RESUMEN
The peripheral nerve injury (PNI) affects the morphology of the whole locomotor apparatus, which can reach the myotendinous junction (MTJ) interface. In the injury condition, the skeletal muscle satellite cells (SC) are triggered, activated, and proliferated to repair their structure, and in the MTJ, the telocytes (TC) are associated to support the interface with the need for remodeling; in that way, these cells can be associated with SC. The study aimed to describe the SC and TC relationship after PNI at the MTJ. Sixteen adult Wistar rats were divided into Control Group (C, n = 8) and PNI Group (PNI, n = 8), PNI was performed by the constriction of the sciatic nerve. The samples were processed for transmission electron microscopy and immunostaining analysis. In the C group was evidenced the arrangement of sarcoplasmic evaginations and invaginations, the support collagen layer with a TC inside it, and an SC through vesicles internally and externally to then. In the PNI group were observed the disarrangement of invaginations and evaginations and sarcomeres degradation at MTJ, as the disposition of telopodes adjacent and in contact to the SC with extracellular vesicles and exosomes in a characterized paracrine activity. These findings can determine a link between the TCs and the SCs at the MTJ remodeling. RESEARCH HIGHLIGHTS: Peripheral nerve injury promotes the myotendinous junction (MTJ) remodeling. The telocytes (TC) and the satellite cells (SC) are present at the myotendinous interface. TC mediated the SC activity at MTJ.
Asunto(s)
Vesículas Extracelulares , Microscopía Electrónica de Transmisión , Ratas Wistar , Células Satélite del Músculo Esquelético , Telocitos , Animales , Telocitos/fisiología , Telocitos/ultraestructura , Células Satélite del Músculo Esquelético/fisiología , Células Satélite del Músculo Esquelético/citología , Ratas , Vesículas Extracelulares/ultraestructura , Vesículas Extracelulares/metabolismo , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/metabolismo , Masculino , Nervio Ciático/ultraestructura , Tendones/fisiología , Músculo Esquelético/ultraestructura , Unión MiotendinosaRESUMEN
Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.
Asunto(s)
Traumatismos de los Nervios Periféricos , Humanos , Anciano , Traumatismos de los Nervios Periféricos/terapia , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/metabolismo , Células de Schwann/metabolismo , Envejecimiento , Regulación de la Expresión Génica , DesnervaciónRESUMEN
Like the seasons of the year, all natural things happen in stages, going through adaptations when challenged, and Schwann cells are a great example of that. During maturation, these cells regulate several steps in peripheral nervous system development. The Spring of the cell means the rise and bloom through organized stages defined by time-dependent regulation of factors and microenvironmental influences. Once matured, the Summer of the cell begins: a high energy stage focused on maintaining adult homeostasis. The Schwann cell provides many neuron-glia communications resulting in the maintenance of synapses. In the peripheral nervous system, Schwann cells are pivotal after injuries, balancing degeneration and regeneration, similarly to when Autumn comes. Their ability to acquire a repair phenotype brings the potential to reconnect axons to targets and regain function. Finally, Schwann cells age, not only by growing old, but also by imposed environmental cues, like loss of function induced by pathologies. The Winter of the cell presents as reduced activity, especially regarding their role in repair; this reflects on the regenerative potential of older/less healthy individuals. This review gathers essential information about Schwann cells in different stages, summarizing important participation of this intriguing cell in many functions throughout its lifetime.
Asunto(s)
Traumatismos de los Nervios Periféricos/patología , Células de Schwann/fisiología , Animales , Senescencia Celular , Homeostasis , Humanos , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/metabolismo , Células de Schwann/patologíaRESUMEN
Experts have called attention to the possible negative impact of the coronavirus disease 2019 (COVID-19)-related cytokine storm syndrome on the progression of leprosy-related disabilities. We assessed the frequency of reactional states in patients co-infected with Mycobacterium leprae and severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS-CoV-2). We consecutively included patients during the first peak of the COVID-19 epidemic in Brazil and analyzed the expressions of genes encoding interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12A, IL-12B, and tumor necrosis factor-α in peripheral blood mononuclear cells. We included 64 leprosy patients and 50 controls. Twelve of the leprosy patients and 14 of the controls had been diagnosed with COVID-19. Co-infection was associated with increased IL-6 (P = 0.043) and IL-12B (P = 0.017) expression. The median disability grades were higher for leprosy/COVID-19 patients; however, the difference was not significant (P = 0.194). Patients co-infected with M. leprae and SARS-CoV-2 may experience a higher-grade proinflammatory state.
Asunto(s)
COVID-19/inmunología , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Lepra/complicaciones , Traumatismos de los Nervios Periféricos/etiología , Adulto , COVID-19/complicaciones , COVID-19/metabolismo , Estudios Transversales , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-12/genética , Interleucina-6/genética , Masculino , Persona de Mediana Edad , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patologíaRESUMEN
Programmed cell death 4 (PDCD4) protein is a tumor suppressor that inhibits translation through the mTOR-dependent initiation factor EIF4A, but its functional role and mRNA targets in neurons remain largely unknown. Our work identified that PDCD4 is highly expressed in axons and dendrites of CNS and PNS neurons. Using loss- and gain-of-function experiments in cortical and dorsal root ganglia primary neurons, we demonstrated the capacity of PDCD4 to negatively control axonal growth. To explore PDCD4 transcriptome and translatome targets, we used Ribo-seq and uncovered a list of potential targets with known functions as axon/neurite outgrowth regulators. In addition, we observed that PDCD4 can be locally synthesized in adult axons in vivo, and its levels decrease at the site of peripheral nerve injury and before nerve regeneration. Overall, our findings demonstrate that PDCD4 can act as a new regulator of axonal growth via the selective control of translation, providing a target mechanism for axon regeneration and neuronal plasticity processes in neurons.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Axones/metabolismo , Dendritas/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Células Cultivadas , Mutación con Ganancia de Función , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Mutación con Pérdida de Función , Masculino , Ratones , Células PC12 , Cultivo Primario de Células , Biosíntesis de Proteínas , Proteínas de Unión al ARN/genética , Ratas , Regulación hacia ArribaRESUMEN
PURPOSE: To evaluate the local nerve myelin recovery and the expression of PSD-95 protein and mRNA in the L4-L6 segment of the spinal cord after applying Brazilein to sciatic nerve injury BALB/c mice model and investigate the regulatory effects of Brazilein on myelin recovery after peripheral nerve injury. METHODS: A total of 160 BALB/c mice were selected to establish the unilateral sciatic nerve injury model and randomly divided into four groups: saline blank control, Brazilein high-dose, medium-dose, and low-dose. Mice were assessed at different time points (1 w, 2 w, 4 w, 8 w) after sciatic nerve injury for the sciatic functional index (SFI) and sciatic nerve function recovery of the injured side by myelin Luxol Fast Blue (LFB) staining of the sciatic nerve. In addition, immunohistochemistry, real time-PCR, and Western blot were used to detect the PSD-95 expression in the spinal cord L4-L6 segments of the injured sciatic nerve at each time point. RESULTS: The results of SFI and sciatic nerve function recovery, as well as, myelin LFB staining of the injured side indicated that all indexes of the Brazilein middle- and high-dose groups were significantly better than the low-dose and blank control groups at each time point. The PSD-95 expression in the L4-L6 segment of the spinal cord was statistically lower in the high- and medium-dose groups than in the low-dose and blank control groups at 1 w, 2 w, and 4 w, while the differences between the groups were not significant at 8 w. CONCLUSION: Brazilein inhibits PSD-95 activation in the corresponding segment of sciatic nerve spinal cord in BALB/c mice after sciatic nerve injury, thereby inhibiting the excessive expression of free radicals and promoting myelin regeneration.
Asunto(s)
Benzopiranos/uso terapéutico , Homólogo 4 de la Proteína Discs Large/antagonistas & inhibidores , Homólogo 4 de la Proteína Discs Large/biosíntesis , Indenos/uso terapéutico , Recuperación de la Función/fisiología , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/metabolismo , Animales , Benzopiranos/farmacología , Homólogo 4 de la Proteína Discs Large/genética , Expresión Génica , Indenos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/metabolismo , Recuperación de la Función/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Neuropatía Ciática/genética , Resultado del TratamientoRESUMEN
Voltage-gated T-type Ca2+ (CaV3) channels regulate diverse physiological events, including neuronal excitability, and have been linked to several pathological conditions such as absence epilepsy, cardiovascular diseases, and neuropathic pain. It is also acknowledged that calcium/calmodulin-dependent protein kinase II and protein kinases A and C regulate the activity of T-type channels. Interestingly, peripheral nerve injury induces tactile allodynia and upregulates CaV3.2 channels and cyclin-dependent kinase 5 (Cdk5) in dorsal root ganglia (DRG) and spinal dorsal horn. Here, we report that recombinant CaV3.2 channels expressed in HEK293 cells are regulatory targets of Cdk5. Site-directed mutagenesis showed that the relevant sites for this regulation are residues S561 and S1987. We also found that Cdk5 may regulate CaV3.2 channel functional expression in rats with mechanical allodynia induced by spinal nerve ligation (SNL). Consequently, the Cdk5 inhibitor olomoucine affected the compound action potential recorded in the spinal nerves, as well as the paw withdrawal threshold. Likewise, Cdk5 expression was upregulated after SNL in the DRG. These findings unveil a novel mechanism for how phosphorylation may regulate CaV3.2 channels and suggest that increased channel activity by Cdk5-mediated phosphorylation after SNL contributes nerve injury-induced tactile allodynia.SIGNIFICANCE STATEMENT Neuropathic pain is a current public health challenge. It can develop as a result of injury or nerve illness. It is acknowledged that the expression of various ion channels can be altered in neuropathic pain, including T-type Ca2+ channels that are expressed in sensory neurons, where they play a role in the regulation of cellular excitability. The present work shows that the exacerbated expression of Cdk5 in a preclinical model of neuropathic pain increases the functional expression of CaV3.2 channels. This finding is relevant for the understanding of the molecular pathophysiology of the disease. Additionally, this work may have a substantial translational impact, since it describes a novel molecular pathway that could represent an interesting therapeutic alternative for neuropathic pain.
Asunto(s)
Canales de Calcio Tipo T/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Potenciales de Acción/fisiología , Animales , Células HEK293 , Humanos , Ligadura , Masculino , Traumatismos de los Nervios Periféricos/metabolismo , Fosforilación , Ratas , Ratas Wistar , Nervios Espinales/lesiones , Nervios Espinales/cirugíaRESUMEN
High voltage-activated (HVA) Ca2+ (CaV) channels are oligomeric complexes formed by an ion-conducting main subunit (Cavα1) and at least two auxiliary subunits (Cavß and CaVα2δ). It has been reported that the expression of CaVα2δ1 increases in the dorsal root ganglia (DRGs) of animals with mechanical allodynia, and that the transcription factor Sp1 regulates the expression of the auxiliary subunit. Hence, the main aim of this work was to investigate the role of Sp1 as a molecular determinant of the exacerbated expression of CaVα2δ-1 in the nerve ligation-induced model of mechanical allodynia. Our results show that ligation of L5/L6 spinal nerves (SNL) produced allodynia and increased the expression of Sp1 and CaVα2δ-1 in the DRGs. Interestingly, intrathecal administration of the Sp1 inhibitor mithramycin A (Mth) prevented allodynia and decreased the expression of Sp1 and CaVα2δ-1. Likewise, electrophysiological recordings showed that incubation with Mth decreased Ca2+ current density in the DRG neurons, acting mostly on HVA channels. These results suggest that L5/L6 SNL produces mechanical allodynia and increases the expression of the transcription factor Sp1 and the subunit CaVα2δ-1 in the DRGs, while Mth decreases mechanical allodynia and Ca2+ currents through HVA channels in sensory neurons by reducing the functional expression of the CaVα2δ-1 subunit.
Asunto(s)
Canales de Calcio/metabolismo , Ganglios Espinales/metabolismo , Neuralgia/metabolismo , Células Receptoras Sensoriales/metabolismo , Factor de Transcripción Sp1/metabolismo , Animales , Femenino , Ganglios Espinales/efectos de los fármacos , Neuralgia/etiología , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/metabolismo , Plicamicina/análogos & derivados , Plicamicina/farmacología , Ratas Wistar , Células Receptoras Sensoriales/efectos de los fármacos , Factor de Transcripción Sp1/antagonistas & inhibidoresRESUMEN
Peripheral nerve injuries severely impair patients' quality of life as full recovery is seldom achieved. Upon axonal disruption, the distal nerve stump undergoes fragmentation, and myelin breaks down; the subsequent regeneration progression is dependent on cell debris removal. In addition to tissue clearance, macrophages release angiogenic and neurotrophic factors that contribute to axon growth. Based on the importance of macrophages for nerve regeneration, especially during the initial response to injury, we treated mice with granulocyte-macrophage colony-stimulating factor (GM-CSF) at various intervals after sciatic nerve crushing. Sciatic nerves were histologically analyzed at different time intervals after injury for the presence of macrophages and indicators of regeneration. Functional recovery was followed by an automated walking track test. We found that GM-CSF potentiated early axon growth, as indicated by the enhanced expression of growth-associated protein at 7 days postinjury. Inducible nitric oxide synthase expression increased at the beginning and at the end of the regenerative process, suggesting that nitric oxide is involved in axon growth and pruning. As expected, GM-CSF treatment stimulated macrophage infiltration, which increased at 7 and 14 days; however, it did not improve myelin clearance. Instead, GM-CSF stimulated early brain-derived neurotrophic factor (BDNF) production, which peaked at 7 days. Locomotor recovery pattern was not improved by GM-CSF treatment. The present results suggest that GM-CSF may have beneficial effects on early axonal regeneration.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Regeneración Nerviosa/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Locomoción/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/metabolismo , Recuperación de la Función/efectos de los fármacos , Nervio Ciático/lesiones , Degeneración Walleriana/tratamiento farmacológico , Degeneración Walleriana/metabolismoRESUMEN
Dorsal root ganglia (DRG) neurons regenerate spontaneously after traumatic or surgical injury. Long noncoding RNAs (lncRNAs) are involved in various biological regulation processes. Conditions of lncRNAs in DRG neuron injury deserve to be further investigated. Transcriptomic analysis was performed by high-throughput Illumina HiSeq2500 sequencing to profile the differential genes in L4-L6 DRGs following rat sciatic nerve tying. A total of 1,228 genes were up-regulated and 1,415 down-regulated. By comparing to rat lncRNA database, 86 known and 26 novel lncRNA genes were found to be differential. The 86 known lncRNA genes modulated 866 target genes subject to gene ontology (GO) and KEGG enrichment analysis. The genes involved in the neurotransmitter status of neurons were downregulated and those involved in a neuronal regeneration were upregulated. Known lncRNA gene rno-Cntnap2 was downregulated. There were 13 credible GO terms for the rno-Cntnap2 gene, which had a putative function in cell component of voltage-gated potassium channel complex on the cell surface for neurites. In 26 novel lncRNA genes, 4 were related to 21 mRNA genes. A novel lncRNA gene AC111653.1 improved rno-Hypm synthesizing huntingtin during sciatic nerve regeneration. Real time qPCR results attested the down-regulation of rno-Cntnap lncRNA gene and the upregulation of AC111653.1 lncRNA gene. A total of 26 novel lncRNAs were found. Known lncRNA gene rno-Cntnap2 and novel lncRNA AC111653.1 were involved in neuropathic pain of DRGs after spared sciatic nerve injury. They contributed to peripheral nerve regeneration via the putative mechanisms.
Asunto(s)
Ganglios Espinales/lesiones , Neuralgia/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , Nervio Ciático/metabolismo , Transcriptoma , Animales , Secuencia de Bases , Western Blotting , Mapeo Cromosómico , Modelos Animales de Enfermedad , Ganglios Espinales/metabolismo , Ganglios Espinales/fisiopatología , Regulación de la Expresión Génica , Masculino , Datos de Secuencia Molecular , Neuralgia/genética , Neuralgia/fisiopatología , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/fisiopatología , ARN Largo no Codificante/genética , ARN Largo no Codificante/fisiología , ARN Mensajero/metabolismo , ARN Mensajero/fisiología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Nervio Ciático/fisiopatologíaRESUMEN
OBJECTIVE: To determine the role of anion exchanger 3 (AE3) in dorsal root ganglion (DRG) in nerve injury-induced chronic nociception in the rat. METHODS: Spared nerve injury (SNI) was used to induce neuropathic pain. Von Frey filaments and Hargreaves test were used to assess tactile allodynia and thermal hyperalgesia, respectively. Drugs were given by intrathecal administration. Western blotting was used to determine AE3 expression in DRG. KEY FINDINGS: SNI produced long-lasting mechanical allodynia and thermal hyperalgesia. AE3 was found in DRG of sham-operated rats. SNI enhanced baseline AE3 expression in L4 and L5 DRGs at days 7 and 14, respectively. In contrast, SNI did not affect AE3 expression in L6 DRG. AE3 expression returned to baseline levels 21 days after SNI. Intrathecal 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) (5-50 µg) pretreatment prevented SNI-induced allodynia and, at a lesser extent, hyperalgesia. Moreover, DIDS (50 µg) reduced SNI-induced AE3 upregulation in L4, but not L5, DRGs. Intrathecal DIDS (5-50 µg) or anti-AE3 antibody (1 µg), but not vehicle, post-treatment (6 days) partially reversed SNI-induced allodynia and hyperalgesia. DIDS or anti-AE3 antibody post-treatment diminished SNI-induced AE3 upregulation in L4 and L5 DRGs. CONCLUSIONS: Data suggest that AE3 is present in DRG and contributes to mechanical allodynia and thermal hyperalgesia in neuropathic rats.
Asunto(s)
Antiportadores de Cloruro-Bicarbonato/biosíntesis , Ganglios Espinales/metabolismo , Hiperalgesia/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Ácido 4,4'-Diisotiocianostilbeno-2,2'-Disulfónico/farmacología , Animales , Autoanticuerpos/farmacología , Antiportadores de Cloruro-Bicarbonato/efectos de los fármacos , Femenino , Hiperalgesia/complicaciones , Hiperalgesia/prevención & control , Inyecciones Espinales , Dimensión del Dolor , Traumatismos de los Nervios Periféricos/complicaciones , RatasRESUMEN
Dorsal root ganglia (DRG) neurons regenerate spontaneously after traumatic or surgical injury. Long noncoding RNAs (lncRNAs) are involved in various biological regulation processes. Conditions of lncRNAs in DRG neuron injury deserve to be further investigated. Transcriptomic analysis was performed by high-throughput Illumina HiSeq2500 sequencing to profile the differential genes in L4-L6 DRGs following rat sciatic nerve tying. A total of 1,228 genes were up-regulated and 1,415 down-regulated. By comparing to rat lncRNA database, 86 known and 26 novel lncRNA genes were found to be differential. The 86 known lncRNA genes modulated 866 target genes subject to gene ontology (GO) and KEGG enrichment analysis. The genes involved in the neurotransmitter status of neurons were downregulated and those involved in a neuronal regeneration were upregulated. Known lncRNA gene rno-Cntnap2 was downregulated. There were 13 credible GO terms for the rno-Cntnap2 gene, which had a putative function in cell component of voltage-gated potassium channel complex on the cell surface for neurites. In 26 novel lncRNA genes, 4 were related to 21 mRNA genes. A novel lncRNA gene AC111653.1 improved rno-Hypm synthesizing huntingtin during sciatic nerve regeneration. Real time qPCR results attested the down-regulation of rno-Cntnap lncRNA gene and the upregulation of AC111653.1 lncRNA gene. A total of 26 novel lncRNAs were found. Known lncRNA gene rno-Cntnap2 and novel lncRNA AC111653.1 were involved in neuropathic pain of DRGs after spared sciatic nerve injury. They contributed to peripheral nerve regeneration via the putative mechanisms.
Asunto(s)
Animales , Masculino , Ratas , Nervio Ciático/metabolismo , ARN Mensajero/genética , Traumatismos de los Nervios Periféricos/metabolismo , ARN Largo no Codificante/metabolismo , Ganglios Espinales/lesiones , Neuralgia/metabolismo , Datos de Secuencia Molecular , Secuencia de Bases , Regulación de la Expresión Génica , Western Blotting , Mapeo Cromosómico , Modelos Animales de Enfermedad , Transcriptoma , Ganglios Espinales/fisiopatología , Ganglios Espinales/metabolismoRESUMEN
Preventing damage caused by nerve degeneration is a great challenge. There is a growing body of evidence implicating extracellular nucleotides and their P2 receptors in many pathophysiological mechanisms. In this work we aimed to investigate the effects of the administration of Brilliant Blue G (BBG) and Pyridoxalphosphate-6-azophenyl-2', 4'- disulphonic acid (PPADS), P2X7 and P2 non-selective receptor antagonists, respectively, on sciatic nerve regeneration. Four groups of mice that underwent nerve crush lesion were used: two control groups treated with vehicle (saline), a group treated with BBG and a group treated with PPADS during 28days. Gastrocnemius muscle weight was evaluated. For functional evaluation we used the Sciatic Functional Index (SFI) and the horizontal ladder walking test. Nerves, dorsal root ganglia and spinal cords were processed for light and electron microscopy. Antinoceptive effects of BBG and PPADS were evaluated through von Frey E, and the levels of IL-1ß and TNF-α were analyzed by ELISA. BBG promoted an increase in the number of myelinated fibers and on axon, fiber and myelin areas. BBG and PPADS led to an increase of TNF-α and IL-1ß in the nerve on day 1 and PPADS caused a decrease of IL-1ß on day 7. Mechanical allodynia was reversed on day 7 in the groups treated with BBG and PPADS. We concluded that BBG promoted a better morphological regeneration after ischiatic crush injury, but this was not followed by anticipation of functional improvement. In addition, both PPADS and BBG presented anti-inflammatory as well as antinociceptive effects.
Asunto(s)
Lesiones por Aplastamiento/tratamiento farmacológico , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/farmacología , Analgésicos/farmacología , Animales , Lesiones por Aplastamiento/metabolismo , Lesiones por Aplastamiento/patología , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patología , Interleucina-1alfa/metabolismo , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Regeneración Nerviosa/fisiología , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Distribución Aleatoria , Receptores Purinérgicos P2X7/metabolismo , Colorantes de Rosanilina/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The aim of this study was to investigate the effect of the anti-inflammatory and anti-fibrotic actions of ANX1 on erectile function (EF). Forty-eight male Wistar rats were randomly distributed into four equal groups: one group (sham operation-control) and three groups (bilateral cavernous nerve (CN) crush injury). Crush injury groups were treated prior to injury with an intravascular injection of either ANX1 (50 or 100 µg kg-1) or vehicle. EF was assessed by CN electrical stimulation at 2 and 7 days after CN injury with histomorphometric and immunohistochemical analysis. ANX1 demonstrated functional preservation as the increase in intracavernous pressure (ICP). A dose-response relationship regarding the effect on penile tissue was confirmed, and preservation of the penile dorsal nerves and anti-apoptotic effects in the corpus cavernosum (real P-value vs injured control). ANX1 treatment prevented collagen deposition and smooth muscle loss in the penis. ANX1 normalized the expression of vascular endothelial growth factor and decreased tumor necrosis factor-α in the lumen of the blood vessels of the organ. ANX1 proved effective in preserving EF in a rat model of neurogenic erectile dysfunction. ANX1 treatment before CN injury in rats improved erectile recovery, enhanced vascular regeneration and preserved the micro-architecture of the corpus cavernosum. The clinical availability of this compound merits application in penile rehabilitation studies following radical prostatectomy.
Asunto(s)
Anexina A1/farmacología , Antiinflamatorios/farmacología , Disfunción Eréctil/tratamiento farmacológico , Erección Peniana/efectos de los fármacos , Pene/efectos de los fármacos , Traumatismos de los Nervios Periféricos/complicaciones , Animales , Anexina A1/uso terapéutico , Modelos Animales de Enfermedad , Disfunción Eréctil/etiología , Disfunción Eréctil/metabolismo , Disfunción Eréctil/fisiopatología , Masculino , Compresión Nerviosa , Erección Peniana/fisiología , Pene/metabolismo , Pene/fisiopatología , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/fisiopatología , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Peripheral nerve injury (PNI) is a serious public health problem that is linked with motor, sensory and autonomic deficits. Given the fact that this type of disorder leads to a decreased quality of life in most patients and adherence of available drugs is limited and have adverse effects, we investigated the efficacy of natural products in a PNI model. The search terms plants, medicinal, nerve regeneration, nerve crush, sciatic nerve as well as MeSH terms or free-text words were used to retrieve English language articles in PubMed, Scopus, Web of Science and LILACS published until July 2015. After sciatic nerve crush, natural products have improved significantly motor performance, sensory function and electrical conductance measured over weeks. Among the pharmacological targets suggested by the action of natural products, there were citations on the activation of the antiapoptotic signaling pathway, modulation in the expression of pro-inflammatory cytokines and neurotrophic factors. The systematic review provides scientific evidence that natural products are pharmacologically effective in the treatment of PNI such as sciatic nerve crush.
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Productos Biológicos/uso terapéutico , Regeneración Nerviosa/efectos de los fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Animales , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patología , Extractos Vegetales/uso terapéuticoRESUMEN
Neurotrophins are crucial in relation to axonal regrowth and remyelination following injury; and neural mobilization (NM) is a noninvasive therapy that clinically is effective in neuropathic pain treatment, but its mechanisms remains unclear. We examined the effects of NM on the regeneration of sciatic nerve after chronic constriction injury (CCI) in rats. The CCI was performed on adult male rats, submitted to 10 sessions of NM, starting 14 days after CCI. Then, the nerves were analyzed using transmission electron microscopy and western blot for neural growth factor (NGF) and myelin protein zero (MPZ). We observed an increase of NGF and MPZ after CCI and NM. Electron microscopy revealed that CCI-NM samples had high numbers of axons possessing myelin sheaths of normal thickness and less inter-axonal fibrosis than the CCI. These data suggest that NM is effective in facilitating nerve regeneration and NGF and MPZ are involved in this effect.
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Manipulaciones Musculoesqueléticas , Proteína P0 de la Mielina/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/metabolismo , Animales , Axones/metabolismo , Axones/ultraestructura , Masculino , Proteína P0 de la Mielina/genética , Factor de Crecimiento Nervioso/genética , Traumatismos de los Nervios Periféricos/terapia , Ratas , Ratas Wistar , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/fisiologíaRESUMEN
Standard vein graft (SVG) and inside out vein graft (IOVG) techniques to promote peripheral nerve regeneration have been widely studied since last two decades. In this experimental study, we attempted to compare these two techniques and analyze the differences in the expression of the neurotrophins during peripheral nerve regeneration. Thirty-six male Wistar rats were used in this sciatic nerve transection model and were divided into two experimental groups (SVG and IOVG) and one sham operated control group. An overall defect of 10 mm was made in the sciatic nerve of the animals in the experimental groups. Each group consisted of two time intervals of 6 and 12 weeks (n = 6). After each experimental interval, sciatic functional index (SFI) along with area and diameter of the axons and fibers of each group were calculated. Muscle mass measurements were also evaluated to see any functional recovery in the groups. Expression of neurotrophins in the graft and distal stump were analyzed with the help of RT-PCR. SFI obtained from walking track analysis showed poor motor recovery in the experimental groups during both time intervals. No significant differences in the histological, morphometric (P > 0.05), and muscle mass measurements (P > 0.05) between the two experimental groups were observed. Analysis of RT-PCR data exhibited an increase in the expression of NT-3 with time in both the grafts (6 weeks 0.428 ± 0.392, 12 weeks 1.089 ± 0.455, P < 0.05) and distal stump (6 weeks 0.411 ± 0.306, 12 weeks 0.807 ± 0.303, P < 0.05) of the SVG group. The study concludes that there is no substantial difference in the nerve regeneration ability between both the techniques. Also, the difference in the level of NT-3 between SVG and IOVG suggests a distinct regulation of NT-3 in peripheral nerve regeneration.
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Regeneración Tisular Dirigida/métodos , Venas Yugulares/trasplante , Factores de Crecimiento Nervioso/metabolismo , Regeneración Nerviosa/fisiología , Traumatismos de los Nervios Periféricos/cirugía , Nervio Ciático/lesiones , Animales , Biomarcadores/metabolismo , Masculino , Factor de Crecimiento Nervioso/metabolismo , Neurotrofina 3/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Ratas , Ratas Wistar , Nervio Ciático/metabolismo , Nervio Ciático/cirugíaRESUMEN
Following axotomy, the contact between motoneurons and muscle fibers is disrupted, triggering a retrograde reaction at the neuron cell body within the spinal cord. Together with chromatolysis, a hallmark of such response to injury is the elimination of presynaptic terminals apposing to the soma and proximal dendrites of the injured neuron. Excitatory inputs are preferentially eliminated, leaving the cells under an inhibitory influence during the repair process. This is particularly important to avoid glutamate excitotoxicity. Such shift from transmission to a regeneration state is also reflected by deep metabolic changes, seen by the regulation of several genes related to cell survival and axonal growth. It is unclear, however, how exactly synaptic stripping occurs, but there is substantial evidence that glial cells play an active role in this process. In one hand, immune molecules, such as the major histocompatibility complex (MHC) class I, members of the complement family and Toll-like receptors are actively involved in the elimination/reapposition of presynaptic boutons. On the other hand, plastic changes that involve sprouting might be negatively regulated by extracellular matrix proteins such as Nogo-A, MAG and scar-related chondroitin sulfate proteoglycans. Also, neurotrophins, stem cells, physical exercise and several drugs seem to improve synaptic stability, leading to functional recovery after lesion. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.
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Axones/fisiología , Plasticidad Neuronal , Traumatismos de los Nervios Periféricos/fisiopatología , Sinapsis/fisiología , Animales , Axones/metabolismo , Axotomía , Encéfalo/metabolismo , Encéfalo/fisiopatología , Humanos , Neuronas Motoras/fisiología , Neuronas Motoras/ultraestructura , Regeneración Nerviosa , Neuroglía/fisiología , Neuroglía/ultraestructura , Traumatismos de los Nervios Periféricos/inmunología , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Sinapsis/metabolismo , Sinapsis/ultraestructuraRESUMEN
Chemokines are associated with both inflammatory and immune responses and play an important role in the pathophysiological process associated with neuropathic pain following peripheral nerve injury. Here, we investigated the involvement of peripheral keratinocyte-derived chemokine (KC) in the pathogenesis of neuropathic pain induced by the partial ligation of the sciatic nerve (PLSN) in mice. PLSN increased KC levels and its mRNA in both the sciatic nerve and spinal cord when compared with sham-operated mice. In addition, PLSN-induced mechanical and thermal hyperalgesia was prevented by systemic (i.v.) treatment with anti-KC antibody either at the time of surgery or on the 4th day after surgery. Also, intrathecal (i.t.) injection of anti-KC antibody prevented mechanical hyperalgesia induced by PLSN when administered at the time of surgery or on the 4th day after surgery. Importantly, the intraneural (i.n.) injection of KC in the mouse sciatic nerve elicited long-lasting mechanical hyperalgesia, which was prevented by the selective CXCR2 antagonist SB225002. The established mechanical hyperalgesia induced by KC was expressively reduced by the treatment with gabapentin, a drug widely used to treat chronic pain in humans. Intraneural KC injection also caused neutrophil migration into the mouse sciatic nerve and the depletion of neutrophils, by pre-treating animals with vinblastine, significantly reduced KC-induced mechanical hyperalgesia. Similar results were obtained for the pre-treatment with indomethacin, a non-selective COX inhibitor. We also demonstrated an increased level of cytokines (IL-1ß, IL-6, and MCP-1, but not TNF-α) after i.n. injection of KC in the mouse sciatic nerve. Together, these findings suggest a role for KC in the development of neuropathic pain in mice by attracting neutrophils to the injured site and increasing the production of proinflammatory mediators. Therefore, strategies to inhibit the action or the release of this chemokine could constitute a therapeutic tool for the management of neuropathic pain in humans.