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1.
Invest Ophthalmol Vis Sci ; 60(14): 4727-4739, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731293

RESUMO

Purpose: Regeneration of optic nerve axons after injury can be facilitated by several approaches, but misguidance at the optic chiasm is often observed. We characterized guidance cues in the embryonic visual system and adult optic chiasm before and after optic nerve crush (ONC) injury to better understand barriers to optic nerve regeneration in adults. Methods: Radial glial (RC2/BLBP/Slit1), developmental (Pax2) and extracellular markers (CSPG: H2B/CS-56) were assessed in C57BL/6J mice by immunohistochemistry. RC2, BLBP, Slit1, and CSPG are known inhibitory guidance cues while Pax2 is a permissive guidance cue. Results: At embryonic day 15.5 (E.15.5), RC2 and BLBP were identified superior to, and extending through, the optic chiasm. The optic chiasm was BLBP-ve in adult uninjured mice but BLBP+ve in adult mice 10 days after ONC injury. The reverse was true for RC2. Both BLBP and RC2 were absent in adult mice 6 weeks post-ONC. Slit1 was present in the optic chiasm midline and optic tracts in embryonic samples but was absent in uninjured adult tissue. Slit1 was observed superior to and at the midline of the optic chiasm 10 days post-ONC but absent 6 weeks after injury. Pax2 was expressed at the junction between the optic nerve and optic chiasm in embryonic brain tissue. In embryonic sections, CS-56 was observed at the junction between the optic chiasm and optic tract, and immediately superior to the optic chiasm. Both 2H6 and CS-56 staining was absent in uninjured and ONC-injured adult brains. Conclusion: Differences in guidance cue expression during development, in adulthood and after injury may contribute to misguidance of regenerating RGC axons in the adult optic chiasm.


Assuntos
Orientação de Axônios/fisiologia , Encéfalo/embriologia , Sinais (Psicologia) , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Quiasma Óptico/metabolismo , Animais , Biomarcadores/metabolismo , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Compressão Nervosa , Proteínas do Tecido Nervoso/metabolismo , Quiasma Óptico/patologia , Traumatismos do Nervo Óptico/metabolismo , Fator de Transcrição PAX2/metabolismo , Gravidez , Células Ganglionares da Retina/metabolismo
2.
Eur. j. anat ; 23(6): 453-458, nov. 2019. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-185088

RESUMO

The possibility to study axial anomalies directly on a skeletal individual is not very frequent. One well preserved skeletal individual from an Italian site dating to the late antique period (5th -4th centuries CE) was studied. This individual shows some interesting skeletal changes in the vertebrae and ribs. A supernumerary rib was found. It is a cervical rib connected to the 1st thoracic rib, presumably with a fibrous bundle. The presence of cervical ribs can produce neurovascular compression of the brachial plexus and subclavian vessels. Because of this, it is often a cause of thoracic out-let syndrome (TOS). In our case the presence of a cervical rib articulated with the first thoracic rib through a probable fibrous band could have re-stricted the space where the brachial plexus and subclavian vessels pass through, creating a state of neurovascular compression, similar


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Assuntos
Humanos , Feminino , Adulto , Costela Cervical/anatomia & histologia , Compressão Nervosa , Síndrome do Desfiladeiro Torácico , Anatomia Transversal/métodos , Costela Cervical/diagnóstico por imagem , Acoplamento Neurovascular , Imagem Tridimensional , Coluna Vertebral/anormalidades , Coluna Vertebral/anatomia & histologia
3.
Neurochem Res ; 44(9): 2230-2236, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31486011

RESUMO

Upper limb nerve injuries are common, and their treatment poses a challenge for physicians and surgeons. Experimental models help in minimum exploration of the functional characteristics of peripheral nerve injuries of forelimbs. This study was conducted to characterize the functional recovery (1, 3, 7, 10, 14, and 21 days) after median and ulnar nerve crush in mice and analyze the histological and biochemical markers of nerve regeneration (after 21 days). Sensory-functional impairments appeared after 1 day. The peripheral nerve morphology, the nerve structure, and the density of myelin proteins [myelin protein zero (P0) and peripheral myelin protein 22 (PMP22)] were analyzed after 21 days. Cold allodynia and fine motor coordination recovery occurred on the 10th day, and grip strength recovery was observed on the 14th day after injury. After 21 days, there was partial myelin sheath recovery. PMP22 recovery was complete, whereas P0 recovery was not. Results suggest that there is complete functional recovery even with partial remyelination of median and ulnar nerves in mice.


Assuntos
Nervo Mediano/fisiopatologia , Recuperação de Função Fisiológica , Remielinização , Nervo Ulnar/fisiopatologia , Animais , Masculino , Nervo Mediano/lesões , Nervo Mediano/metabolismo , Camundongos , Proteína P0 da Mielina/metabolismo , Proteínas da Mielina/metabolismo , Compressão Nervosa , Nervo Ulnar/lesões , Nervo Ulnar/metabolismo
4.
Neuron ; 103(4): 642-657.e7, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31255486

RESUMO

Neuronal subtypes show diverse injury responses, but the molecular underpinnings remain elusive. Using transgenic mice that allow reliable visualization of axonal fate, we demonstrate that intrinsically photosensitive retinal ganglion cells (ipRGCs) are both resilient to cell death and highly regenerative. Using RNA sequencing (RNA-seq), we show genes that are differentially expressed in ipRGCs and that associate with their survival and axon regeneration. Strikingly, thrombospondin-1 (Thbs1) ranked as the most differentially expressed gene, along with the well-documented injury-response genes Atf3 and Jun. THBS1 knockdown in RGCs eliminated axon regeneration. Conversely, RGC overexpression of THBS1 enhanced regeneration in both ipRGCs and non-ipRGCs, an effect that was dependent on syndecan-1, a known THBS1-binding protein. All structural domains of the THBS1 were not equally effective; the trimerization and C-terminal domains promoted regeneration, while the THBS type-1 repeats were dispensable. Our results identify cell-type-specific induction of Thbs1 as a novel gene conferring high regenerative capacity.


Assuntos
Regeneração Nervosa/fisiologia , Células Ganglionares da Retina/fisiologia , Trombospondina 1/fisiologia , Animais , Apoptose , Axônios/metabolismo , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Genes Reporter , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Compressão Nervosa , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/fisiopatologia , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Opsinas de Bastonetes/deficiência , Opsinas de Bastonetes/fisiologia , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/fisiologia , Trombospondina 1/biossíntese , Trombospondina 1/genética , Transcrição Genética
5.
Invest Ophthalmol Vis Sci ; 60(6): 2380-2387, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141609

RESUMO

Purpose: To determine whether tauopathies are associated with impaired autophagy and involved in the death of retinal ganglion cells (RGCs) of rats from an optic nerve crush (ONC). Methods: Short interfering RNA (siRNA) of the tau gene (si-Tau) or nontargeting siRNA (si-NC) was injected intravitreally 48 hours prior to ONC. The effects of silencing the tau gene on neuroprotection were determined by the number of Tuj-1-stained RGCs on days 7 and 14 after the ONC. The changes in the expressions of phosphorylated tau, P62, and LC3B were determined by immunoblots and immunohistochemistry on day 7. Results: Autophagy was impaired in the retina on day 7 after the ONC as the P62 level increased by 3.1-fold from the sham control level with a reduction in the ratio LC3B2/LC3B1. There was a 2.1-fold increase of phosphorylated tau (ser 396) in the retina, and si-Tau depressed the increase by 1.3-fold (n = 3 each). The expressions of tau and P62 were well colocalized. They were observed in the somas of RGCs and retinal nerve fibers (RNFs), and these expressions were increased after the ONC. Pretreatment by si-Tau showed significant protection in the number of RGCs after the ONC. Specifically, the density of RGCs was 540 ± 74.5 cells/mm2 on day 14 in the si-NC group, while the level was maintained at 1321 ± 192 cells/mm2 in the si-Tau group (n = 4 each). Conclusions: Silencing the tau gene is neuroprotective, and tauopathies may be involved in the death of RGCs after ONC. Impaired autophagy may be involved in ONC-induced tauopathies.


Assuntos
Autofagia/fisiologia , Compressão Nervosa , Neuroproteção/fisiologia , Traumatismos do Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/fisiologia , Proteínas tau/fisiologia , Animais , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Inativação Gênica , Masculino , Ratos , Proteínas tau/metabolismo
6.
Neurosci Lett ; 706: 110-113, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31078677

RESUMO

Two novel pyrimidine derivatives, RG2 and RG6, were studied using a rat's model of peripheral nerve injury. Toe-spreading reflex and skin sensitivity to pinch in the foot were monitored to follow recovery of motor and sensory functions in the treated animals. The remyelation rate in the distal segment of the damaged nerve was also studied using morphological analysis of cross-sections of the nerve stained with methylene blue. The obtained data demonstrate a high stimulating effect of RG2 and RG6 on the restoration of motor and sensory functions of the sciatic nerve, as well as on the post-traumatic regeneration of myelin fibers. Possible mechanisms of the observed effects are discussed.


Assuntos
Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Pirimidinas/farmacologia , Nervo Isquiático/efeitos dos fármacos , Animais , Masculino , Compressão Nervosa , Pirimidinas/uso terapêutico , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Nervo Isquiático/lesões
7.
Neuron ; 103(1): 39-51.e5, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31122676

RESUMO

Despite robust effects on immature neurons, growth factors minimally promote axon regeneration in the adult central nervous system (CNS). Attempting to improve growth-factor responsiveness in mature neurons by dedifferentiation, we overexpressed Lin28 in the retina. Lin28-treated retinas responded to insulin-like growth factor-1 (IGF1) by initiating retinal ganglion cell (RGC) axon regeneration after axotomy. Surprisingly, this effect was cell non-autonomous. Lin28 expression was required only in amacrine cells, inhibitory neurons that innervate RGCs. Ultimately, we found that optic-nerve crush pathologically upregulated activity in amacrine cells, which reduced RGC electrical activity and suppressed growth-factor signaling. Silencing amacrine cells or pharmacologically blocking inhibitory neurotransmission also induced IGF1 competence. Remarkably, RGCs regenerating across these manipulations localized IGF1 receptor to their primary cilia, which maintained their signaling competence and regenerative ability. Thus, our results reveal a circuit-based mechanism that regulates CNS axon regeneration and implicate primary cilia as a regenerative signaling hub.


Assuntos
Axônios/fisiologia , Fator de Crescimento Neural/fisiologia , Regeneração Nervosa/fisiologia , Receptores Pré-Sinápticos/fisiologia , Células Amácrinas/fisiologia , Animais , Cílios/metabolismo , Cílios/ultraestrutura , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Compressão Nervosa , Traumatismos do Nervo Óptico/patologia , Proteínas de Ligação a RNA/genética , Receptor IGF Tipo 1/metabolismo , Retina/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos
8.
J Mol Neurosci ; 68(3): 475-484, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993644

RESUMO

Retinal ganglion cell (RGC) apoptosis is considered an important pathological hallmark of glaucoma. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with potent neuroprotective properties. In our previous study, we found that the expression of PACAP and its high-affinity receptor PACAP receptor type 1 (PAC1R) increased markedly after optic nerve crush (ONC), and occurred mainly in the ganglion cell layer of the retina. This suggests that the upregulation of PACAP may play a vital role in inhibiting RGC death after ONC. Therefore, in the present study, we investigate the specific effects and underlying mechanism of PACAP in RGC death after ONC. Vehicle (physiological saline) or PACAP (1 nM to 200 nM) solution was injected into the vitreous body. Seven days later, the retinas were harvested, and the surviving RGCs were retrogradely labeled with Fluoro-Gold (FG; Fluorochrome) at different concentrations of PACAP. Immunofluorescence double staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to observe the effects of PACAP on RGC apoptosis. Our results showed that PACAP treatment inhibited caspase-3-mediated RGC apoptosis, promoted the phosphorylation of cAMP response element binding protein (CREB), up-regulated the expression of B-cell lymphoma 2 (Bcl-2), and ultimately improved RGC survival. These results suggest that PACAP may prevent RGC apoptosis after ONC via activation of CREB-mediated Bcl-2 transcription. The study thus contributes to a basic understanding of the mechanism by which PACAP decreased RGC apoptosis and provides a theoretical basis for future clinical application of PACAP in the treatment of glaucoma.


Assuntos
Apoptose , Fármacos Neuroprotetores/farmacologia , Atrofia Óptica/tratamento farmacológico , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Masculino , Compressão Nervosa , Fármacos Neuroprotetores/uso terapêutico , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Transdução de Sinais
9.
Invest Ophthalmol Vis Sci ; 60(5): 1748-1759, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31022296

RESUMO

Purpose: We investigate if the BMP4/Smad1 intracellular signaling pathway is neuroprotective and axogenic in adult rodent retinal ganglion cells (RGC) in vivo and in vitro. Methods: Adult retinal cultures were prepared from intact and after optic nerve crush (ONC) injured rats that have been stimulated to survive and regenerate using an intravitreal peripheral nerve (PN) graft. Laser capture microdissection (LCM) then was used to isolate RGC with and without neurites. Quantitative RT-PCR determined changes in BMP4/Smad1 signaling pathway mRNA. Immunohistochemistry confirmed localization of BMP4 and activation of Smad1 in ONC+PN-stimulated RGC in vivo. BMP4 peptide was used to stimulate RGC survival and neurite/axon regeneration in vitro and in vivo. Finally, the rapamycin sensitivity of the effects was determined in BMP4-stimulated RGC in vitro and in vivo. Results: In retinal cultures prepared from intact and ONC+PN-stimulated rats, RGC with neurites had upregulated regeneration-related and BMP4/Smad1 signaling pathway mRNA levels, while low levels of these mRNAs were present in RGC isolated without neurites. An optimal dose of 200 ng/mL BMP4 peptide in vitro promoted approximately 30% RGC survival and disinhibited RGC neurite outgrowth, despite the presence of inhibitory CNS myelin extracts. BMP4 also promoted approximately 30% RGC survival in vivo and stimulated significant RGC axon regeneration at 100, 200, and 400 µm beyond the lesion site. Finally, the response of RGC to BMP4 treatment in vitro and in vivo was rapamycin-insensitive. Conclusions: Activation of the BMP4/Smad1 pathway promotes survival and axon regeneration independent of mTOR and, therefore, may be of therapeutic interest.


Assuntos
Axônios/fisiologia , Proteína Morfogenética Óssea 4/metabolismo , Regeneração Nervosa/fisiologia , Células Ganglionares da Retina/fisiologia , Transdução de Sinais/fisiologia , Proteína Smad1/metabolismo , Animais , Proteína Morfogenética Óssea 4/farmacologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Feminino , Imuno-Histoquímica , Compressão Nervosa , Traumatismos do Nervo Óptico/fisiopatologia , RNA Mensageiro/genética , RNA Interferente Pequeno , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Serina-Treonina Quinases TOR/metabolismo
10.
Invest Ophthalmol Vis Sci ; 60(5): 1556-1565, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995294

RESUMO

Purpose: We implemented optical coherence tomography angiography (OCT-A) in mice to: (1) develop quantitative parameters from OCT-A images, (2) measure the reproducibility of the parameters, and (3) determine the impact of experimental models of inner and outer retinal damage on OCT-A findings. Methods: OCT-A images were acquired with a customized system (Spectralis Multiline OCT2). To assess reproducibility, imaging was performed five times over 1 month. Inner retinal damage was induced with optic nerve transection, crush, or intravitreal N-methyl-d-aspartic acid injection in transgenic mice with fluorescently labeled retinal ganglion cells (RGCs). Light-induced retinal damage was induced in albino mice. Mice were imaged at baseline and serially post injury. Perfusion density, vessel length, and branch points were computed from OCT-A images of the superficial, intermediate, and deep vascular plexuses. Results: The range of relative differences measured between sessions across the vascular plexuses were: perfusion density (2.8%-7.0%), vessel length (1.9%-4.1%), and branch points (1.9%-5.0%). In mice with progressive RGC loss, imaged serially and culminating in around 70% loss in the fluorescence signal and 18% loss in inner retinal thickness, there were no measurable changes in any OCT-A parameter up to 4 months post injury that exceeded measurement variability. However, light-induced retinal damage elicited a progressive loss of the deep vascular plexus signal, starting as early as 3 days post injury. Conclusions: Vessel length and branch points were generally the most reproducible among the parameters. Injury causing RGC loss in mice did not elicit an early change in the OCT-A signal.


Assuntos
Angiofluoresceinografia , Modelos Animais , Doenças Retinianas/diagnóstico por imagem , Células Ganglionares da Retina/patologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Animais , Feminino , Injeções Intravítreas , Luz/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , N-Metilaspartato/toxicidade , Compressão Nervosa , Traumatismos do Nervo Óptico/diagnóstico por imagem , Lesões Experimentais por Radiação/diagnóstico por imagem , Reprodutibilidade dos Testes , Retina/diagnóstico por imagem , Retina/efeitos dos fármacos , Retina/efeitos da radiação , Doenças Retinianas/fisiopatologia
11.
Invest Ophthalmol Vis Sci ; 60(4): 965-977, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30884523

RESUMO

Purpose: Retinal ischemia, a common cause of several vision-threatening diseases, contributes to the death of retinal neurons, particularly retinal ganglion cells (RGCs). Heat shock transcription factor 1 (HSF1), a stress-responsive protein, has been shown to be important in response to cellular stress stimuli, including ischemia. This study is to investigate whether HSF1 has a role in retinal neuronal injury in a mouse model of retinal ischemia-reperfusion (IR). Methods: IR was induced by inserting an infusion needle into the anterior chamber of the right eye and elevating a saline reservoir connected to the needle to raise the intraocular pressure to 110 mm Hg for 45 minutes. HSF1, Hsp70, molecules in the endoplasmic reticulum (ER) stress branches, tau phosphorylation, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR. Results: HSF1 expression was significantly increased in the retina 6 hours after IR. Using our novel transgenic mice carrying full-length human HSF gene, we demonstrated that IR-induced retinal neuronal apoptosis and necroptosis were abrogated 12 hours after IR. RGCs and their function were preserved in the HSF1 transgenic mice 7 days after IR. Mechanistically, the beneficial effects of HSF1 may be mediated by its induction of chaperone protein Hsp70 and alleviation of ER stress, leading to decreased tau phosphorylation and attenuated inflammatory response 12 to 24 hours after IR. Conclusions: These data provide compelling evidence that HSF1 is neuroprotective against retinal IR injury, and boosting HSF1 expression may be a beneficial strategy to limit neuronal degeneration in retinal diseases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição de Choque Térmico/genética , Traumatismos do Nervo Óptico/genética , Traumatismo por Reperfusão/genética , Doenças Retinianas/genética , Animais , Western Blotting , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico HSP70/genética , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Leucostasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Compressão Nervosa , Neuroproteção/fisiologia , Traumatismos do Nervo Óptico/prevenção & controle , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/prevenção & controle , Doenças Retinianas/prevenção & controle , Tomografia de Coerência Óptica , Proteínas tau/metabolismo
12.
Invest Ophthalmol Vis Sci ; 60(2): 634-649, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30743263

RESUMO

Purpose: Integrin adherence to the extracellular matrix (ECM) is essential for retinal ganglion cell (RGC) survival: damage causes production and release of ECM degrading matrix metalloproteinases (MMPs) that disrupt integrin ligation, leading to RGC death. The interplay of MMPs, integrins, and focal adhesion kinase (FAK) was studied in RGCs after optic nerve injury. Methods: Optic nerve transection and optic nerve crush were used to study RGC survival and regeneration, respectively. Treatments were administered intravitreally or into the cut end of the optic nerve. RGC survival was assessed by fluorescence or confocal microscopy; cell counting, peptide levels, and localization were assessed by Western blot and immunohistochemistry. Results: MMP-9 was most strongly increased and localized to RGCs after injury. Pan-MMP, MMP-2/-9, and MMP-3 inhibition all significantly enhanced RGC survival and increased RGC axon regeneration. FAK activation was decreased at 4 days postaxotomy, when apoptosis begins. FAK inhibition reduced RGC survival and abrogated the neuroprotective effects of MMP inhibition, whereas FAK activation increased RGC survival despite MMP activation. Integrin ligation with CD29 antibody or glycine-arginine-glycine-aspatate-serine (GRGDS) peptide increased RGC survival after axotomy. Conclusions: ECM-integrin ligation promotes RGC survival and axon regeneration via FAK activation.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Integrina beta1/metabolismo , Metaloproteinases da Matriz/metabolismo , Traumatismos do Nervo Óptico/fisiopatologia , Regeneração/fisiologia , Células Ganglionares da Retina/fisiologia , Animais , Western Blotting , Contagem de Células , Sobrevivência Celular/fisiologia , Matriz Extracelular/enzimologia , Feminino , Imuno-Histoquímica , Inibidores de Metaloproteinases de Matriz/farmacologia , Microscopia Confocal , Microscopia de Fluorescência , Compressão Nervosa , Oligopeptídeos/farmacologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/citologia
13.
J Mol Neurosci ; 68(3): 465-474, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30415445

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been demonstrated to play a crucial part in protecting retinal ganglion cells (RGCs) from apoptosis in various retinal injury animal models. PACAP has two basic groups of receptors: PACAP receptor type 1 (PAC1R) and vasoactive intestinal polypeptide/PACAP receptors (VPAC1R and VPAC2R). However, few studies illustrated the spatial and temporal expression changes of endogenous PACAP and its receptors in a rodent optic nerve crush (ONC) model. In this study, a significant upregulation of PACAP and PAC1R in the retina after ONC was observed in both protein and RNA levels. The peak level of PACAP and PAC1R expression could be found on the fifth day following ONC. In addition, immunofluorescent labeling indicated that PACAP and PAC1R were localized mainly in RGCs. On the contrary, VPAC1R and VPAC2R were hardly detected in the retina. Collectively, the spatiotemporal expression of PACAP and its high-affinity receptor PAC1R were remarkably changed after ONC, and mainly expressed in the ganglion cell layer of the retina. This suggested that the upregulation of PACAP and PAC1R may play a vital role in RGC death after ONC.


Assuntos
Atrofia Óptica/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Células Ganglionares da Retina/metabolismo , Animais , Masculino , Compressão Nervosa , Atrofia Óptica/patologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Ratos , Ratos Sprague-Dawley , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Células Ganglionares da Retina/patologia
14.
Mol Neurobiol ; 56(3): 1812-1824, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29931510

RESUMO

Peripheral nerve injury requires optimal conditions in both macro-environment and microenvironment for promotion of axonal regeneration. However, most repair strategies of traumatic peripheral nerve injury often lead to dissatisfying results in clinical outcome. Though various strategies have been carried out to improve the macro-environment, the underlying molecular mechanism of axon regeneration in the microenvironment provided by nerve conduit remains unclear. In this study, we evaluate the effects of from adipose-derived mesenchymal stem cells (adMSCs) originating exosomes with respect to sciatic nerve regeneration and neurite growth. Molecular and immunohistochemical techniques were used to investigate the presence of characteristic exosome markers. A co-culture system was established to determine the effect of exosomes on neurite elongation in vitro. The in vivo walking behaviour of rats was evaluated by footprint analysis, and the nerve regeneration was assessed by immunocytochemistry. adMSCs secrete nano-vesicles known as exosomes, which increase neurite outgrowth in vitro and enhance regeneration after sciatic nerve injury in vivo. Furthermore, we showed the presence of neural growth factors transcripts in adMSC exosomes for the first time. Our results demonstrate that exosomes, constitutively produced by adMSCs, are involved in peripheral nerve regeneration and have the potential to be utilised as a therapeutic tool for effective tissue-engineered nerves.


Assuntos
Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regeneração Nervosa/fisiologia , Crescimento Neuronal/fisiologia , Traumatismos dos Nervos Periféricos/metabolismo , Nervo Isquiático/fisiologia , Animais , Feminino , Masculino , Compressão Nervosa , Ratos , Ratos Wistar , Nervo Isquiático/lesões
15.
Mol Neurobiol ; 56(5): 3175-3192, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30105671

RESUMO

Neural insults and neurodegenerative diseases typically result in permanent functional deficits, making the identification of novel pro-regenerative molecules and mechanisms a primary research topic. Nowadays, neuroregenerative research largely focuses on improving axonal regrowth, leaving the regenerative properties of dendrites largely unstudied. Moreover, whereas developmental studies indicate a strict temporal separation of axogenesis and dendritogenesis and thus suggest a potential interdependency of axonal and dendritic outgrowth, a possible axon-dendrite interaction during regeneration remains unexplored. To unravel the inherent dendritic response of vertebrate neurons undergoing successful axonal regeneration, regeneration-competent adult zebrafish of either sex, subjected to optic nerve crush (ONC), were used. A longitudinal study in which retinal ganglion cell (RGC) dendritic remodeling and axonal regrowth were assessed side-by-side after ONC, revealed that-as during development-RGC axogenesis precedes dendritogenesis during central nervous system (CNS) repair. Moreover, dendrites majorly shrank before the start of axonal regrowth and were only triggered to regrow upon RGC target contact initiation, altogether suggestive for a counteractive interplay between axons and dendrites after neuronal injury. Strikingly, both retinal mechanistic target of rapamycin (mTOR) and broad-spectrum matrix metalloproteinase (MMP) inhibition after ONC consecutively inhibited RGC synapto-dendritic deterioration and axonal regrowth, thus invigorating an antagonistic interplay wherein mature dendrites restrain axonal regrowth. Altogether, this work launches dendritic shrinkage as a prerequisite for efficient axonal regrowth of adult vertebrate neurons, and indicates that molecular/mechanistic analysis of dendritic responses after damage might represent a powerful target-discovery platform for neural repair.


Assuntos
Axônios/metabolismo , Sistema Nervoso Central/fisiologia , Dendritos/metabolismo , Regeneração Nervosa , Peixe-Zebra/fisiologia , Animais , Axônios/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia , Compressão Nervosa , Regeneração Nervosa/efeitos dos fármacos , Traumatismos do Nervo Óptico/patologia , Traumatismos do Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
16.
Int J Impot Res ; 31(1): 1-8, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30072768

RESUMO

To determine if the insulin-like growth factor-1 (IGF-1) pathway is involved in the improvement in erectile function recovery in rats after nerve crush injury treated with pioglitazone (Pio). Sprague-Dawley rats were divided into four groups. The first group received sham operation (n = 5). The second group underwent bilateral cavernous nerve injury (BCNI, n = 7). The third group received BCNI and Pio treatment (BCNI + Pio, n = 7), whereas the fourth group underwent BCNI with Pio treatment and IGF-1 inhibition (BCNI + Pio + JB-1, n = 7). The IGF-1 receptor (IGF-1R) was inhibited by JB-1, a small molecular antagonist of the receptor. After 14 days of treatment, erectile function was measured via intracorporal pressure normalized to mean arterial pressure (ICP/MAP) and the major pelvic ganglion and cavernous nerve harvested for western blot and immunohistochemistry (IHC) of phosphorylated-IGF-1Rß (p-IGF-1Rß), phosphorylated-ERK1/2 (p-ERK1/2), and neuronal NOS (nNOS). BCNI + Pio animals exhibited improvements in ICP/MAP, similar to Sham animals, and BCNI + Pio + JB-1 rats demonstrated a reduced ICP/MAP similar to BCNI-only rats at all measured voltages. Western blot results showed upregulation of p-IGF-1Rß was observed in the BCNI + Pio group. Low levels of p-ERK1/2 were seen in the JB-1-treated animals. The immunoblot results were supported by IHC findings. Intense IHC staining of nNOS was detected in the BCNI + Pio group. The group treated with JB-1 showed minimal protein expression of p-ERK1/2, nNOS, and p-IGF-1Rß. Pio improves erectile function in rats undergoing BCNI via an IGF-1-mediated pathway.


Assuntos
Disfunção Erétil/tratamento farmacológico , Ereção Peniana/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/complicações , Pioglitazona/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Disfunção Erétil/etiologia , Masculino , Compressão Nervosa , Óxido Nítrico Sintase Tipo I/metabolismo , Fosforilação/efeitos dos fármacos , Pioglitazona/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
Neuropharmacology ; 148: 96-106, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30594697

RESUMO

Neurodegenerative diseases affect millions of people worldwide. Optic neuropathies are the most commonly occurring neurodegenerative diseases, characterized by progressive retinal ganglion cell (RGC) degeneration. We recently reported that Prominin-1, a protein found on the surface of stem cells, interacts with VEGF and enhances its activity. VEGF is known to have various protective roles in the nervous system. Subsequently, we have developed a 12-mer peptide derived from Prominin-1, named PR1P, and investigated its effects on neuronal survival of damaged RGCs in a rat model of optic nerve crush (ONC). PR1P prevented RGC apoptosis resulting in improvement of retinal function in the rat ONC model. PR1P treatment significantly increased phosphorylation of ERK and AKT and expression its downstream proteins c-fos and Egr-1 in the retina. Additionally, PR1P beneficially increased the MMP-9/TIMP-1 ratio and promoted glial activation in the retina of ONC rats. Thus, PR1P displayed neuroprotective effects through enhanced VEGF-driven neuronal survival and reconstruction of the extracellular environment in ONC model. Our data indicate that PR1P may be a promising new clinical candidate for the treatment of neurodegenerative diseases.


Assuntos
Matriz Extracelular/efeitos dos fármacos , Degeneração Neural/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Humanos , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Compressão Nervosa , Neuroglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Traumatismos do Nervo Óptico/prevenção & controle , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Retina/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/biossíntese
18.
Rev. epidemiol. controle infecç ; 9(3): 256-257, 2019. ilus
Artigo em Português | LILACS | ID: biblio-1047440

RESUMO

Qual seu diagnóstico? Paciente feminina atendida no posto de saúde com queixas de lesões hipercrômicas e pruriginosas no dorso. Também relatou dor em coluna toracolombar e lombossacra de longa data. Realizou ressonancia que evidenciou compressão de raízes nervosas em alguns pontos, mas sem sinais de compressão medular. Analisando anamnese, exame fisico e exame de imagem a paciente foi diagnosticada com notalgia parestética.(AU)


Assuntos
Humanos , Parestesia , Prurido , Compressão Nervosa
19.
J Oral Sci ; 60(4): 526-535, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30587687

RESUMO

The effects of transplanted human dental pulp-derived cells (DPCs) on peripheral nerve regeneration were studied in a rat model of sciatic nerve crush injury. In one group, DPCs were transplanted into the compression site (cell transplantation group); the control group underwent no transplantation (crushed group). Sciatic nerve regeneration was determined based on the recovery of motor function and histological and immunohistochemical analyses. The cell transplantation group showed improved motor function compared with the crushed group using the CatWalk XT system, which corresponded to a higher ratio of tibialis to anterior muscle weight 14 days after surgery. Histological analysis revealed a smaller interspace area and few vacuoles in the sciatic nerve after cell transplantation compared with the crushed group. The myelin sheath was visualized with Luxol Fast Blue (LFB) staining and anti-myelin basic protein (anti-MBP) antibody labeling; the percentages of LFB- and MBP-positive areas were higher in the cell transplantation group than in the crushed group. Human mitochondria-positive cells were also identified in the sciatic nerve at the transplantation site 14 days after surgery. Taken together, the observed correlation between morphological findings and functional outcomes following DPC transplantation indicates that DPCs promote peripheral nerve regeneration in rats.


Assuntos
Polpa Dentária/citologia , Compressão Nervosa , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Animais , Modelos Animais de Doenças , Humanos , Técnicas Imunoenzimáticas , Masculino , Ratos , Ratos Endogâmicos F344
20.
Sci Rep ; 8(1): 16443, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30401804

RESUMO

VGF nerve growth factor inducible (VGF) is a polypeptide that is induced by neurotrophic factors and is involved in neurite growth and neuroprotection. The mRNA of the Vgf gene has been detected in the adult rat retina, however the roles played by VGF in the retina are still undetermined. Thus, the purpose of this study was to determine the effects of VGF on the retinal ganglion cells (RGCs) of mice in the optic nerve crush (ONC) model, rat-derived primary cultured RGCs and human induced pluripotent stem cells (iPSCs)-derived RGCs. The mRNA and protein of Vgf were upregulated after the ONC. Immunostaining showed that the VGF was located in glial cells including Müller glia and astrocytes but not in the retinal neurons and their axons. AQEE-30, a VGF peptide, suppressed the loss of RGCs induced by the ONC, and it increased survival rat-derived RGCs and promoted the outgrowth of neurites of rat and human iPSCs derived RGCs in vitro. These findings indicate that VGF plays important roles in neuronal degeneration and has protective effects against the ONC on RGCs. Thus, VGF should be considered as a treatment of RGCs degeneration.


Assuntos
Apoptose , Compressão Nervosa/efeitos adversos , Fatores de Crescimento Neural/metabolismo , Neuropeptídeos/metabolismo , Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Camundongos , Fatores de Crescimento Neural/genética , Neuritos/metabolismo , Neuritos/patologia , Neuropeptídeos/genética , Nervo Óptico/metabolismo , Ratos , Ratos Sprague-Dawley
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