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1.
Analyst ; 146(2): 454-462, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33491017

RESUMO

Neuronal cell microengineering involving micropatterning and polydimethylsiloxane (PDMS) microfluidics enables promising advances in microscale neuron control. However, a facile methodology for the precise and effective manipulation of neurons on a cell-repellent PDMS substrate remains challenging. Herein, a simple and straightforward strategy for neuronal cell patterning and neuronal network construction on PDMS based on microfluidics-assisted modification of functionalized Pluronic is described. The cell patterning process simply involves a one-step microfluidic modification and routine in vitro culture. It is demonstrated that multiple types of neuronal cell arrangements with various spatial profiles can be conveniently produced using this patterning tool. The precise control of neuronal cells with high patterning fidelity up to single cell resolution, as well as high adhesion and differentiation, is achieved too. Furthermore, neuronal network construction using the respective cell population and single cell patterning prove to be applicable. This achievement provides a convenient and feasible methodology for engineering neuronal cells on PDMS substrates, which will be useful for applications in many neuron-related microscale analytical research fields, including cell engineering, neurobiology, neuropharmacology, and neuronal sensing.


Assuntos
Engenharia Celular/instrumentação , Dimetilpolisiloxanos/química , Dimetilpolisiloxanos/farmacologia , Dispositivos Lab-On-A-Chip , Rede Nervosa/citologia , Neurônios/citologia , Poloxâmero/química , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Imagem Óptica
2.
PLoS One ; 15(7): e0236050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678832

RESUMO

Neurotrophic factors have been regarded having promising potentials for neuronal protection and regeneration, and thus promoting beneficial effects of kinesiological functions. They can be suspected to play important roles in cell/tissue grafting for various neural diseases. The clinical applications of such trophic factors to the central nervous system (CNS), however, have caused problematic side effects on account of the distinctive bioactive properties. In the course of developing synthetic compounds reflecting beneficial properties of basic fibroblast growth factor (bFGF), we conducted screening candidates that stimulate to trigger the intracellular tyrosine phosphorylation of FGF receptor and lead to the subsequent intracellular signaling in neurons. A small synthetic molecule SUN13837 was characterized by mimicking the beneficial properties of bFGF, which have been known as its specific activities when applied to CNS. What is more remarkable is that SUN13837 is eliminated the bioactivity to induce cell proliferation of non-neuronal somatic cells. On the bases of studies of pharmacology, behavior, physiology and histology, the present study reports that SUN13837 is characterized as a promising synthetic compound for treatment of devastating damages onto the rat spinal cord.


Assuntos
Materiais Biomiméticos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Feminino , Crescimento Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
3.
Life Sci ; 256: 117959, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32531375

RESUMO

Resveratrol has the ability to promote functional recovery after sciatic nerve crush injury (SNCI), though the mechanism through which this occurs in not fully understood. Resveratrol can promote autophagy, a key process in Wallerian degeneration; thus, we hypothesized that resveratrol could promote recovery from SNCI by promoting Schwann cell autophagy and acceleration of Wallerian degeneration. Motor function recovery was assessed by calculating Sciatic Function Indexes (SFIs) at days 7, 14, 21, 28 post SNCI. Autophagy and myelin clearance were assessed by microtubule-associated protein light chain 3B (LC3B) and myelin protein zero (MPZ) immunofluorescence and Western blot analysis on the fourth day after SNCI. The autophagy of Schwann cells following resveratrol administration was quantified by immunofluorescence in RSC96 cells. Immunofluorescence and Transmission electron microscopy (TEM) were also used in Resveratrol treated sciatic nerve four days post-SNCI to find LC3B positive areas and typical double membrane structures represent for autophagy. The SNCI+resveratrol (crush+Res) groups recovered faster than the SNCI+vehicles (crush+V) group. On day four, almost all of the myelin had regenerated in the crush+Res rats, while the crush+V group's myelin remained intact and the expression levels of LC3-II/I was the highest. On day 28 post-injury, both the control and crush+Res groups' myelin neurofibers reached peak numbers as did the thickness of the myelin sheath. Both in vitro and in vivo immunofluorescence showed that LC3B was colocalized with Schwann cells. This is the first study to observe that resveratrol can promote recovery from SCNI by accelerating the myelin clearance process by promoting autophagy of Schwann cells.


Assuntos
Autofagia/efeitos dos fármacos , Lesões por Esmagamento/fisiopatologia , Compressão Nervosa , Recuperação de Função Fisiológica/efeitos dos fármacos , Resveratrol/farmacologia , Células de Schwann/patologia , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Lesões por Esmagamento/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora/efeitos dos fármacos , Proteína P0 da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Regeneração Nervosa/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Nervo Isquiático/efeitos dos fármacos
5.
Invest Ophthalmol Vis Sci ; 61(5): 51, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32460313

RESUMO

Purpose: The purpose of this study was to determine if treatment with telmisartan, an angiotensin II type 1 receptor blocker (ARB), protects against retinal ganglion cell (RGC) degeneration in a mouse glaucoma model with induced elevation of intraocular pressure (IOP). Methods: IOP elevation was induced by injection of polystyrene microbeads into the anterior chamber of the right eye of 3-month-old C57BL/6J mice, with the left eye serving as contralateral control. Starting the day of microbead injection, mice were maintained on solid food pellets with or without incorporated telmisartan. IOP was measured by Tono Lab tonometry prior to and weekly after microbead injection. Twelve weeks postinjection, mice were euthanized to obtain optic nerves for analysis of RGC axons. The total numbers of optic nerve axons were determined manually and automatedly using AxonJ. Degenerating axons were counted manually. Results: IOP elevation induced by microbead injection was similar in magnitude and duration in vehicle and telmisartan-fed mice, although IOP was reduced 5.8% in uninjected mice treated with telmisartan (P = 0.0027). Axon loss determined by manual and automated methods was greater in vehicle compared to telmisartan-treated mice (manual: 9.5% vs. 1.8%, P = 0.044; automated: 14.2% vs. 2.9%, P = 0.0375). An increase in the percent of axons undergoing degeneration was observed in nerves from microbead-injected eyes that was greater in vehicle-treated compared to telmisartan-treated mice (49.0% vs. -0.58%, P = 0.0019). Conclusions: Elevation of IOP by microbead injection led to loss of RGC axons in vehicle-treated mice that was largely prevented by telmisartan treatment, suggesting a neuroprotective effect of telmisartan.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Axônios/efeitos dos fármacos , Axônios/patologia , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
6.
Sci Rep ; 10(1): 7815, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385407

RESUMO

A high-resolution, three-dimensional, optical imaging technique for the murine brain was developed to identify the effects of different therapeutic windows for preclinical brain research. This technique tracks the same cells over several weeks. We conducted a pilot study of a promising drug to treat diffuse axonal injury (DAI) caused by traumatic brain injury, using two different therapeutic windows, as a means to demonstrate the utility of this novel longitudinal imaging technique. DAI causes immediate, sporadic axon damage followed by progressive secondary axon damage. We administered minocycline for three days commencing one hour after injury in one treatment group and beginning 72 hours after injury in another group to demonstrate the method's ability to show how and when the therapeutic drug exerts protective and/or healing effects. Fewer varicosities developed in acutely treated mice while more varicosities resolved in mice with delayed treatment. For both treatments, the drug arrested development of new axonal damage by 30 days. In addition to evaluation of therapeutics for traumatic brain injury, this hybrid microlens imaging method should be useful to study other types of brain injury and neurodegeneration and cellular responses to treatment.


Assuntos
Axônios/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesão Axonal Difusa/tratamento farmacológico , Minociclina/farmacologia , Animais , Axônios/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Lesão Axonal Difusa/diagnóstico por imagem , Lesão Axonal Difusa/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Imagem Óptica
7.
Sci Rep ; 10(1): 6734, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317735

RESUMO

Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer. However, it frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is an oral antidiabetic drug. Previous studies have shown that DPP-4 inhibitors have pleiotropic effects, including neuroprotection. In this study, we investigated the effects of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models. In PC12 cells, alogliptin attenuated neurite disorders induced by oxaliplatin and cisplatin. The repeated injection of oxaliplatin caused mechanical allodynia and axonal degeneration of the sciatic nerve in rats. These neuropathies were ameliorated by co-administration of alogliptin. Moreover, alogliptin did not attenuate tumor cytotoxicity of oxaliplatin in the cultured colon, gastric, or pancreatic cancer cell lines and tumor-bearing mice. These findings suggest that alogliptin may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.


Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Hiperalgesia/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Piperidinas/farmacologia , Uracila/análogos & derivados , Aloenxertos , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuritos/efeitos dos fármacos , Neuritos/patologia , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Carga Tumoral/efeitos dos fármacos , Uracila/farmacologia
8.
J Nanobiotechnology ; 18(1): 64, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334582

RESUMO

BACKGROUND: The primary strategy to repair peripheral nerve injuries is to bridge the lesions by promoting axon regeneration. Thus, the ability to direct and manipulate neuronal cell axon regeneration has been one of the top priorities in the field of neuroscience. A recent innovative approach for remotely guiding neuronal regeneration is to incorporate magnetic nanoparticles (MNPs) into cells and transfer the resulting MNP-loaded cells into a magnetically sensitive environment to respond to an external magnetic field. To realize this intention, the synthesis and preparation of ideal MNPs is an important challenge to overcome. RESULTS: In this study, we designed and prepared novel fluorescent-magnetic bifunctional Fe3O4·Rhodamine 6G@polydopamine superparticles (FMSPs) as neural regeneration therapeutics. With the help of their excellent biocompatibility and ability to interact with neural cells, our in-house fabricated FMSPs can be endocytosed into cells, transported along the axons, and then aggregated in the growth cones. As a result, the mechanical forces generated by FMSPs can promote the growth and elongation of axons and stimulate gene expression associated with neuron growth under external magnetic fields. CONCLUSIONS: Our work demonstrates that FMSPs can be used as a novel stimulator to promote noninvasive neural regeneration through cell magnetic actuation.


Assuntos
Axônios/fisiologia , Óxido Ferroso-Férrico/química , Indóis/química , Nanopartículas de Magnetita/química , Polímeros/química , Rodaminas/química , Animais , Axônios/efeitos dos fármacos , Caderinas/genética , Caderinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Exocitose , Regulação da Expressão Gênica/efeitos dos fármacos , Indóis/farmacologia , Nanopartículas de Magnetita/toxicidade , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Regeneração Nervosa/efeitos dos fármacos , Ácido Oleico/química , Células PC12 , Polímeros/farmacologia , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Ratos
9.
Sci Rep ; 10(1): 3970, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132628

RESUMO

Paclitaxel induces peripheral neuropathy as a side effect of cancer treatment. The underlying causes are unclear, but epidermal, unmyelinated axons have been shown to be the first to degenerate. We previously utilized an in vivo zebrafish model to show that the epidermal matrix-metalloproteinase 13 (MMP-13) induces degeneration of unmyelinated axons, whereas pharmacological inhibition of MMP-13 prevented axon degeneration. However, the precise functions by which MMP-13 is regulated and affects axons remained elusive. In this study, we assessed mitochondrial damage and reactive oxygen species (ROS) formation as possible inducers of MMP-13, and we analyzed MMP-13-dependent damage. We show that the small ROS, H2O2, is increased in basal keratinocytes following treatment with paclitaxel. Cytoplasmic H2O2 appears to derive, at least in part, from mitochondrial damage, leading to upregulation of MMP-13, which in turn underlies increased epidermal extracellular matrix degradation. Intriguingly, also axonal mitochondria show signs of damage, such as fusion/fission defects and vacuolation, but axons do not show increased levels of H2O2. Since MMP-13 inhibition prevents axon degeneration but does not prevent mitochondrial vacuolation, we suggest that vacuolization occurs independently of axonal damage. Finally, we show that MMP-13 dysregulation also underlies paclitaxel-induced peripheral neuropathy in mammals, indicating that epidermal mitochondrial H2O2 and its effectors could be targeted for therapeutic interventions.


Assuntos
Epiderme/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Mitocôndrias/efeitos dos fármacos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Ativação Enzimática/efeitos dos fármacos , Epiderme/metabolismo , Mitocôndrias/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Regulação para Cima/efeitos dos fármacos , Peixe-Zebra
10.
PLoS One ; 15(3): e0230080, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155215

RESUMO

Human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) have shown potential in facilitating recovery from spinal cord injury (SCI) through communicating with microglia/macrophages (MG/MΦ). We here focused on chemokines as a candidate for the communication. Selected MG/MΦ-related chemokines were determined gene expression after SCI and further focused CCL2/CCR2 and CCL5/CCR5 to estimate role of the chemokines by hMSCs. Male C57/BL6 mice were subjected to spinal cord transection. Gene expression was assayed in the spinal cords following SCI for selected MG/MΦ-related chemokines and their receptors. hMSCs (5×105 cells) were then transplanted into parenchyma of the spinal cord, and the expressions of the Ccl2/Ccr2 and Ccl5/Ccr5 axes, inflammation, MG/MΦ-polarization, and axonal regeneration were evaluated to measure the influence of the hMSCs. Finally, mouse CCL5 was injected into the spinal cords. Acute increases in gene expression after SCI were observed for most chemokines, including Ccl2; chronic increases were observed for Ccl5. CCL2+-cells merged with NeuN+-neurons. CCR2+ immunoreactivity was principally observed in Ly-6G+/iNOS+-granulocytes on postoperative day (pod) 1, and CCL5+ and CCR5+ immunoreactivity overlapped with NeuN+-neurons and F4/80+-MG/MΦ on pod 14. The hMSC transplantation enhanced Ccl2 and Ccl5 and improved locomotor activity. The hMSC implantation did not alter the number of Ly-6G+/CCR2+ but decreased Il1, Elane, and Mpo on pod 3. Conversely, hMSC transplantation increased expression of Zc3h12a (encodes MCP-1-induced protein) on pod 14. Moreover, hMSC increased the Aif1, and two alternatively activated macrophage (AAM)-related genes, Arg1 and Chil3 (Ym1), as well as axonal regenerative markers, Dpysl2 and Gap43. Gene expression indicative of AAM polarization and axonal regeneration were partially recovered by CCL5 injection. These results suggest that hMSC implantation increases Ccl2 and Ccl5, improves locomotor activity, enhances MG/MΦ polarization to AAM, and increases the gene expression of axonal regenerative markers. These functions of hMSCs might be partially mediated by the CCL2/CCR2 and CCL5/CCR5 axes.


Assuntos
Axônios/patologia , Quimiocina CCL2/farmacologia , Quimiocina CCL5/farmacologia , Transplante de Células-Tronco Mesenquimais , Traumatismos da Medula Espinal/terapia , Animais , Axônios/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Receptores CCR2/metabolismo , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
11.
PLoS Biol ; 18(3): e3000296, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163401

RESUMO

The steady increase in the prevalence of obesity and associated type II diabetes mellitus is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of this metabolic disease. Offspring of obese dams developed glucose intolerance and displayed increased body weight, adiposity, and food intake. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were up-regulated in the hypothalamus of neonates born to obese mothers. Neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reversed leptin resistance in the offspring of obese dams.


Assuntos
Estresse do Retículo Endoplasmático , Hipotálamo/crescimento & desenvolvimento , Obesidade Materna/metabolismo , Animais , Animais Recém-Nascidos , Axônios/efeitos dos fármacos , Axônios/metabolismo , Composição Corporal , Peso Corporal , Dieta/efeitos adversos , Estresse do Retículo Endoplasmático/genética , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/embriologia , Hipotálamo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pâncreas/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Pró-Opiomelanocortina/metabolismo , Ácido Tauroquenodesoxicólico/farmacologia , alfa-MSH/metabolismo
12.
Muscle Nerve ; 61(6): 796-800, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32133655

RESUMO

INTRODUCTION: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear. METHODS: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures. RESULTS: Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P < .001), increased relative refractory period (P = .011), and caused neuromyotonia-like after-activity. Cooling exacerbated these changes and prolonged the accommodation half-time. DISCUSSION: The findings suggest that a combined effect of oxaliplatin and cooling facilitates nerve excitability changes and neuromyotonia-like after-activity in peripheral nerve axons. A possible mechanism is the slowing in gating of voltage-dependent fast sodium and slow potassium channels, which results in symptoms of cold allodynia.


Assuntos
Antineoplásicos/efeitos adversos , Axônios/fisiologia , Temperatura Baixa/efeitos adversos , Hiperalgesia/induzido quimicamente , Neurônios Motores/fisiologia , Oxaliplatina/efeitos adversos , Idoso , Axônios/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Feminino , Seguimentos , Humanos , Hiperalgesia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neurônios Motores/efeitos dos fármacos , Estudos Prospectivos , Resultado do Tratamento
13.
Sci China Life Sci ; 63(9): 1-10, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32201927

RESUMO

Optic neuropathies lead to blindness; the common pathology is the degeneration of axons of the retinal ganglion cells. In this study, we used a rat model of retinal ischemia-reperfusion and a one-time intravitreal brain-derived neurotrophic factor (BDNF) injection; then we examined axon transportation function, continuity, physical presence of axons in different part of the optic nerve, and the expression level of proteins involved in axon transportation. We found that in the disease model, axon transportation was the most severely affected, followed by axon continuity, then the number of axons in the distal and proximal optic nerve. BDNF treatment relieved all reductions and significantly restored function. The molecular changes were more minor, probably due to massive gliosis of the optic nerve, so interpretation of protein expression data should be done with some caution. The process in this acute model resembles a fast-forward of changes in the chronic model of glaucoma. Therefore, impairment in axon transportation appears to be a common early process underlying different optic neuropathies. This research on effective intervention can be used to develop interventions for all optic neuropathies targeting axon transportation.


Assuntos
Transporte Axonal/efeitos dos fármacos , Axônios/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Pressão Intraocular/efeitos dos fármacos , Animais , Escala de Avaliação Comportamental , Cegueira/prevenção & controle , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Modelos Animais de Doenças , Glaucoma/metabolismo , Injeções Intraoculares , Masculino , Nervo Óptico/metabolismo , Ratos Sprague-Dawley , Retina/metabolismo , Células Ganglionares da Retina/metabolismo
14.
Int J Nanomedicine ; 15: 315-332, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021182

RESUMO

Purpose: The clinical outcome of spinal cord injury is usually poor due to the lack of axonal regeneration and glia scar formation. As one of the most classical supporting cells in neural regeneration, Schwann cells (SCs) provide bioactive substrates for axonal migration and release molecules that regulate axonal growth. However, the effect of SC transplantation is limited by their poor migration capacity in the astrocyte-rich central nervous system. Methods: In this study, we first magnetofected SCs with chondroitinase ABC-polyethylenimine functionalized superparamagnetic iron oxide nanoparticles (ChABC/PEI-SPIONs) to induce overexpression of ChABC for the removal of chondroitin sulfate proteoglycans. These are inhibitory factors and forming a dense scar that acts as a barrier to the regenerating axons. In vitro, we observed the migration of SCs in the region of astrocytes after the application of a stable external magnetic field. Results: We found that magnetofection with ChABC/PEI-SPIONs significantly up-regulated the expression of ChABC in SCs. Under the driven effect of the directional magnetic field (MF), the migration of magnetofected SCs was enhanced in the direction of the magnetic force. The number of SCs with ChABC/PEI-SPIONs migrated and the distance of migration into the astrocyte region was significantly increased. The number of SCs with ChABC/PEI-SPIONs that migrated into the astrocyte region was 11.6- and 4.6-fold higher than those observed for the intact control and non-MF groups, respectively. Furthermore, it was found that SCs with ChABC/PEI-SPIONs were in close contact with astrocytes and no longer formed boundaries in the presence of MF. Conclusion: The mobility of the SCs with ChABC/PEI-SPIONs was enhanced along the axis of MF, holding the potential to promote nerve regeneration by providing a bioactive microenvironment and relieving glial obstruction to axonal regeneration in the treatment of spinal cord injury.


Assuntos
Astrócitos/fisiologia , Condroitina ABC Liase/metabolismo , Nanopartículas de Magnetita/uso terapêutico , Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Animais , Astrócitos/citologia , Axônios/efeitos dos fármacos , Movimento Celular , Células Cultivadas , Condroitina ABC Liase/genética , Condroitina ABC Liase/farmacologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Feminino , Campos Magnéticos , Nanopartículas de Magnetita/química , Masculino , Regeneração Nervosa/efeitos dos fármacos , Polietilenoimina/química , Ratos , Ratos Sprague-Dawley , Células de Schwann/citologia , Traumatismos da Medula Espinal/terapia
15.
Anesthesiology ; 133(1): 185-194, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31977524

RESUMO

BACKGROUND: Postoperative pain caused by trauma to nerves and tissue around the surgical site is a major problem. Perioperative steps to reduce postoperative pain include local anesthetics and opioids, the latter of which are addictive and have contributed to the opioid epidemic. Cryoneurolysis is a nonopioid and long-lasting treatment for reducing postoperative pain. However, current methods of cryoneurolysis are invasive, technically demanding, and are not tissue-selective. This project aims to determine whether ice slurry can be used as a novel, injectable, drug-free, and tissue-selective method of cryoneurolysis and resulting analgesia. METHODS: The authors developed an injectable and selective method of cryoneurolysis using biocompatible ice slurry, using rat sciatic nerve to investigate the effect of slurry injection on the structure and function of the nerve. Sixty-two naïve, male Sprague-Dawley rats were used in this study. Advanced Coherent anti-Stokes Raman Scattering microscopy, light, and fluorescent microscopy imaging were used at baseline and at various time points after treatment for evaluation and quantification of myelin sheath and axon structural integrity. Validated motor and sensory testing were used for evaluating the sciatic nerve function in response to ice slurry treatment. RESULTS: Ice slurry injection can selectively target the rat sciatic nerve. Being injectable, it can infiltrate around the nerve. The authors demonstrate that a single injection is safe and selective for reversibly disrupting the myelin sheaths and axon density, with complete structural recovery by day 112. This leads to decreased nocifensive function for up to 60 days, with complete recovery by day 112. There was up to median [interquartile range]: 68% [60 to 94%] reduction in mechanical pain response after treatment. CONCLUSIONS: Ice slurry injection selectively targets the rat sciatic nerve, causing no damage to surrounding tissue. Injection of ice slurry around the rat sciatic nerve induced decreased nociceptive response from the baseline through neural selective cryoneurolysis.


Assuntos
Crioterapia/métodos , Gelo , Bloqueio Nervoso/métodos , Nervo Isquiático , Analgesia , Animais , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Injeções , Masculino , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestrutura , Nociceptividade , Medição da Dor , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/ultraestrutura , Caminhada
16.
Ecotoxicol Environ Saf ; 191: 110159, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31962214

RESUMO

Mercury chloride (HgCl2) is a chemical pollutant widely found in the environment. This form of mercury is able to promote several damages to the Central Nervous System (CNS), however the effects of HgCl2 on the spinal cord, an important pathway for the communication between the CNS and the periphery, are still poorly understood. The aim of this work was to investigate the effects of HgCl2 exposure on spinal cord of adult rats. For this, animals were exposed to a dose of 0.375 mg/kg/day, for 45 days. Then, they were euthanized, the spinal cord collected and we investigated the mercury concentrations in medullary parenchyma and the effects on oxidative biochemistry, proteomic profile and tissue structures. Our results showed that exposure to this metal promoted increased levels of Hg in the spinal cord, impaired oxidative biochemistry by triggering oxidative stress, mudulated antioxidant system proteins, energy metabolism and myelin structure; as well as caused disruption in the myelin sheath and reduction in neuronal density. Despite the low dose, we conclude that prolonged exposure to HgCl2 triggers biochemical changes and modulates the expression of several proteins, resulting in damage to the myelin sheath and reduced neuronal density in the spinal cord.


Assuntos
Poluentes Ambientais/toxicidade , Cloreto de Mercúrio/toxicidade , Neurônios Motores/efeitos dos fármacos , Doenças Neurodegenerativas/induzido quimicamente , Proteoma/metabolismo , Medula Espinal/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Masculino , Neurônios Motores/metabolismo , Neurônios Motores/ultraestrutura , Bainha de Mielina/ultraestrutura , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Proteômica , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Medula Espinal/ultraestrutura
17.
Invest Ophthalmol Vis Sci ; 61(1): 4, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31999819

RESUMO

Purpose: Neurotrophic keratopathy is a degenerative disease that may be improved by nerve growth factor (NGF). Our aim was to investigate the use of pergolide, a dopamine (D1 and D2) receptor agonist known to increase the synthesis and release of NGF for regeneration of damaged corneal nerve fibers. Methods: Pergolide function was evaluated by measuring axon length and NGF levels by enzyme-linked immunosorbent assay in cultured chicken dorsal root ganglion (DRG) cells with serial doses of pergolide (10, 25, 50, 150, and 300 µg/ml) and with different concentrations of a D1 antagonist. Pergolide function was further evaluated by cornea nerve fiber density and wound healing in a cornea scratch mouse model. Results: Pergolide increased DRG axon length significantly at a dose between 50 and 300 µg/ml. Different concentrations of D1 antagonist (12, 24, 48, and 96 µg/ml) inhibited DRG axon length growth with pergolide (300 µg/ml). Pergolide (50 µg/ml) upregulated NGF expression in DRG cells at both 24 hours and 48 hours. Pergolide improved cornea nerve fiber density at both 1 week and 2 weeks. Pergolide also improved cornea wound healing. Conclusions: We demonstrated that pergolide can act to promote an increase in NGF which promotes corneal nerve regeneration and would therefore improve corneal sensation and visual acuity in eyes with peripheral neurotrophic keratopathy.


Assuntos
Lesões da Córnea/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Fibras Nervosas/efeitos dos fármacos , Pergolida/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Galinhas , Agonistas de Dopamina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Camundongos , Regeneração Nervosa , Pergolida/farmacologia , Cicatrização/fisiologia
18.
Int J Mol Sci ; 21(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936248

RESUMO

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1ß), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1ß was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1ß neutralization are still poorly understood. The present study investigated the role of IL-1ß on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1ß neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1ß attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.


Assuntos
Anticorpos Neutralizantes/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Interleucina-1beta/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Globo Pálido/efeitos dos fármacos , Globo Pálido/patologia , Humanos , Interleucina-1beta/genética , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia
19.
Exp Neurol ; 324: 113138, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794745

RESUMO

After spinal cord injury (SCI), the inhibitory molecules derived from scars at the lesion sites and the limited regenerative capacity of neuronal axons pose difficulties for the recovery after SCI. Remodeling of cytoskeleton structures including microtubule assembly and tubulin post-translational modification are widely accepted to play a crucial role in initiation of growth cone and regrowth of injured axon. Although increasing studies have focused on the association between tubulin acetylation and autophagy due to the role of tubulin acetylation in organelles and substances transport, there are no studies exploring the effect of tubulin acetylation on autophagy after spinal cord injury (SCI). Here, we found that histone deacetylase 6 (HDAC6) was significantly up-regulated after SCI, while inhibition of HDAC6 by Tubastatin A induced functional recovery after SCI. In view of enzyme-dependent and -independent mechanisms of HDAC6 to adjust diverse cellular processes, such as autophagy, the ubiquitin proteasome system and post-translational modification of tubulin, we mainly focused on the significance of HDAC6 in axonal regeneration and autophagy after SCI. Western blotting, Co-immunoprecipitation and immunofluorescence staining were conducted to showed that Tubastatin A treatment in nocodazole-treated cells and mice suffering from SCI prompted acetylation and stabilization of microtubules and thus restored transport function, which may contribute to restored autophagic flux and increased axonal length. Whereas inhibition of degradation of autolysosomes by bafilomycin A1 (Baf-A1) reversed functional recovery caused by Tubastatin A, revealing the association between tubulin acetylation and autophagy, which supports HDAC6 inhibition as a potential target for SCI treatment.


Assuntos
Autofagia/efeitos dos fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Indóis/uso terapêutico , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Animais , Transporte Axonal/efeitos dos fármacos , Axônios/efeitos dos fármacos , Axônios/patologia , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/antagonistas & inibidores , Indóis/antagonistas & inibidores , Locomoção , Macrolídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Nocodazol/farmacologia , Células PC12 , Ratos
20.
Toxicol Lett ; 320: 95-102, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760062

RESUMO

Exposure to organic solvent in industry, including n-hexane is correlated with central-peripheral axonopathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). However, the underlying mechanism is still largely unknown. Recently identified microRNAs (miRNAs) may play important roles in toxicant exposure and in the process of toxicant-induced neuropathys. To examine the role of miRNAs in HD-induced toxicity, neuropathic animal model was successfully built. miRNA microarray analysis revealed 105 differentially expressed miRNAs after HD exposure. Bioinformatics analysis showed that "Axon" and "Neurotrophin Signaling Pathway" was the top significant GO term and pathway, respectively. 7 miRNAs both related to "Axon" and "Neurotrophin Signaling Pathway" were screened out and further confirmed by Real-Time PCR. Correspondingly, the deregulation expression levels of proteins of four target genes (GSK3ß, Map3k1, BDNF and MAP1B) were further confirmed via western blot, verifying the results of gene target analysis. Taken together, our results showed that the axon-related miRNAs to be associated with MAP1B or neurotrophin signal pathways changed in nerve tissues following HD exposure. These miRNAs may play important roles in HD-induced neurotoxicity.


Assuntos
Axônios/efeitos dos fármacos , Hexanonas/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , Nervo Isquiático/efeitos dos fármacos , Solventes/toxicidade , Medula Espinal/efeitos dos fármacos , Animais , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Transcriptoma
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