RESUMEN
We have previously reported that morroniside promoted motor activity after spinal cord injury (SCI) in rats. However, the mechanism by which morroniside induces recovery of injured spinal cord (SC) remains unknown. In the current study, RNA sequencing (RNA-seq) was employed to evaluate changes of gene expressions at the transcriptional level of the injured spinal cords in morroniside-administrated rats. Principal component analysis, analysis of enriched Gene Ontology (GO), enrichment analyses Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and other bioinformatics analyses were executed to distinguish differentially expressed genes (DEGs). The results of RNA-seq confirmed the anti-inflammatory and anti-apoptotic effects of morroniside on injured SC tissues, and provided the basis for additional research of the mechanisms involving the protective effects of morroniside on SCI.
Asunto(s)
Antiinflamatorios/administración & dosificación , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/efectos de los fármacos , Glicósidos/administración & dosificación , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Glicósidos/farmacología , Análisis de Componente Principal , Distribución Aleatoria , Ratas , Análisis de Secuencia de ARN , Traumatismos de la Médula Espinal/etiología , Traumatismos de la Médula Espinal/genéticaRESUMEN
Spinal cord injury (SCI) is a disabling condition that often leads to permanent neurological deficits without an effective treatment. Reactive oxygen species (ROS) produced during oxidative stress play a vital role in the pathogenesis following SCI. The antioxidant morroniside is the main active component of the Chinese medicine Cornus officinalis. In recent years, it has been reported that morroniside has therapeutic effects on damage to multiple organs mediated by oxidative damage, but the effect of morroniside on SCI has not been reported. The purpose of this study was therefore to assess the therapeutic effect of morroniside on SCI, and to identify its underlying mechanism by direct intragastric administration immediately after SCI. Our study showed that morroniside treatment improved the functional recovery of rats following SCI. This behavioral improvement was associated with the higher survival in neurons and oligodendrocytes following SCI, which increased the capacity of injured spinal cord (SC) to form myelin and repair tissue, eventually contributing to improved neurological outcome. Furthermore, our study found that oxygen free radicals increased and antioxidant enzyme activity decreased in the injured SC. Interestingly, morroniside treatment decreased oxygen free radical levels and increased antioxidant enzyme activities. Together, our results suggested that morroniside may be an effective treatment for improving outcomes following SCI, and that its antioxidant activity may be one of the mechanisms by which morroniside exerts neuroprotective effects on SCI.
Asunto(s)
Glicósidos/farmacología , Fármacos Neuroprotectores/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Supervivencia Celular/efectos de los fármacos , Cornus/química , Femenino , Locomoción , Neuronas/patología , Oligodendroglía/patología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Recuperación de la Función , Traumatismos de la Médula Espinal/patologíaRESUMEN
MicroRNAs (miRNAs) are involved in a series of pathology of spinal cord injury (SCI). Although, locally expressed miRNAs have advantages in studying the pathological mechanism, they cannot be used as biomarkers. The "free circulation" miRNAs can be used as biomarkers, but they have low concentration and poor stability in body fluids. Exosomal miRNAs in body fluids have many advantages comparing with free miRNAs. Therefore, we hypothesized that the specific miRNAs in the central nervous system might be transported to the peripheral circulation and concentrated in exosomes after injury. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and subactue SCI rats were analyzed. The results showed that SCI can lead to changes of serum exosomal miRNAs. These changed miRNAs and their associated signaling pathways may explain the pathological mechanism of suacute SCI. More importantly, we found some valuable serum exosomal miRNAs for diagnosis and prognosis of SCI.
Asunto(s)
Exosomas/genética , MicroARNs/metabolismo , Traumatismos de la Médula Espinal/genética , Animales , Perfilación de la Expresión Génica , ARN Pequeño no Traducido/metabolismo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Traumatismos de la Médula Espinal/sangre , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patologíaRESUMEN
Previous studies have shown that caspase-1 plays an important role in the acute inflammatory response of spinal cord injury (SCI). VX765, a novel and irreversible caspase1 inhibitor, has been reported to effectively intervene in inflammation. However, the effect of VX765 on genomewide transcription in acutely injured spinal cords remains unknown. Therefore, in the present study, RNAsequencing (RNASeq) was used to analyze the effect of VX765 on the local expression of gene transcription 8 h following injury. The differentially expressed genes (DEGs) underwent enrichment analysis of functions and pathways by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Parallel analysis of western blot confirmed that VX765 can effectively inhibit the expression and activation of caspase1. RNASeq showed that VX765 treatment resulted in 1,137 upregulated and 1,762 downregulated DEGs. These downregulated DEGs and their associated signaling pathways, such as focal adhesion, cytokinecytokine receptor interaction, leukocyte transendothelial migration, extracellular matrixreceptor interaction, phosphatidylinositol 3kinaseprotein kinase B, Rap1 and hypoxia inducible factor1 signaling pathway, are mainly associated with inflammatory response, local hypoxia, macrophage differentiation, adhesion migration and apoptosis of local cells. This suggests that the application of VX765 in the acute phase can improve the local microenvironment of SCI by inhibiting caspase1. However, whether VX765 can be used as a therapeutic drug for SCI requires further exploration. The sequence data have been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA548970).
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de Caspasas/farmacología , Dipéptidos/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Transcriptoma/efectos de los fármacos , para-Aminobenzoatos/farmacología , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Caspasa 1/metabolismo , Inhibidores de Caspasas/uso terapéutico , Dipéptidos/uso terapéutico , Femenino , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , para-Aminobenzoatos/uso terapéuticoRESUMEN
MicroRNAs (miRNAs) are involved in a series of pathology of spinal cord injury (SCI). Although, locally expressed miRNAs have advantages in studying the pathological mechanism, they cannot be used as biomarkers. The "free circulation" miRNAs can be used as biomarkers, but they have low concentration and poor stability in body fluids. Exosomal miRNAs in body fluids have many advantages comparing with free miRNAs. Therefore, we hypothesized that the specific miRNAs in the central nervous system might be transported to the peripheral circulation and concentrated in exosomes after injury. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and subactue SCI rats were analyzed. The results showed that SCI can lead to changes of serum exosomal miRNAs. These changed miRNAs and their associated signaling pathways may explain the pathological mechanism of suacute SCI. More importantly, we found some valuable serum exosomal miRNAs for diagnosis and prognosis of SCI.
Asunto(s)
MicroARN Circulante/genética , Exosomas/genética , Traumatismos de la Médula Espinal/genética , Transcriptoma , Animales , Biomarcadores/sangre , MicroARN Circulante/sangre , Exosomas/metabolismo , Femenino , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/sangreAsunto(s)
Carbazoles/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Femenino , Actividad Motora/efectos de los fármacos , NAD/metabolismo , Neuronas/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoAsunto(s)
Exosomas/metabolismo , MicroARNs/sangre , Traumatismos de la Médula Espinal/sangre , Traumatismos de la Médula Espinal/genética , Enfermedad Aguda , Animales , Regulación hacia Abajo/genética , Exosomas/ultraestructura , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , MicroARNs/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Médula Espinal/patología , Regulación hacia Arriba/genéticaAsunto(s)
Inmunidad Adaptativa/inmunología , Macrófagos/inmunología , Traumatismos de la Médula Espinal/inmunología , Transcriptoma/genética , Inmunidad Adaptativa/genética , Traslado Adoptivo/métodos , Animales , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Inflamación/genética , Inflamación/inmunología , Fármacos Neuroprotectores/inmunología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/genética , Transducción de Señal/inmunología , Médula Espinal/inmunología , Traumatismos de la Médula Espinal/genética , Receptores Toll-Like/genética , Transcriptoma/inmunologíaRESUMEN
Previous studies by our group have demonstrated that the transplantation of exogenous platelet-derived growth factor (PDGF)-AA-overexpressing oligodendrocyte progenitor cells (OPCs) promotes tissue repair and recovery of neurological function in a rat model of spinal cord injury (SCI). However, it remains unclear whether treatment with PDGF-AA also affects endogenous oligodendrocytes (OLs) or even neurons, thus promoting further functional recovery after SCI. In the present study, we evaluated the therapeutic potential of PDGF-AA treatment by direct subcutaneous injection of PDGF-AA immediately after SCI. We demonstrated that PDGF-AA injection resulted in increased tissue sparing, myelination and functional recovery in rats following SCI. Further experimentation confirmed that PDGF-AA increased the survival of endogenous OPCs and OLs, and promoted the proliferation of OPCs and their differentiation into OLs. Moreover, PDGF-AA also protected motor neurons from death in the injured spinal cord. These results indicated that PDGF-AA administration may be an effective treatment for SCI.