting nanocomposites were evaluated in vitro using SH-SY5Y human neuroblastoma cells. NIR activation at λ = 980 nm promoted cell proliferation and downregulated neuronal and glial differentiation markers, suggesting the potential application of GBMs in minimally invasive stimulation of cells for tissue regeneration.


Assuntos
Grafite , Nanopartículas , Neuroblastoma , Humanos , Neurônios , Neuroglia , Eletrodos
19.
Exp Neurol ; 359: 114233, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36174748

RESUMO

Müller glia are a cellular source for neuronal regeneration in vertebrate retinas. However, the capacity for retinal regeneration varies widely across species. Understanding the mechanisms that regulate the reprogramming of Müller glia into progenitor cells is key to reversing the loss of vision that occurs with retinal diseases. In the mammalian retina, NFkB signaling promotes glial reactivity and represses the reprogramming of Müller glia into progenitor cells. Here we investigate different cytokines, growth factors, cell signaling pathways, and damage paradigms that influence NFkB-signaling in the mouse retina. We find that exogenous TNF and IL1ß potently activate NFkB-signaling in Müller glia in undamaged retinas, and this activation is independent of microglia. By comparison, TLR1/2 agonist indirectly activates NFkB-signaling in Müller glia, and this activation depends on the presence of microglia as Tlr2 is predominantly expressed by microglia, but not other types of retinal cells. Exogenous FGF2 did not activate NFkB-signaling, whereas CNTF, Osteopontin, WNT4, or inhibition of GSK3ß activated NFkB in Müller glia in the absence of neuronal damage. By comparison, dexamethasone, a glucocorticoid agonist, suppressed NFkB-signaling in Müller glia in damaged retinas, in addition to reducing numbers of dying cells and the accumulation of reactive microglia. Although NMDA-induced retinal damage activated NFkB in Müller glia, optic nerve crush had no effect on NFkB activation within the retina, whereas glial cells within the optic nerve were responsive. We conclude that the NFkB pathway is activated in retinal Müller glia in response to many different cell signaling pathways, and activation often depends on signals produced by reactive microglia.


Assuntos
Células Ependimogliais , Microglia , Animais , Camundongos , Microglia/metabolismo , Citocinas/metabolismo , NF-kappa B/metabolismo , Neuroglia/metabolismo , Retina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proliferação de Células , Mamíferos
20.
Exp Neurol ; 359: 114273, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36375510

RESUMO

The mechanism of neuropathic pain after spinal cord injury is complex, and the communication between neurons, glia, and blood vessels in neurovascular units significantly affects the occurrence and development of neuropathic pain. After spinal cord injury, a domino chain reaction occurs in the neuron-glia-vessel, which affects the permeability of the blood-spinal cord barrier and jointly promotes the development of neuroinflammation. This article discusses the signal transduction between neuro-glial-endothelial networks from a multidimensional point of view and reviews its role in neuropathic pain after spinal cord injury.


Assuntos
Neuralgia , Traumatismos da Medula Espinal , Humanos , Neuralgia/etiologia , Traumatismos da Medula Espinal/complicações , Neuroglia/fisiologia , Medula Espinal , Neurônios
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