RESUMEN

Investigate the effect of Alteplase and Aspirin on the functional outcomes of patients with acute ischemic stroke with mild non-disabling neurological deficit. In this single-center, randomized controlled study, we selected 60 patients with acute ischemic stroke with mild non-disabling neurological deficit admitted to our hospital from January 2021 to January 2022, and randomly divided them into the study group (n = 30) and the control group (n = 30), the control group was given the Aspirin treatment, the study group was given the Alteplase treatment, and the changes in neurological recovery, daily living ability, exercise ability, balance ability, cognitive function, and short-term prognosis outcomes were observed in these 2 groups. The factors influencing the short-term outcome of Alteplase therapy in patients with acute ischemic stroke were analyzed. The National Institutes of Health Neurological Deficit Score (NIHSS) scores at T1 and T2 of the study group were lower than those in the control group, but the scores of Barthel indicators (BI), Fugl-Meyer Motor Assessment Scale (FMA), Berg Balance Scale (BBS) and Montreal Cognitive Assessment Scale (MoCA) of the study group were higher than those in the control group, and the difference was statistically significant (P < .05). The short-term prognostic outcomes of these 2 groups were not significantly different (P > .05). The effect of the use of Alteplase or Aspirin on short-term functional outcomes in patients with acute ischemic stroke and mild non-disabling neurological deficit is not much different.

Asunto(s)

Aspirina , Fibrinolíticos , Accidente Cerebrovascular Isquémico , Activador de Tejido Plasminógeno , Humanos , Aspirina/uso terapéutico , Femenino , Masculino , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Fibrinolíticos/uso terapéutico , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del Tratamiento , Recuperación de la Función/efectos de los fármacos , Actividades Cotidianas , Pronóstico

RESUMEN

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.

Asunto(s)

Ferroptosis , Factor 2 Relacionado con NF-E2 , Recuperación de la Función , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Ferroptosis/efectos de los fármacos , Ratas , Recuperación de la Función/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Masculino , Ciclohexilaminas/farmacología , Estrés Oxidativo/efectos de los fármacos , Fenilendiaminas/farmacología , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Microglía/metabolismo , Microglía/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)

RESUMEN

BACKGROUND: Traumatic brain injury (TBI), which is the brain impairment and lesion caused by the external force injuring the head and the underlying brain, can cause pediatric death, disability, neurological disorders, and even lifelong disability. This study was to explore the effect of riboflavin (RF) on neurological rehabilitation and functional recovery after TBI. METHODS: The rat models of TBI were constructed by treating rats with controlled cortical impact (CCI). By treating TBI rats with RF, we investigated whether the administration of RF would affect the sensorimotor function and cognitive ability recovery through adhesive removal test, modified neurological severity score (mNSS), corner test, wire-grip test and the Morris water maze. The effects of RF on lesion volume and water content were investigated using hematoxylin and eosin (H&E) staining and wet-dry method. The Nissl staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to demonstrate the effect of RF on neural apoptosis. Inflammation-related cytokines of interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß1 were measured by enzyme-linked immunosorbent assay (ELISA) to evaluate the effect of RF on neuroinflammation. The impact of RF on oxidative stress was assessed by measuring malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, and the platelet endothelial cell adhesion molecule-1 (CD31) staining for observing vessel density, the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for measuring vascular endothelial growth factor (VEGF) mRNA expression and western blot for VEGF protein expression were used for evaluated angiogenesis. RESULTS: The administration of RF could facilitate the recovery of neurological function by promoting the recovery of sensorimotor function and cognitive ability (p < 0.05). Furthermore, RF could reduce the lesion volume and water content after TBI and ameliorate neural apoptosis, neuroinflammation, and oxidative stress (p < 0.05). Finally, RF increased vessel density (p < 0.01) and VEGF levels (p < 0.01) in brain tissues after TBI, promoting angiogenesis. CONCLUSION: RF benefits neurological rehabilitation after TBI by promoting neurological function recovery, ameliorating the pathogenesis after TBI, and facilitating brain vascular remodeling. These findings provide a novel mechanism for RF treating pediatric TBI.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Riboflavina , Animales , Ratas , Lesiones Traumáticas del Encéfalo/rehabilitación , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/fisiopatología , Riboflavina/farmacología , Riboflavina/uso terapéutico , Masculino , Humanos , Ratas Sprague-Dawley , Niño , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Citocinas/metabolismo , Recuperación de la Función/efectos de los fármacos

RESUMEN

Following spinal cord injury (SCI), the regenerative capacity of the central nervous system (CNS) is severely limited by the failure of axonal regeneration. The regeneration of CNS axons has been shown to occur by grafting predegenerated peripheral nerves (PPNs) and to be promoted by the transplantation of neural precursor cells (NPCs). The introduction of a combinatorial treatment of PPNs and NPCs after SCI has to address the additional problem of glial scar formation, which prevents regenerating axons from leaving the implant and making functional connections. Previously, we discovered that the synthetic sulfoglycolipid Tol-51 inhibits astrogliosis. The objective was to evaluate axonal regeneration and locomotor function improvement after SCI in rats treated with a combination of PPN, NPC, and Tol-51. One month after SCI, the scar tissue was removed and replaced with segments of PPN or PPN+Tol-51; PPN+NPC+Tol-51. The transplantation of a PPN segment favors regenerative axonal growth; in combination with Tol-51 and NPC, 30% of the labeled descending corticospinal axons were able to grow through the PPN and penetrate the caudal spinal cord. The animals treated with PPN showed significantly better motor function. Our data demonstrate that PPN implants plus NPC and Tol-51 allow successful axonal regeneration in the CNS.

Asunto(s)

Regeneración Nerviosa , Células-Madre Neurales , Nervios Periféricos , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/patología , Ratas , Regeneración Nerviosa/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/trasplante , Células-Madre Neurales/citología , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/patología , Femenino , Axones/efectos de los fármacos , Glucolípidos/farmacología , Recuperación de la Función/efectos de los fármacos

RESUMEN

Stroke is a leading cause of permanent disability worldwide. Despite intensive research over the last decades, key anti-inflammatory strategies that have proven beneficial in pre-clinical animal models have often failed in translation. The importance of neutrophils as pro- and anti-inflammatory peripheral immune cells has often been overlooked in ischemic stroke. However, neutrophils rapidly infiltrate into the brain parenchyma after stroke and secrete an array of pro-inflammatory factors including reactive oxygen species, proteases, cytokines, and chemokines exacerbating damage. In this study, we demonstrate the neuroprotective and anti-inflammatory effect of benserazide, a clinically used DOPA decarboxylase inhibitor, using both in vitro models of inflammation and in vivo mouse models of focal cerebral ischemia. Benserazide significantly attenuated PMA-induced NETosis in isolated human neutrophils. Furthermore, benserazide was able to protect both SH-SY5Y and iPSC-derived human cortical neurons when challenged with activated neutrophils demonstrating the clinical relevance of this study. Additional in vitro data suggest the ability of benserazide to polarize macrophages towards M2-phenotypes following LPS stimulation. Neuroprotective effects of benserazide are further demonstrated by in vivo studies where peripheral administration of benserazide significantly attenuated neutrophil infiltration into the brain, altered microglia/macrophage phenotypes, and improved the behavioral outcome post-stroke. Overall, our data suggest that benserazide could serve as a drug candidate for the treatment of ischemic stroke. The importance of our results for future clinical trials is further underlined as benserazide has been approved by the European Medicines Agency as a safe and effective treatment in Parkinson's disease when combined with levodopa.

Asunto(s)

Benserazida , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Neutrófilos , Benserazida/farmacología , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/inmunología , Accidente Cerebrovascular Isquémico/metabolismo , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Modelos Animales de Enfermedad , Recuperación de la Función/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo

RESUMEN

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.

Asunto(s)

Flavonoles , Janus Quinasa 2 , Macrófagos , Microglía , Factor de Transcripción STAT3 , Transducción de Señal , Traumatismos de la Médula Espinal , Animales , Humanos , Masculino , Ratones , Ratas , Polaridad Celular/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/administración & dosificación , Flavonoles/farmacología , Janus Quinasa 2/metabolismo , Janus Quinasa 2/genética , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Células PC12 , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/inmunología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética

RESUMEN

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.

Asunto(s)

Estrés Oxidativo , Especies Reactivas de Oxígeno , Recuperación de la Función , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Animales , Recuperación de la Función/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Gases em Plasma/farmacología , Gases em Plasma/uso terapéutico , Femenino , Ratas , Regeneración Nerviosa/efectos de los fármacos , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

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.

Asunto(s)

Proteínas Quinasas Activadas por AMP , Diferenciación Celular , Proliferación Celular , Ferroptosis , Metformina , Células-Madre Neurales , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Metformina/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Animales , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Proliferación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Transducción de Señal/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Recuperación de la Función/efectos de los fármacos

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopamine-producing neurons in the brain, causing motor symptoms like tremors and stiffness. Although current treatments like medication and deep brain stimulation can alleviate symptoms, they don't address the root cause of neuron loss. Therefore, cell replacement therapy emerges as a promising treatment strategy. However, the generation of engraftable dopaminergic (DA) cells in clinically relevant quantities is still a challenge. Recent advances in cell reprogramming technologies open up vast possibilities to produce patient-specific cells of a desired type in therapeutic quantities. The main cell reprogramming strategies involve the enforced expression of individual or sets of genes through viral transduction or transfection, or through small molecules, known as the chemical approach, which is a much easier and safer method. In our previous studies, using a small molecule approach (combinations of epigenetic modifiers and SMAD inhibitors such asDorsomorphin and SB431542), we have been able to generate DA progenitors from human mesenchymal stem cells (hMSCs). The aim of this study was to further improve the method for the generation of DA progenitors and to test their therapeutic effect in an animal model of Parkinson's. The results showed that the addition of an autophagy enhancer (AE) to our DA cell induction protocol further increased the yield of DA progenitor cells. The results also showed that DA progenitors transplanted into the mouse model of PD survived, integrated, and improved PD motor symptoms. These data suggest that chemically-produced DA cells can be very promising and safe cellular therapeutics for PD.

Asunto(s)

Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Oxidopamina , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Ratones , Oxidopamina/toxicidad , Humanos , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Trastornos Parkinsonianos/terapia , Ratones Endogámicos C57BL , Células-Madre Neurales/trasplante , Células-Madre Neurales/efectos de los fármacos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Masculino , Células Madre Mesenquimatosas , Células Cultivadas

Asunto(s)

Regeneración , Animales , Humanos , Corazón/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Regeneración/efectos de los fármacos , Medicina Regenerativa/métodos

RESUMEN

OBJECTIVES: This study aims to evaluate the histopathological, biochemical, and functional effects of N-acetylcysteine (NAC), which has antioxidant, anti-inflammatory, and cytoprotective activity, on nerve regeneration in rats with sciatic nerve crush (axonotmesis) injury. MATERIALS AND METHODS: This study used 16 male Wistar rats, which were divided into treatment and control groups. A standard axonotmesis-type surgical injury was induced in the left sciatic nerves of all rats. The treatment group was given 300 mg/kg of intraperitoneal NAC once a day, whereas the control group received an equal volume of saline solution. After conducting gait analyses, the sciatic functional index (SFI) was used for functional assessment. After gait analysis, all animals were euthanized. Blood samples were examined biochemically. The left sciatic nerves and left triceps surae muscles were examined histopathologically. RESULTS: Histopathologically, the thickness of the perineurium, axonal degeneration, axonolysis, edema, inflammation, muscle atrophy, and muscle degeneration were all significantly lower in the treatment group (p<0.05). Functionally, SFI-1, SFI-2, and SFI-3 were significantly higher in the treatment group (p<0.05). Biochemically, while the native thiol level and native thiol/total thiol ratio were significantly higher in the treatment group (p<0.003), the disulfide/total thiol ratio was significantly higher in the control group (p<0.005). Significant correlations were found between six of the seven gait parameters and the histopathological findings (p<0.05). CONCLUSION: Our study results suggest that NAC may contribute positively to the histopathological and functional recovery of sciatic nerve injury in rats. Furthermore, NAC may have an antioxidant effect on thiol-disulfide homeostasis at a biochemical level. We believe that NAC has a stimulatory effect on healing following nerve injuries.

Asunto(s)

Acetilcisteína , Regeneración Nerviosa , Ratas Wistar , Nervio Ciático , Animales , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Masculino , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Nervio Ciático/lesiones , Regeneración Nerviosa/efectos de los fármacos , Ratas , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Cicatrización de Heridas/efectos de los fármacos , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/patología , Recuperación de la Función/efectos de los fármacos

RESUMEN

Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived histone lactylation in the repair of spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and lactylation are upregulated in the spinal cord after SCI. Notably, H4K12la was significantly elevated in the microglia of the injured spinal cord, whereas exogenous lactate treatment further elevated H4K12la in microglia after SCI. Functionally, lactate treatment promoted microglial proliferation, scar formation, axon regeneration, and locomotor function recovery after SCI. Mechanically, lactate-mediated H4K12la elevation promoted PD-1 transcription in microglia, thereby facilitating SCI repair. Furthermore, a series of rescue experiments confirmed that a PD-1 inhibitor or microglia-specific AAV-sh-PD-1 significantly reversed the therapeutic effects of lactate following SCI. This study illustrates the function and mechanism of lactate/H4K12la/PD-1 signaling in microglia-mediated tissue repair and provides a novel target for SCI therapy.

Asunto(s)

Histonas , Ácido Láctico , Microglía , Recuperación de la Función , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Animales , Microglía/metabolismo , Microglía/efectos de los fármacos , Histonas/metabolismo , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Ácido Láctico/metabolismo , Ratas , Lisina/metabolismo , Lisina/análogos & derivados , Lisina/farmacología , Ratones , Cicatriz/metabolismo , Cicatriz/patología , Femenino , Ratas Sprague-Dawley , Ratones Endogámicos C57BL , Masculino , Locomoción/efectos de los fármacos , Locomoción/fisiología

RESUMEN

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.

Asunto(s)

Ratones Endogámicos C57BL , Polisacáridos , Recuperación de la Función , Remielinización , Traumatismos de la Médula Espinal , Animales , Polisacáridos/farmacología , Ratones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Remielinización/efectos de los fármacos , Remielinización/fisiología , Recuperación de la Función/efectos de los fármacos , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Femenino , Microambiente Celular/efectos de los fármacos

RESUMEN

Objective. Macrophages and astrocytes play a crucial role in the aftermath of a traumatic spinal cord injury (SCI). Infiltrating macrophages adopt a pro-inflammatory phenotype while resident astrocytes adopt a neurotoxic phenotype at the injury site, both of which contribute to neuronal death and inhibit axonal regeneration. The cytokine interleukin-4 (IL-4) has shown significant promise in preclinical models of SCI by alleviating the macrophage-mediated inflammation and promoting functional recovery. However, its effect on neurotoxic reactive astrocytes remains to be elucidated, which we explored in this study. We also studied the beneficial effects of a sustained release of IL-4 from an injectable biomaterial compared to bolus administration of IL-4.Approach. We fabricated a heparin-based coacervate capable of anchoring and releasing bioactive IL-4 and tested its efficacyin vitroandin vivo. Main results. We show that IL-4 coacervate is biocompatible and drives a robust anti-inflammatory macrophage phenotype in culture. We also show that IL-4 and IL-4 coacervate can alleviate the reactive neurotoxic phenotype of astrocytes in culture. Finally, using a murine model of contusion SCI, we show that IL-4 and IL-4 coacervate, injected intraspinally 2 d post-injury, can reduce macrophage-mediated inflammation, and alleviate neurotoxic astrocyte phenotype, acutely and chronically, while also promoting neuroprotection with significant improvements in hindlimb locomotor recovery. We observed that IL-4 coacervate can promote a more robust regenerative macrophage phenotypein vitro, as well as match its efficacyin vivo,compared to bolus IL-4.Significance. Our work shows the promise of coacervate as a great choice for local and prolonged delivery of cytokines like IL-4. We support this by showing that the coacervate can release bioactive IL-4, which acts on macrophages and astrocytes to promote a pro-regenerative environment following a SCI leading to robust neuroprotective and functional outcomes.

Asunto(s)

Astrocitos , Interleucina-4 , Recuperación de la Función , Traumatismos de la Médula Espinal , Animales , Femenino , Ratones , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Células Cultivadas , Preparaciones de Acción Retardada/administración & dosificación , Interleucina-4/administración & dosificación , Interleucina-4/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Fenotipo , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/metabolismo

RESUMEN

Ultrastructural studies of contusive spinal cord injury (SCI) in mammals have shown that the most prominent acute changes in white matter are periaxonal swelling and separation of myelin away from their axon, axonal swelling, and axonal spheroid formation. However, the underlying cellular and molecular mechanisms that cause periaxonal swelling and the functional consequences are poorly understood. We hypothesized that periaxonal swelling and loss of connectivity between the axo-myelinic interface impedes neurological recovery by disrupting conduction velocity, and glial to axonal trophic support resulting in axonal swelling and spheroid formation. Utilizing in vivo longitudinal imaging of Thy1YFP+ axons and myelin labeled with Nile red, we reveal that periaxonal swelling significantly increases acutely following a contusive SCI (T13, 30 kdyn, IH Impactor) versus baseline recordings (laminectomy only) and often precedes axonal spheroid formation. In addition, using longitudinal imaging to determine the fate of myelinated fibers acutely after SCI, we show that ∼73% of myelinated fibers present with periaxonal swelling at 1 h post SCI and âˆ¼ 51% of those fibers transition to axonal spheroids by 4 h post SCI. Next, we assessed whether cation-chloride cotransporters present within the internode contributed to periaxonal swelling and whether their modulation would increase white matter sparing and improve neurological recovery following a moderate contusive SCI (T9, 50 kdyn). Mechanistically, activation of the cation-chloride cotransporter KCC2 did not improve neurological recovery and acute axonal survival, but did improve chronic tissue sparing. In distinction, the NKKC1 antagonist bumetanide improved neurological recovery, tissue sparing, and axonal survival, in part through preventing periaxonal swelling and disruption of the axo-myelinic interface. Collectively, these data reveal a novel neuroprotective target to prevent periaxonal swelling and improve neurological recovery after SCI.

Asunto(s)

Axones , Recuperación de la Función , Miembro 2 de la Familia de Transportadores de Soluto 12 , Traumatismos de la Médula Espinal , Sustancia Blanca , Animales , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Axones/efectos de los fármacos , Axones/patología , Femenino , Vaina de Mielina/patología , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/metabolismo , Ratones , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Bumetanida/farmacología

RESUMEN

A bioinspired hydrogel composed of hyaluronic acid-graft-dopamine (HADA) and a designer peptide HGF-(RADA)4-DGDRGDS (HRR) was presented to enhance tissue integration following spinal cord injury (SCI). The HADA/HRR hydrogel manipulated the infiltration of PDGFRß+ cells in a parallel pattern, transforming dense scars into an aligned fibrous substrate that guided axonal regrowth. Further incorporation of NT3 and curcumin promoted axonal regrowth and survival of interneurons at lesion borders, which served as relays for establishing heterogeneous axon connections in a target-specific manner. Notable improvements in motor, sensory, and bladder functions resulted in rats with complete spinal cord transection. The HADA/HRR + NT3/Cur hydrogel promoted V2a neuron accumulation in ventral spinal cord, facilitating the recovery of locomotor function. Meanwhile, the establishment of heterogeneous neural connections across the hemisected lesion of canines was documented in a target-specific manner via neuronal relays, significantly improving motor functions. Therefore, biomaterials can inspire beneficial biological activities for SCI repair.

Asunto(s)

Matriz Extracelular , Hidrogeles , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Animales , Hidrogeles/química , Ratas , Matriz Extracelular/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Perros , Axones/metabolismo , Axones/efectos de los fármacos , Regeneración Nerviosa/efectos de los fármacos , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Recuperación de la Función/efectos de los fármacos , Dopamina/metabolismo , Femenino , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Médula Espinal/metabolismo

RESUMEN

This study aimed to assess the impact of conditioned medium from epidermal neural crest stem cells (EPI-NCSCs-CM) on functional recovery following spinal cord injury (SCI), while also exploring the involvement of the PI3K-AKT signaling pathway in regulating neuronal apoptosis. EPI-NCSCs were isolated from 10-day-old Sprague-Dawley rats and cultured for 48 h to obtain EPI-NCSC-CM. SHSY-5Y cells were subjected with H2O2 treatment to induce apoptosis. Cell viability and survival rates were evaluated using the CCK-8 assay and calcein-AM/PI staining. SCI contusion model was established in adult Sprague-Dawley rats to assess functional recovery, utilizing the Basso, Beattie and Bresnahan (BBB) scoring system, inclined test, and footprint observation. Neurological restoration after SCI was analyzed through electrophysiological recordings. Histological analysis included hematoxylin and eosin (H&E) staining and Nissl staining to evaluate tissue organization. Apoptosis and oxidative stress levels were assessed using TUNEL staining and ROS detection methods. Additionally, western blotting was performed to examine the expression of apoptotic markers and proteins related to the PI3K/AKT signaling pathway. EPI-NCSC-CM significantly facilitated functional and histological recovery in SCI rats by inhibiting neuronal apoptosis through modulation of the PI3K/AKT pathway. Administration of EPI-NCSCs-CM alleviated H2O2-induced neurotoxicity in SHSY-5Y cells in vitro. The use of LY294002, a PI3K inhibitor, underscored the crucial role of the PI3K/AKT signaling pathway in regulating neuronal apoptosis. This study contributes to the ongoing exploration of molecular pathways involved in spinal cord injury (SCI) repair, focusing on the therapeutic potential of EPI-NCSC-CM. The research findings indicate that EPI-NCSC-CM exerts a neuroprotective effect by suppressing neuronal apoptosis through activation of the PI3K/AKT pathway in SCI rats. These results highlight the promising role of EPI-NCSC-CM as a potential treatment strategy for SCI, emphasizing the significance of the PI3K/AKT pathway in mediating its beneficial effects.

Asunto(s)

Apoptosis , Células-Madre Neurales , Neuronas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Medios de Cultivo Condicionados/farmacología , Células-Madre Neurales/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Cresta Neural/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacos , Masculino

RESUMEN

We aimed to study the reparative effects of orientin against spinal cord injury (SCI) in rats and explore its potential mechanisms. Sprague-Dawley rats were divided into Sham, SCI, Orientin, and SB203580 [an inhibitor of p38 mitogen-activated protein kinase (p38MAPK)] groups. In the SCI group, rats underwent Allen's beat. SCI animals in Orientin and SB203580 groups were respectively treated with 40 mg kg-1 orientin and 3 mg kg-1 SB203580 once daily. Functional recovery was evaluated based on Basso, Beattie, and Bresnahan scoring. Histopathological analysis was performed using hematoxylin-eosin and Nissl staining. Cell apoptosis was examined by TUNEL staining. The relative quantity of apoptosis-related proteins, glial fibrillary acidic protein (GFAP), neurofilament 200 (NF200), and brain derived neurotrophic factor (BDNF) was detected via western blotting. The indices related to inflammation and oxidation were measured using agent kits. The p38MAPK/inducible nitric oxide synthase (iNOS) signaling activity was detected using real-time quantitative PCR, western blotting, and immunohistochemical staining. Orientin was revealed to effectively mitigate cell apoptosis, neuroinflammation, and oxidative stress in impaired tissues. Meanwhile, orientin exerted great neuroprotective effects by abating GFAP expression, and up-regulating the expression of NF200 and BDNF, and significantly suppressed the p38MAPK/iNOS signaling. Orientin application could promote the repair of secondary SCI through attenuating oxidative stress and inflammatory response, reducing cell apoptosis and suppressing p38MAPK/iNOS signaling.

Asunto(s)

Apoptosis , Flavonoides , Glucósidos , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Fármacos Neuroprotectores/farmacología , Flavonoides/farmacología , Ratas , Apoptosis/efectos de los fármacos , Glucósidos/farmacología , Glucósidos/uso terapéutico , Masculino , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Imidazoles/farmacología , Piridinas

RESUMEN

BACKGROUND: Traumatic brain injury (TBI) is a significant public health issue, often resulting from traffic accidents and falls, leading to a wide spectrum of outcomes from mild concussions to severe brain damage. The neurorehabilitation of TBI focuses on enhancing recovery and improving quality of life. Zolpidem, traditionally used for short-term management of insomnia, has shown potential in improving cognitive functions and language in TBI patients. Advances in neuroimaging techniques, such as functional near-infrared spectroscopy (fNIRS), have facilitated the exploration of the effects of therapeutic interventions on brain activity and functional connectivity in TBI patients. CASE SUMMARY: We present the case of a 34-year-old male who sustained a TBI from a traffic collision. Despite severe impairments in cognitive and language functions, administration of 10 mg of zolpidem resulted in temporary but significant improvements in these areas, as evidenced by increased Mini-Mental State Examination scores and observed behavioral changes. fNIRS assessments before and after zolpidem administration revealed notable changes in cerebral cortex activity, including increased left hemisphere activation and a shift in functional connectivity to the bilateral frontal lobes, corresponding with the patient's improvement. CONCLUSION: This case study highlights the potential of zolpidem, a medication traditionally used for insomnia, in enhancing cognitive and verbal functions in a patient with TBI, suggesting a potential therapeutic role for zolpidem in neurorehabilitation, supported by changes in brain activity and connectivity observed through fNIRS. However, further investigation is warranted to validate these findings and elucidate zolpidem's long-term effects on cognitive and functional outcomes in TBI patients.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Espectroscopía Infrarroja Corta , Zolpidem , Humanos , Zolpidem/uso terapéutico , Zolpidem/administración & dosificación , Masculino , Adulto , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Cognición/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Lenguaje , Piridinas/uso terapéutico

RESUMEN

BACKGROUND: Health-related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real-world effects of trazodone once-a-day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD. METHODS: This 8-week prospective, observational, open-label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient-reported Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) from baseline to week 8. Secondary outcomes included change in Q-LES-Q-SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF-SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith-Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ-5) at baseline and week 8. RESULTS: The study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q-LES-Q-SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, -15.7 [8.3]; TzOAD, -21.0 [9.8]); PROMIS SF-SD 8b (SSRI, -9.9 [12.6]; TzOAD, -22.0 [12.6]). Mean change scores in Q-LES-Q-SF, MADRS, and PROMIS SF-SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, -9.2 [7.4]; TzOAD, -14.3 [7.5]), SHAPS (SSRI, -6.6 [4.3]; TzOAD, -8.3 [4.4]), and PDQ-5 (SSRI, -5.8 [4.5]; TzOAD, -7.7 [5.0]). CONCLUSIONS: In adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group.

Asunto(s)

Trastorno Depresivo Mayor , Calidad de Vida , Inhibidores Selectivos de la Recaptación de Serotonina , Trazodona , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Femenino , Masculino , Trazodona/farmacología , Trazodona/administración & dosificación , Adulto , Persona de Mediana Edad , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estudios Prospectivos , Recuperación de la Función/efectos de los fármacos , Resultado del Tratamiento , Antidepresivos de Segunda Generación/administración & dosificación , Antidepresivos de Segunda Generación/uso terapéutico , Antidepresivos de Segunda Generación/farmacología