RESUMO
Traumatic spinal cord injury is characterized by immediate and irreversible tissue loss at the lesion site and secondary tissue damage. Secondary injuries should, in principle, be preventable, although no effective treatment options currently exist for patients with acute spinal cord injury. Traumatized tissues release excessive amounts of adenosine triphosphate and activate the P2X purinoceptor 7/pannexin1 complex, which is associated with secondary injury. We investigated the neuroprotective effects of the blue dye Brilliant Blue FCF, a selective inhibitor of P2X purinoceptor 7/pannexin1 that is approved for use as a food coloring, by comparing it with Brilliant Blue G, a P2X7 purinoceptor antagonist, and carbenoxolone, which attenuates P2X purinoceptor 7/pannexin1 function, in a rat spinal cord injury model. Brilliant Blue FCF administered early after spinal cord injury reduced spinal cord anatomical damage and improved motor recovery without apparent toxicity. Brilliant Blue G had the highest effect on this neurological recovery, with Brilliant Blue FCF and carbenoxolone having comparable improvement. Furthermore, Brilliant Blue FCF administration reduced local astrocytic and microglial activation and neutrophil infiltration, and no differences in these histological effects were observed between compounds. Thus, Brilliant Blue FCF protects spinal cord neurons after spinal cord injury and suppresses local inflammatory responses as well as Brilliant Blue G and carbenoxolone.
Assuntos
Trifosfato de Adenosina , Carbenoxolona , Conexinas , Proteínas do Tecido Nervoso , Recuperação de Função Fisiológica , Corantes de Rosanilina , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Animais , Conexinas/metabolismo , Conexinas/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Carbenoxolona/farmacologia , Carbenoxolona/uso terapêutico , Corantes de Rosanilina/farmacologia , Corantes de Rosanilina/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Recuperação de Função Fisiológica/efeitos dos fármacos , Ratos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Ratos Sprague-Dawley , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Feminino , Infiltração de Neutrófilos/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the mechanism underlying the neuroprotective effect of linarin (LIN) against microglia activation-mediated inflammation and neuronal apoptosis following spinal cord injury (SCI). METHODS: Fifty C57BL/6J mice (8- 10 weeks old) were randomized to receive sham operation, SCI and linarin treatment at 12.5, 25, and 50 mg/kg following SCI (n=10). Locomotor function recovery of the SCI mice was assessed using the Basso Mouse Scale, inclined plane test, and footprint analysis, and spinal cord tissue damage and myelination were evaluated using HE and LFB staining. Nissl staining, immunofluorescence assay and Western blotting were used to observe surviving anterior horn motor neurons in injured spinal cord tissue. In cultured BV2 cells, the effects of linarin against lipopolysaccharide (LPS)induced microglia activation, inflammatory factor release and signaling pathway changes were assessed with immunofluorescence staining, Western blotting, RT-qPCR, and ELISA. In a BV2 and HT22 cell co-culture system, Western blotting was performed to examine the effect of linarin against HT22 cell apoptosis mediated by LPS-induced microglia activation. RESULTS: Linarin treatment significantly improved locomotor function (P < 0.05), reduced spinal cord damage area, increased spinal cord myelination, and increased the number of motor neurons in the anterior horn of the SCI mice (P < 0.05). In both SCI mice and cultured BV2 cells, linarin effectively inhibited glial cell activation and suppressed the release of iNOS, COX-2, TNF-α, IL-6, and IL-1ß, resulting also in reduced neuronal apoptosis in SCI mice (P < 0.05). Western blotting suggested that linarin-induced microglial activation inhibition was mediated by inhibition of the TLR4/NF- κB signaling pathway. In the cell co-culture experiments, linarin treatment significantly decreased inflammation-mediated apoptosis of HT22 cells (P < 0.05). CONCLUSION: The neuroprotective effect of linarin is medicated by inhibition of microglia activation via suppressing the TLR4/NFκB signaling pathway, which mitigates neural inflammation and reduce neuronal apoptosis to enhance motor function of the SCI mice.
Assuntos
Apoptose , Camundongos Endogâmicos C57BL , Microglia , NF-kappa B , Transdução de Sinais , Traumatismos da Medula Espinal , Receptor 4 Toll-Like , Animais , Camundongos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptor 4 Toll-Like/metabolismo , Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Cumarínicos/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , GlicosídeosRESUMO
Patients with spinal cord injury (SCI) have permanent devastating motor and sensory disabilities. Secondary SCI is known for its complex progression and presents with sophisticated aberrant inflammation, vascular changes, and secondary cellular dysfunction, which aggravate the primary damage. Since their initial discovery, the potent neuroprotective effects and powerful delivery abilities of exosomes (Exos) have been reported in different research fields, including SCI. In this study, we summarize therapeutic advances related to the application of Exos in preclinical animal studies. Subsequently, we discuss the mechanisms of action of Exos derived from diverse cell types, including neurogenesis, angiogenesis, blood-spinal cord barrier preservation, anti-apoptosis, and anti-inflammatory potential. We also evaluate the relationship between the Exo delivery cargo and signaling pathways. Finally, we discuss the challenges and advantages of using Exos to offer innovative insights regarding the development of efficient clinical strategies for SCI.
Assuntos
Exossomos , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Exossomos/metabolismo , Humanos , Animais , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologiaRESUMO
INTRODUCTION: Spinal cord injury (SCI) may bring lifelong consequences for affected patients and a high financial burden to the health care system. SOURCE OF DATA: Published peer-reviewed scientific articles identified from EMBASE, Google Scholar, PubMed and Scopus. AREAS OF AGREEMENT: Surgery and blood pressure management are the main targets in acute SCI to avoid secondary damage. AREAS OF CONTROVERSY: The management of secondary chronic SCI is challenging, with unpredictable outcomes. GROWING POINTS: Given the lack of consensus on pharmacological therapy for acute and secondary chronic SCI, the present study analyses the currently available drugs and treatment options to manage secondary chronic SCI. AREAS TIMELY FOR DEVELOPING RESEARCH: Different approaches exist for the pharmacological management of secondary chronic SCI. One of the most investigated drugs, 4-aminopyridine, improves central motor conduction and shows improvement in neurological signs. Positive results in different areas have been observed in patients receiving the anti-spastic drugs tizanidine and baclofen or Granulocyte colony-stimulating factor. Growth hormone showed only minimal or no significant effects, and the therapy of secondary chronic SCI with riluzole has been poorly researched to date.
Assuntos
Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Humanos , Doença Crônica , Riluzol/uso terapêutico , 4-Aminopiridina/uso terapêutico , Clonidina/uso terapêutico , Clonidina/análogos & derivados , Baclofeno/uso terapêuticoRESUMO
AIM: We aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism. METHODS: Rats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post-injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post-injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord. RESULTS: CLP290 and bumetanide alleviated SCI-associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate-Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K+-Cl-cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na+-K+-Cl-cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non-significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group. CONCLUSION: Combined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhances GABAA receptor-mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short-term effect.
Assuntos
Bumetanida , Cotransportadores de K e Cl- , Neuralgia , Ratos Sprague-Dawley , Membro 2 da Família 12 de Carreador de Soluto , Traumatismos da Medula Espinal , Simportadores , Animais , Bumetanida/farmacologia , Bumetanida/uso terapêutico , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Neuralgia/metabolismo , Ratos , Masculino , Simportadores/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Quimioterapia Combinada , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Acetatos , IndenosRESUMO
Traumatic spinal cord injury (tSCI) has complex pathophysiological events that begin after the initial trauma. One such event is fibroglial scar formation by fibroblasts and reactive astrocytes. A strong inhibition of axonal growth is caused by the activated astroglial cells as a component of fibroglial scarring through the production of inhibitory molecules, such as chondroitin sulfate proteoglycans or myelin-associated proteins. Here, we used neural precursor cells (aldynoglia) as promoters of axonal growth and a fibrin hydrogel gelled under alkaline conditions to support and guide neuronal cell growth, respectively. We added Tol-51 sulfoglycolipid as a synthetic inhibitor of astrocyte and microglia in order to test its effect on the axonal growth-promoting function of aldynoglia precursor cells. We obtained an increase in GFAP expression corresponding to the expected glial phenotype for aldynoglia cells cultured in alkaline fibrin. In co-cultures of dorsal root ganglia (DRG) and aldynoglia, the axonal growth promotion of DRG neurons by aldynoglia was not affected. We observed that the neural precursor cells first clustered together and then formed niches from which aldynoglia cells grew and connected to groups of adjacent cells. We conclude that the combination of alkaline fibrin with synthetic sulfoglycolipid Tol-51 increased cell adhesion, cell migration, fasciculation, and axonal growth capacity, promoted by aldynoglia cells. There was no negative effect on the behavior of aldynoglia cells after the addition of sulfoglycolipid Tol-51, suggesting that a combination of aldynoglia plus alkaline fibrin and Tol-51 compound could be useful as a therapeutic strategy for tSCI repair.
Assuntos
Axônios , Fibrina , Gânglios Espinais , Animais , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/citologia , Axônios/metabolismo , Axônios/efeitos dos fármacos , Fibrina/metabolismo , Hidrogéis/química , Hidrogéis/farmacologia , Ratos , Glicolipídeos/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/citologia , Movimento Celular/efeitos dos fármacosAssuntos
Fármacos Neuroprotetores , Ozônio , Traumatismos da Medula Espinal , Ubiquinona , Ubiquinona/análogos & derivados , Ubiquinona/uso terapêutico , Ubiquinona/farmacologia , Animais , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/terapia , Ratos , Fármacos Neuroprotetores/uso terapêutico , Ozônio/uso terapêutico , Modelos Animais de DoençasRESUMO
Neuromuscular inhibitors have been quickly advanced from being used only for aesthetic purposes to being used as a treatment for musculoskeletal pain and muscle spasticity. This phenomenon stems from the diminished force exerted by muscles, which are essential for bone remodeling. In this context, it is hypothesized that botulinum toxin (BTX) might exert a direct influence on bone resorption. Although such treatments have the potential to provide patients with significant relief, bone loss occurring due to elective muscle paralysis has yet to be examined in clinical trials. The disuse model resulting from spinal cord injury, characterized by the absence of ground reaction and muscle forces, provides an ideal context for exploring the skeletal ramifications of intramuscular BTX injection. This approach enables an investigation into the intricate interplay between muscle and bone, encompassing the impact of spasticity on bone preservation, the potential positive and negative outcomes of BTX on bone metabolism, and the involvement of the autonomic nervous system in bone remodeling regulation. This paper presents a narrative review of research findings on the disturbance of the typical balance between muscles and bones caused by acute muscle paralysis from BTX, resulting in osteopenia and bone resorption.
Assuntos
Toxinas Botulínicas , Espasticidade Muscular , Traumatismos da Medula Espinal , Humanos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Toxinas Botulínicas/administração & dosagem , Toxinas Botulínicas/uso terapêutico , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/uso terapêutico , Animais , Osso e Ossos/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Reabsorção Óssea , Músculo Esquelético/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológicoRESUMO
BACKGROUND: Inadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated. METHODS: The proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot. RESULTS: Metformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK). CONCLUSION: Metformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.
Assuntos
Proteínas Quinases Ativadas por AMP , Diferenciação Celular , Proliferação de Células , Ferroptose , Metformina , Células-Tronco Neurais , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Metformina/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Animais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Proliferação de Células/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
The impact of primary and secondary injuries of spinal cord injury (SCI) results in the demise of numerous neurons, and there is still no efficacious pharmacological intervention for it. Recently, studies have shown that endoplasmic reticulum stress (ERS) plays a pivotal role in recovery of neurological function after spinal cord injury. As a process to cope with intracellular accumulation of misfolded and unfolded proteins which triggers ERS, the unfolded protein response (UPR) plays an important role in maintaining protein homeostasis. And, a recently disclosed small molecule AA147, which selectively activates activating transcription factor 6 (ATF6), has shown promising pharmacological effects in several disease models. Thus, it seems feasible to protect the neurons after spinal cord injury by modulating UPR. In this study, primary neurons were isolated from E17-19 C57BL/6J mouse embryos and we observed that AA147 effectively promoted the survival of neurons and alleviated neuronal apoptosis after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. This was evident through a decrease in the proportion of PI-positive and TUNEL-positive cells, an increase in BCL-2 expression, and a decrease in the expression of BAX and C-caspase3. In in-vivo experiments, these findings were corroborated by TUNEL staining and immunohistochemistry. It was also found that AA147 enhanced three arms of the unfolded protein response with reduced CHOP expression. Besides, AA147 mitigated the accumulation of ROS in neurons probably by upregulating catalase expression. Furthermore, spinal cord injury models of C57BL/6J mice were established and behavioral experiments revealed that AA147 facilitated the recovery of motor function following SCI. Thus, pharmacologic activation of ATF6 represents a promise therapeutic approach to ameliorate the prognosis of SCI.
Assuntos
Fator 6 Ativador da Transcrição , Sobrevivência Celular , Camundongos Endogâmicos C57BL , Neurônios , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Camundongos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Fator 6 Ativador da Transcrição/metabolismo , Células Cultivadas , Masculino , Feminino , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
Spinal cord injury (SCI) presents a critical medical challenge, marked by substantial neural damage and persistent functional deficits. This study investigates the therapeutic potential of cold atmospheric plasma (CAP) for SCI, utilizing a tailored dielectric barrier discharge (DBD) device to conduct comprehensive in vivo and in vitro analyses. The findings show that CAP treatment significantly improves functional recovery after SCI, reduces neuronal apoptosis, lowers inflammation, and increases axonal regeneration. These findings illustrate the efficacy of CAP in fostering a conducive environment for recovery by modulating inflammatory responses, enhancing neuronal survival, and encouraging regenerative processes. The underlying mechanism involves CAP's reactive oxygen species (ROS) reduction, followed by activating antioxidant enzymes. These findings position CAP as a pioneering approach for spinal cord injury (SCI) treatment, presenting opportunities for improved neural recovery and establishing a new paradigm in SCI therapy.
Assuntos
Estresse Oxidativo , Espécies Reativas de Oxigênio , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Recuperação de Função Fisiológica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Gases em Plasma/farmacologia , Gases em Plasma/uso terapêutico , Feminino , Ratos , Regeneração Nervosa/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
INTRODUCTION: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. CONCLUSION: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.
Assuntos
Camundongos Endogâmicos C57BL , Polissacarídeos , Recuperação de Função Fisiológica , Remielinização , Traumatismos da Medula Espinal , Animais , Polissacarídeos/farmacologia , Camundongos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Remielinização/efeitos dos fármacos , Remielinização/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Feminino , Microambiente Celular/efeitos dos fármacosRESUMO
Spinal cord injury (SCI) often leads to neurogenic lower urinary tract dysfunction, causing dysuria and affecting patients' well-being. This study aimed to evaluate the efficacy of a urethral sphincter botulinum toxin A (BoNT-A) injection in patients with SCI and dysuria. This was a retrospective study including 118 patients with SCI who underwent a urethral BoNT-A injection following a standardized protocol for refractory voiding dysfunction. The protocol involved injecting BoNT-A into the urethral sphincter under cystoscopic guidance. Patient demographics, bladder condition parameters, and treatment outcomes were analyzed. Logistic regression and receiver operating characteristic curve analyses were performed to identify predictors of treatment success. Of the 118 patients, 71 (60.1%) showed satisfactory treatment outcomes after the injection. Post-injection status, bladder management, and injection frequency varied significantly among patients with satisfactory and unsatisfactory treatment outcomes. Age, bladder compliance, intravesical pressure, and bladder contractility were indicators of satisfactory outcomes. The first sensation of bladder filling of ≤263 mL, intravesical pressure of ≤28, and bladder contractility index of ≥14 were highly correlated with satisfactory outcomes. A urethral sphincter BoNT-A injection shows promise in managing dysuria in patients with SCI. Understanding bladder condition parameters and patient demographics helps optimize patient selection for this intervention. Further studies are needed to validate these findings and refine treatment protocols.
Assuntos
Toxinas Botulínicas Tipo A , Disuria , Traumatismos da Medula Espinal , Uretra , Humanos , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/complicações , Estudos Retrospectivos , Disuria/tratamento farmacológico , Disuria/etiologia , Masculino , Pessoa de Meia-Idade , Adulto , Uretra/efeitos dos fármacos , Feminino , Resultado do Tratamento , Idoso , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/uso terapêutico , Adulto Jovem , Injeções , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacosRESUMO
Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca2+ or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain.
Assuntos
Analgésicos Opioides , AMP Cíclico , Gabapentina , Neuralgia , Transdução de Sinais , Traumatismos da Medula Espinal , Animais , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , AMP Cíclico/metabolismo , Ratos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Analgésicos Opioides/farmacologia , Gabapentina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Masculino , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Sinergismo Farmacológico , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacosRESUMO
The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.
Assuntos
Hidrogéis , Metilprednisolona , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Hidrogéis/administração & dosagem , Hidrogéis/química , Quitosana/química , Quitosana/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Ácido Hialurônico/química , Ácido Hialurônico/administração & dosagem , Óleos/química , Ratos , Masculino , Liberação Controlada de FármacosRESUMO
A thorough summary of recent findings on neuroprotective tactics for spinal cord injury (SCI) can be found in the paper "An Updated Systematic Review of Neuroprotective Agents in the Treatment of Spinal Cord Injury". This review highlights the diverse neuroprotective drugs' mechanisms of action, effectiveness, and translational potential. It also emphasizes the necessity of carefully planned clinical studies to close the gap between preclinical data and clinical applications. The authors provide priceless ideas for improving SCI treatment by carefully examining the most recent clinical and preclinical research. For doctors and researchers committed to enhancing the therapeutic results for people with spinal cord injuries, this review is a vital resource.
Assuntos
Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Humanos , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Revisões Sistemáticas como AssuntoRESUMO
Spinal cord injury (SCI) is one of the most serious health problems, with no effective therapy. Recent studies indicate that Fisetin, a natural polyphenolic flavonoid, exhibits multiple functions, such as life-prolonging, antioxidant, antitumor, and neuroprotection. However, the restorative effects of Fisetin on SCI and the underlying mechanism are still unclear. In the present study, we found that Fisetin reduced LPS-induced apoptosis and oxidative damage in PC12 cells and reversed LPS-induced M1 polarization in BV2 cells. Additionally, Fisetin safely and effectively promoted the motor function recovery of SCI mice by attenuating neurological damage and promoting neurogenesis at the lesion. Moreover, Fisetin administration inhibited glial scar formation, modulated microglia/macrophage polarization, and reduced neuroinflammation. Network pharmacology, RNA-seq, and molecular biology revealed that Fisetin inhibited the activation of the JAK2/STAT3 signaling pathway. Notably, Colivelin TFA, an activator of JAK2/STAT3 signaling, attenuated Fis-mediated neuroinflammation inhibition and therapeutic effects on SCI mice. Collectively, Fisetin promotes functional recovery after SCI by inhibiting microglia/macrophage M1 polarization and the JAK2/STAT3 signaling pathway. Thus, Fisetin may be a promising therapeutic drug for the treatment of SCI.
Assuntos
Flavonóis , Janus Quinase 2 , Macrófagos , Microglia , Fator de Transcrição STAT3 , Transdução de Sinais , Traumatismos da Medula Espinal , Animais , Humanos , Masculino , Camundongos , Ratos , Polaridade Celular/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/administração & dosagem , Flavonóis/farmacologia , Janus Quinase 2/metabolismo , Janus Quinase 2/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/imunologia , Células PC12 , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/imunologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
AIMS: To explore the role of voltage-gated calcium channels (VGCC) in 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride's improvement of spinal cord injury (SCI) induced detrusor sphincter dyssynergia and the expressions of the 5-hydroxy tryptamine (5-HT) 2A receptors and VGCCs in lumbosacral cord after SCI. METHODS: Female Sprague-Dawley rats were randomized into normal control group and SCI group (N = 15 each). Cystometrogram (CMG), simultaneous CMG, and external urethral sphincter electromyography (EUS-EMG) were conducted in all groups under urethane anesthesia. Drugs were administered intrathecally during CMG and EUS-EMG. Rats were euthanized and L6-S1 spinal cord were acquired for immunofluorescence. RESULTS: In SCI rats, intrathecal administration of 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride or L-type VGCC blocker, nifedipine, could significantly increase voiding volume, voiding efficiency, and the number of high-frequency oscillations. They could also prolong EUS bursting activity duration on EUS-EMG. Moreover, the effect of 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride can be eliminated with the combined administration of L-type VGCC agonist, (±)-Bay K 8644. No significant differences were observed in CMG after intrathecal administration of T-type VGCC blocker TTA-P2. Additionally, immunofluorescence of the lumbosacral cord in control and SCI rats showed that the 5-HT2A receptor and Cav1.2 immunolabeling-positive neurons in the anterior horn of the lumbosacral cord were increased in SCI rats. CONCLUSIONS: Our study demonstrated that 5-HT2A/2C agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride may improve SCI-induced DSD by inhibiting the L-type voltage-gated calcium channel in lumbosacral cord motoneurons.
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Canais de Cálcio Tipo L , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/complicações , Feminino , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Ratos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , AnfetaminasRESUMO
Spinal cord injury (SCI) results in irreversible neurological impairment. After SCI, Ferritinophagy-induced free iron released from ferritin can lead to extensive lipid peroxidation and aggravate neurological damage. NRF2/HO-1 pathway is to endow cells with a protective effect against oxidative stress, and it plays an important role in the transcriptional activation of a series of antioxidant and detoxification genes. UAMC-3203 is a ferrostatin-1(Fer-1) analogue with better solubility and stability, which can more effectively inhibit ferroptosis after SCI. A rat SCI model was constructed, and the recovery of motor function was observed after treatment with UAMC-3203. ELISA was employed to assess the impact of UAMC-3203 on inflammation-related factors, while immunofluorescence was utilized to investigate the influence of UAMC-3203 on neuronal count as well as the activation of astrocytes and microglia/macrophages. Malondialdehyde (MDA) were detected to reflect the level of oxidation products. Western blot analysis was used to measure the level of ferroptosis markers and the expression of NRF2/HO-1. Our findings demonstrate that UAMC-3203 inhibits the production of reactive oxygen species (ROS) and lipid peroxides, preventing ferroptosis and reducing neuronal degeneration. Additionally, UAMC-3203 suppresses astrocyte proliferation and microglia/macrophage activation, as well as the release of ferroptosis-related inflammatory factors. These combined effects contribute to the preservation of spinal cord tissue and the facilitation of motor function recovery. UAMC-3203 maybe inhibit ferroptosis after SCI to promote functional recovery.
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Ferroptose , Fator 2 Relacionado a NF-E2 , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Ferroptose/efeitos dos fármacos , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Modelos Animais de Doenças , Masculino , Cicloexilaminas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Microglia/metabolismo , Microglia/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Heme Oxigenase (Desciclizante)RESUMO
Spinal cord contusion injury results in Wallerian degeneration of spinal cord axonal tracts, which are necessary for locomotor function. Axonal swelling and loss of axonal density at the contusion site, characteristic of Wallerian degeneration, commence within hours of injury. Tempol, a superoxide dismutase mimetic, was previously shown to reduce the loss of spinal cord white matter and improve locomotor function in an experimental model of spinal cord contusion, suggesting that tempol treatment might inhibit Wallerian degeneration of spinal cord axons. Here, we report that tempol partially inhibits Wallerian degeneration, resulting in improved locomotor recovery. We previously reported that Wallerian degeneration is reduced by inhibitors of aldose reductase (AR), which converts glucose to sorbitol in the polyol pathway. We observed that tempol inhibited sorbitol production in the injured spinal cord to the same extent as the AR inhibitor, sorbinil. Tempol also prevented post-contusion upregulation of AR (AKR1B10) protein expression within degenerating axons, as previously observed for AR inhibitors. Additionally, we hypothesized that tempol inhibits axonal degeneration by preventing loss of the glutathione pool due to polyol pathway activity. Consistent with our hypothesis, tempol treatment resulted in greater glutathione content in the injured spinal cord, which was correlated with increased expression and activity of gamma glutamyl cysteine ligase (γGCL; EC 6.3.2.2), the rate-limiting enzyme for glutathione synthesis. Administration of the γGCL inhibitor buthionine sulfoximine abolished all observed effects of tempol administration. Together, these results support a pathological role for polyol pathway activation in glutathione depletion, resulting in Wallerian degeneration after spinal cord injury (SCI). Interestingly, methylprednisolone, oxandrolone, and clenbuterol, which are known to spare axonal tracts after SCI, were equally effective in inhibiting polyol pathway activation. These results suggest that prevention of AR activation is a common target of many disparate post-SCI interventions.