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1.
Nat Commun ; 11(1): 4504, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908131

RESUMO

The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.


Assuntos
Microambiente Celular/imunologia , Sistemas de Liberação de Medicamentos/instrumentação , Fator de Crescimento Neural/administração & dosagem , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/terapia , Tecidos Suporte , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Preparações de Ação Retardada/administração & dosagem , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interleucina-4/administração & dosagem , Lipossomos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Fator de Crescimento Neural/farmacocinética , Regeneração Nervosa/imunologia , Ratos , Recuperação de Função Fisiológica/imunologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Traumatismos da Medula Espinal/imunologia
2.
PLoS One ; 15(8): e0237231, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853250

RESUMO

In this study, we examined the effect of differing gap lengths on regeneration of transected recurrent laryngeal nerves using silicon tubes containing type I collagen gel and the ability of this regeneration to result in restoration of vocal fold movements in rats. We simulated nerve gaps in Sprague-Dawley rats by transecting the left recurrent laryngeal nerves and bridged the nerve stumps using silicon tubes containing type 1 collagen gel. Three experimental groups, in which the gap lengths between the stumps were 1, 3, or 5 mm, were compared with a control group in which the nerve was transected but was not bridged. After surgery, we observed vocal fold movements over time with a laryngoscope. At week 15, we assessed the extent of nerve regeneration in the tube, histologically and electrophysiologically. We also assessed the degree of atrophy of the thyroarytenoid muscle (T/U ratio). Restoration of vocal fold movements was observed in 9 rats in the 1-mm group, in 6 rats in the 3-mm group, and in 3 rats in the 5-mm group. However, in most rats, restoration was temporary, with only one rat demonstrating continued vocal fold movements at week 15. In electromyograph, evoked potentials were observed in rats in the 1-mm and 3-mm groups. Regenerated tissue in the tube was thickest in the 1-mm group, followed by the 3-mm and 5-mm groups. The regenerated tissue showed the presence of myelinated and unmyelinated nerve fibers. In assessment of thyroarytenoid muscle atrophy, the T/U ratio was highest in the 1-mm group, followed by the 3-mm and 5-mm groups. We successfully regenerated the nerves and produced a rat model of recurrent laryngeal nerve regeneration that demonstrated temporary recovery of vocal fold movements. This rat model could be useful for assessing novel treatments developing in the future.


Assuntos
Colágeno/uso terapêutico , Regeneração Nervosa , Traumatismos do Nervo Laríngeo Recorrente/terapia , Nervo Laríngeo Recorrente/fisiopatologia , Animais , Materiais Biocompatíveis/química , Colágeno/administração & dosagem , Modelos Animais de Doenças , Géis/administração & dosagem , Géis/uso terapêutico , Masculino , Regeneração Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Laríngeo Recorrente/fisiologia , Traumatismos do Nervo Laríngeo Recorrente/fisiopatologia , Silício/química
3.
Artigo em Inglês | MEDLINE | ID: mdl-32575426

RESUMO

Recent advances in phytomedicine have explored some potential candidates for nerve regeneration, including hydroxytyrosol (HT). This study was undertaken to explore the potential effects of HT on human Schwann cells' proliferation. Methods: The primary human Schwann cell (hSC) was characterized, and the proliferation rate of hSC supplemented with various concentrations of HT was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis and protein expression of glial fibrillary acidic protein (GFAP) and p75 nerve growth factor receptor (p75 NGFR) were evaluated via the immunofluorescence technique. Results: In vitro culture of hSCs revealed spindle-like, bipolar morphology with the expression of specific markers of hSC. Hydroxytyrosol at 10 and 20 ng/mL significantly increased the proliferation of hSCs by 30.12 ± 5.9% and 47.8 ± 6.7% compared to control (p < 0.05). Cell cycle analysis showed that HT-treated hSCs have a higher proliferation index (16.2 ± 0.2%) than the control (12.4 ± 0.4%) (p < 0.01). In addition, HT significantly increased the protein expression of GFAP and p75NGFR (p < 0.05). Conclusion: HT stimulates the proliferation of hSCs in vitro, indicated by a significant increase in the hSC proliferation index and protein expression of hSCs' proliferation markers, namely p75 NGFR and GFAP.


Assuntos
Antioxidantes , Proliferação de Células , Regeneração Nervosa , Álcool Feniletílico/análogos & derivados , Células de Schwann , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Regeneração Nervosa/efeitos dos fármacos , Álcool Feniletílico/farmacologia , Células de Schwann/efeitos dos fármacos
4.
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.
PLoS One ; 15(4): e0231194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271817

RESUMO

Various injuries to the neural tissues can cause irreversible damage to multiple functions of the nervous system ranging from motor control to cognitive function. The limited treatment options available for patients have led to extensive interest in studying the mechanisms of neuronal regeneration and recovery from injury. Since many neurons are terminally differentiated, by increasing cell survival following injury it may be possible to minimize the impact of these injuries and provide translational potential for treatment of neuronal diseases. While several cell types are known to survive injury through plasma membrane repair mechanisms, there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair as a therapy in neurons. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in skeletal muscle. Interestingly, recombinant human MG53 (rhMG53) can be applied exogenously to increase membrane repair capacity both in vitro and in vivo. Increasing the membrane repair capacity of neurons could potentially minimize the death of these cells and affect the progression of various neuronal diseases. In this study we assess the therapeutic potential of rhMG53 to increase membrane repair in cultured neurons and in an in vivo mouse model of neurotrauma. We found that a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair both in vitro and in vivo. These findings provide direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for neuronal injury.


Assuntos
Regeneração Nervosa , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Cicatrização , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Lesões por Esmagamento/patologia , Lesões por Esmagamento/fisiopatologia , Modelos Animais de Doenças , Humanos , Proteínas de Membrana/metabolismo , Membranas , Camundongos Endogâmicos C57BL , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Recombinantes/farmacologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Proteínas com Motivo Tripartido/farmacologia , Cicatrização/efeitos dos fármacos
6.
Muscle Nerve ; 62(1): 119-127, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32243602

RESUMO

INTRODUCTION: Many reports have indicated that adipose-derived stem cells (ADSCs) are effective for nerve regeneration. We investigated nerve regeneration by combining a polyglycolic acid collagen (PGA-c) tube, which is approved for clinical use, and Schwann cell-like differentiated ADSCs (dADSCs). METHODS: Fifteen-millimeter-long gaps in the sciatic nerve of rats were bridged in each group using tubes (group I), with tubes injected with dADSCs (group II), or by resected nerve (group III). RESULTS: Axonal outgrowth was greater in group II than in group I. Tibialis anterior muscle weight revealed recovery only in group III. Latency in nerve conduction studies was equivalent in group II and III, but action potential was lower in group II. Transplanted dADSCs maintained Schwann cell marker expression. ATF3 expression level in the dorsal root ganglia was equivalent in groups II and III. DISCUSSION: dADSCs maintained their differentiated state in the tubes and are believed to have contributed to nerve regeneration.


Assuntos
Tecido Adiposo/fisiologia , Diferenciação Celular/fisiologia , Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Nervo Isquiático/fisiologia , Transplante de Células-Tronco/métodos , Tecido Adiposo/citologia , Tecido Adiposo/transplante , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno/administração & dosagem , Feminino , Regeneração Nervosa/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Ácido Poliglicólico/administração & dosagem , Ratos , Ratos Wistar , Células de Schwann/transplante , Nervo Isquiático/efeitos dos fármacos , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Células-Tronco/fisiologia
7.
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
8.
Yakugaku Zasshi ; 140(2): 129-137, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32009033

RESUMO

(-)-2S,3S,4S,5S-Talaumidin (1) exhibits potent neurotrophic activities such as neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in nerve growth factor (NGF)-differentiated PC12 cells. To examine the stereochemistry-activity relationship of 1, systematic syntheses of seven stereoisomers of 1 were accomplished via Evans aldol reaction, diastereoselective hydroboration, and Mitsunobu reaction. All stereoisomers showed moderate-to-potent neurite-outgrowth promotion in NGF-differentiated PC12 cells. In particular, (-)-2S,3R,4S,5R-1e having all-cis-substituted configuration exhibited the most significant neurite-outgrowth promotion. Subsequently, we developed a short-step synthetic route for talaumidin derivatives so as to explore new neurotrophic compounds that could be obtained on a large scale. First, we synthesized derivative 2a, which is a racemic compound of (-)-1e, and compared its neurotrophic activity with (-)-1e. It was found that the neurotrophic activity of racemic 2a was similar to that of (-)-1e. Using the same synthetic route, several talaumidin derivatives were synthesized to optimize the oxy-functionality on aromatic rings. Thereby, bis(methylenedioxybenzene) derivative 2b was found to exhibit the highest neurotrophic activity. In addition, examination of the structure-activity relationship of 2b indicated that the 2,5-diphenyl structure was crucial moiety, and the two methyl groups on the tetrahydrofuran (THF) ring could enhance the neurotrophic activity. Furthermore, 2a and 2b were found to induce mouse optic nerve regeneration in vivo.


Assuntos
Desenvolvimento de Medicamentos , Furanos , Animais , Furanos/farmacologia , Humanos , Regeneração Nervosa/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Nervo Óptico/fisiologia , Ratos , Relação Estrutura-Atividade
9.
J Clin Neurosci ; 72: 370-377, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31952974

RESUMO

The aim of this study was to determine the curative effects of high-dose (100 mg/kg) melatonin on peripheral nerve injury. Forty male Wistar albino rats were randomized into four groups as sham, vehicle, melatonin, and ischemia and their right sciatic nerves were exposed. The process was terminated in the sham group. In the other groups, nerve injury was induced by clip compression. The vehicle group was intraperitoneally administered ethanol 0.1 cc (melatonin solvent), while the melatonin group was intraperitoneally administered a single dose of melatonin (100 mg/kg). Following the surgery, sciatic nerve functional index (SFI) was measured using walking track analysis on days 7, 14, and 21, and latency, amplitude, and muscle action potentials (MAP) field values were measured using electroneuromyography (ENMG) on day 21. Histopathologically, edema, axonal degeneration, myelin damage, and inflammatory response were evaluated in all groups. SFI values were noted to be statistically significantly different among the vehicle, melatonin, and ischemia groups, and the melatonin group showed a faster recovery. In the ENMG evaluations, higher amplitude and field values in the melatonin group indicated that melatonin accelerated peripheral nerve recovery. Histopathologically, although fibers with loss of myelin were identified in the melatonin group, the myelin sheath was preserved in general and the axonal structure was noted to be normal. A single injection of high-dose melatonin was found to preserve myelin sheath, prevent axonal loss, and accelerate functional recovery during the nerve regeneration in peripheral nerve injury.


Assuntos
Melatonina/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Animais , Axônios/patologia , Masculino , Bainha de Mielina/patologia , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/patologia
10.
J Neurosci ; 40(7): 1483-1500, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31911460

RESUMO

Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knock-out of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knock-out in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knock-out mice occurred in tandem with a skewing of reactive astrocyte signatures toward a prorepair phenotype. In cell culture, the promyelinating effects of PAR1 loss of function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of promyelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether, findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.SIGNIFICANCE STATEMENT Replacement of oligodendroglia and myelin regeneration holds tremendous potential to improve function across neurological conditions. Here we demonstrate Protease Activated Receptor 1 (PAR1) is an important regulator of the capacity for myelin regeneration across two experimental murine models of myelin injury. PAR1 is a G-protein-coupled receptor densely expressed in the CNS, however there is limited information regarding its physiological roles in health and disease. Using a combination of PAR1 knock-out mice, oligodendrocyte monocultures and oligodendrocyte-astrocyte cocultures, we demonstrate blocking PAR1 improves myelin production by a mechanism related to effects across glial compartments and linked in part to regulatory actions toward growth factors such as BDNF. These findings set the stage for development of new clinically relevant myelin regeneration strategies.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Regeneração Nervosa/efeitos dos fármacos , Receptor PAR-1/antagonistas & inibidores , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Axônios/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Quelantes/toxicidade , Técnicas de Cocultura , Cobre , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Perfilação da Expressão Gênica , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Knockout , Bainha de Mielina/fisiologia , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Receptor PAR-1/deficiência , Receptor PAR-1/fisiologia , Teste de Desempenho do Rota-Rod , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
11.
Cell Prolif ; 53(1): e12730, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746040

RESUMO

OBJECTIVES: In peripheral neuropathy, the underlying mechanisms of nerve and muscle degeneration include chronic inflammation and oxidative stress in fibrotic tissues. (-)-Epigallocatechin gallate (EGCG) is a major, active component in green tea and may scavenge free radical oxygen and attenuate inflammation. Conservative treatments such as steroid injection only deal with early, asymptomatic, peripheral neuropathy. In contrast, neurolysis and nerve conduit implantation work effectively for treating advanced stages. MATERIALS AND METHODS: An EGCG-loaded polycaprolactone (PCL) porous scaffold was fabricated using an integrated moulding method. We evaluated proliferative, oxidative and inflammatory activity of rat Schwann cells (RSCs) and rat skeletal muscle cells (RSMCs) cultured on different scaffolds in vitro. In a rat radiation injury model, we assessed the morphological, electrophysiological and functional performance of regenerated sciatic nerves and gastrocnemius muscles, as well as oxidative stress and inflammation state. RESULTS: RSCs and RSMCs exhibited higher proliferative, anti-oxidant and anti-inflammatory states in an EGCG/PCL scaffold. In vivo studies showed improved nerve and muscle recovery in the EGCG/PCL group, with increased nerve myelination and muscle fibre proliferation and reduced macrophage infiltration, lipid peroxidation, inflammation and oxidative stress indicators. CONCLUSIONS: The EGCG-modified PCL porous nerve scaffold alleviates cellular oxidative stress and repairs peripheral nerve and muscle structure in rats. It attenuates oxidative stress and inflammation in vivo and may provide further insights into peripheral nerve repair in the future.


Assuntos
Catequina/análogos & derivados , Regeneração Nervosa/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Poliésteres , Lesões Experimentais por Radiação/tratamento farmacológico , Células de Schwann/metabolismo , Nervo Isquiático/fisiologia , Tecidos Suporte/química , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Poliésteres/química , Poliésteres/farmacologia , Porosidade , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Ratos , Células de Schwann/patologia , Nervo Isquiático/lesões , Nervo Isquiático/patologia
12.
Life Sci ; 241: 117102, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790691

RESUMO

Peripheral nerve injuries are common conditions that often lead to dysfunctions. Although much knowledge exists on the several factors that mediate the complex biological process involved in peripheral nerve regeneration, there is a lack of effective treatments that ensure full functional recovery. Naringenin (NA) is the most abundant flavanone found in citrus fruits and it has promising neuroprotective, anti-inflammatory and antioxidant effects. This study aimed to enhance peripheral nerve regeneration using an inclusion complex containing NA and hydroxypropyl-ß-cyclodextrin (HPßCD), named NA/HPßCD. A mouse sciatic nerve crush model was used to evaluate the effects of NA/HPßCD on nerve regeneration. Sensory and motor parameters, hyperalgesic behavior and the sciatic functional index (SFI), respectively, improved with NA treatment. Western blot analysis revealed that the levels of p75NTR ICD and p75NTR full length as well phospho-JNK/total JNK ratios were preserved by NA treatment. In addition, NA treatment was able to decrease levels of caspase 3. The concentrations of TNF-α and IL-1ß were decreased in the lumbar spine, on the other hand there was an increase in IL-10. NA/HPßCD presented a better overall morphological profile but it was not able to increase the number of myelinated fibers. Thus, NA was able to enhance nerve regeneration, and NA/HPßCD decreased effective drug doses while maintaining the effect of the pure drug, demonstrating the advantage of using the complex over the pure compound.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Flavanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/fisiologia , Animais , Hiperalgesia/tratamento farmacológico , Interleucina-10/metabolismo , Masculino , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Medição da Dor , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Glia ; 68(1): 111-127, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444939

RESUMO

Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation-induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia-derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin-28a, cell cycle-related genes and critical cytokines. Surprisingly, we identify microglia/macrophage-mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.


Assuntos
Regeneração Nervosa/fisiologia , Retina/lesões , Retina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Inflamação/metabolismo , Regeneração Nervosa/efeitos dos fármacos , RNA Mensageiro/metabolismo , Retina/efeitos dos fármacos , Sirolimo/farmacologia , Peixe-Zebra
14.
Int J Mol Sci ; 20(23)2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810304

RESUMO

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy.


Assuntos
Fator de Crescimento de Hepatócito/genética , Inflamação/genética , Regeneração Nervosa/genética , Traumatismos da Medula Espinal/terapia , Diferenciação Celular/genética , Fator de Crescimento de Hepatócito/uso terapêutico , Humanos , Inflamação/terapia , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia , Transplante de Células-Tronco
15.
J Enzyme Inhib Med Chem ; 34(1): 712-727, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852270

RESUMO

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid - DBMA hybrids (1-13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer's disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), ß-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone - DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Metilaminas/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Masculino , Metilaminas/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química
16.
Med Sci Monit ; 25: 10067-10076, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31882570

RESUMO

BACKGROUND The aim of this study was to explore the effect of metformin by inducing autophagy for enhancing functional recovery of peripheral nerve in rats with sciatic nerve crush injury. MATERIAL AND METHODS Autophagy was determined by electron microscopy, immunofluorescence, and Western blot analysis. Motor function recovery was studied by the footprint intensity method. Axonal growth and regeneration were detected through Western blot while axonal remyelination was analysed through immunocytochemistry. Sensory and functional recovery were assessed by reflexive motor function analysis. RESULTS The present study deciphered the role of autophagy induction by metformin in motor functions and peripheral nerve regeneration following sciatic nerve crush injury in rats. The process was detected by measuring autophagosomes and the expression of microtubule-associated protein 1A/1B-light chain 3 upon metformin treatment of sciatic nerve crush-injured rats. Neurobehavioral recovery by metformin was tested by CatWalk gait analysis, and we quantified expression of myelin basic protein MBP and neurofilament NF200 at the damage sight by immunoblotting. In metformin-treated injured rats, autophagy was upregulated, by which the number of dead cells was decreased. Motor function was also recovered after metformin treatment, which was accompanied by upregulation of MBP and NF200 through autophagy induction. Surprisingly, the motor regenerative capability was reduced by treatment with 3-methyl adenine (an autophagy inhibitor) in nerve-injured rats. CONCLUSIONS Our study revealed that pharmacological induction of autophagy has an important and active role in the regeneration of nerve and motor function regain.


Assuntos
Lesões por Esmagamento/fisiopatologia , Metformina/farmacologia , Compressão Nervosa , Recuperação de Função Fisiológica/efeitos dos fármacos , Nervo Isquiático/lesões , Animais , Autofagia/efeitos dos fármacos , Axônios/metabolismo , Lesões por Esmagamento/patologia , Feminino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Proteínas de Neurofilamentos/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Regulação para Cima/efeitos dos fármacos
17.
Bull Exp Biol Med ; 168(2): 224-228, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776958

RESUMO

This study aimed at assessing the regenerative effect of p-tyrosol in transient global cerebral ischemia modeled in adult male Wistar rats by reversible occlusion of the three major vessels originating from the aortic arch and supplying the blood to the brain. p-Tyrosol was administered intraperitoneally in a dose of 20 mg/kg over 10 days after surgery. The death of NeuN+ mature neurons and the number of newly formed DCX+ neurons were assessed in the CA1 field of the hippocampus that is highly susceptible to damage in this model. We found that ischemia induced death of more than 50% mature neurons in the hippocampal CA1 field (p<0.001). p-Tyrosol stimulated the formation and growth of new neurons in the normally non-proliferative CA1 region of the hippocampus (p<0.05) and produced a neuroprotective effect on mature neurons (p<0.01).


Assuntos
Região CA1 Hipocampal/fisiologia , Ataque Isquêmico Transitório/patologia , Neurogênese/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Álcool Feniletílico/análogos & derivados , Animais , Região CA1 Hipocampal/citologia , Modelos Animais de Doenças , Masculino , Regeneração Nervosa/efeitos dos fármacos , Álcool Feniletílico/farmacologia , Ratos , Ratos Wistar
18.
Pak J Pharm Sci ; 32(4(Supplementary)): 1761-1766, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31680070

RESUMO

Peripheral nerve injury is a complex condition which results in restricted physical activity. Despite the tremendous efforts to figure out effective remedies, the complete functional retrieval is still a goal to be achieved. So, the need of hour is the exploration of potential natural compounds to recover this functional loss. Here, we have investigated the role of a local plant "Neurada procumbens" in ameliorating the functional recovery after an induced nerve compression injury in a mouse model. A dose of N. procumbens (50mg/kg of body weight) was administered orally from the day of injury to onwards. The motor functional recovery was assessed by evaluating muscle grip strength and sciatic functional index; while the sensory functions were gauged by the hotplate test. The serological parameters were carried out to analyze the effect of N. procumbens on oxidative stress level. The recovery of sensory and motor functions was significantly improved and perceived earlier in the treatment group. Moreover, the elevated antioxidant level was statistically significant in the treatment group. These results indicate that the supplementation of N. procumbens accelerates functional recovery after sciatic nerve crush injury.


Assuntos
Traumatismos dos Nervos Periféricos/tratamento farmacológico , Preparações de Plantas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Camundongos , Atividade Motora/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
19.
Yakugaku Zasshi ; 139(11): 1385-1390, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685734

RESUMO

In neurodegenerative diseases, such as Alzheimer's disease (AD) and spinal cord injury (SCI), inhibited axonal regeneration lead to irreversible functional impairment. Although many agents that eliminate axonal growth impediments have been clinically investigated, none induced functional recovery. I hypothesized that the removal of impediments alone was not enough and that promoting axonal growth and neuronal network reconstruction were needed for recovery from neurodegenerative diseases. To promote axonal growth, I have focused on neurons and microglia. In vitro models of AD and SCI were developed by culturing neurons in the presence of amyloid ß (Aß) and chondroitin sulfate proteoglycan, respectively. These were then used to identify several extracts of herbal medicines and their constituents that promoted axonal growth. Oral administration of these extracts and their constituents improved memory and motor function in in vivo mouse models of AD and SCI, respectively. The bioactive compounds in these extracts were identified by analyzing brain and spinal cord samples from the mice. Their protein targets were identified using the drug affinity responsive target stability method. Analysis of early events in the axons after culture with Aß revealed that the inhibition of endocytosis was sufficient to prevent the axonal atrophy and memory deficits caused by Aß. The compounds that increased M2 microglia were observed to promote axonal normalization and growth; they were also found to recover memory and motor function in mice models of AD and SCI, respectively. The above results indicate that axonal growth plays important roles in the recovery from AD and SCI.


Assuntos
Axônios/fisiologia , Medicina Herbária , Regeneração Nervosa , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/farmacologia , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Estimulação Química
20.
Bull Exp Biol Med ; 167(6): 723-727, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31655996

RESUMO

We studied the involvement of cAMP/PKA signaling in the realization of the growth potential of neural progenitors and secretion of neurotrophic growth factors by glial elements under conditions of ethanol-induced neurodegeneration in vitro and in vivo. The stimulating role of cAMP and PKA in cell cycle progression of the neural progenitor cells and in production of neurotrophins by the cells in nervous tissue under the optimal conditions to vital activity was demonstrated. Ethanol inverted the role of cAMP/PKA signaling pathways in determination of the proliferation-differentiation status of neural stem cells. Selective blockade of adenylate cyclase or PKA in neural stem cells increased the rate of their division against the background of relative decrease in differentiation rate. In addition, cAMP/PKA signaling does not longer participate in neurotrophin production by glial cells in neurodegeneration. These findings suggest that inhibitors of activity/expression of adenylate cyclase and PKA can be considered as possible drugs with regenerative activity for the treatment of nervous system pathologies provoked by alcohol.


Assuntos
Inibidores de Adenilil Ciclases/farmacologia , Transtorno Amnésico Alcoólico/fisiopatologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , AMP Cíclico/fisiologia , Etanol/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Inibidores de Adenilil Ciclases/uso terapêutico , Adenilil Ciclases/metabolismo , Transtorno Amnésico Alcoólico/metabolismo , Transtorno Amnésico Alcoólico/patologia , Transtorno Amnésico Alcoólico/terapia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Regeneração Nervosa/fisiologia , Tecido Nervoso/efeitos dos fármacos , Tecido Nervoso/fisiologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Doenças Neurodegenerativas/induzido quimicamente , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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