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1.
Life Sci ; 252: 117642, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32259600

RESUMO

AIMS: To determine whether ginsenoside Rg1 is involved in scratch wound healing through altered expression of related molecules in astrocytes and improved functional recovery after spinal cord injury (SCI). MATERIALS AND METHODS: Astrocytes were isolated from rats, followed by Rg1 treatment. The wound healing test was performed to observe the scratch wound healing in different groups. The expression of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), and components of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway were detected by western blot. Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the altered expression of laminin (LN) and fibronectin (FN). A revised Allen's method for the SCI model was performed, followed by Rg1 treatment. Then, functional scoring was conducted to evaluate the functional recovery. Hematoxylin-eosin (HE) staining showed changes in the void area. Finally, western blot assessed the expression of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). KEY FINDINGS: Rg1 mediated scratch wound healing through inducing an increased release of LN, FN, NGF, GDNF, and bFGF in vitro. Additionally, Rg1 activated the PI3K/Akt signaling pathway and promoted the functional recovery of hindlimb movement in rats. Furthermore, Rg1 significantly reduced the void area and downregulated the expression of GFAP and CSPGs. SIGNIFICANCE: Rg1 not only enhanced the scratch wound repair in vitro through the release of astroglial neurotrophic factors, adhesion factors, and inhibitory factors, but it also improved the functional recovery in vivo following SCI.


Assuntos
Astrócitos/efeitos dos fármacos , Ginsenosídeos/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Astrócitos/metabolismo , Feminino , Masculino , Fatores de Crescimento Neural/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia
2.
Environ Toxicol ; 35(6): 714-721, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32149473

RESUMO

Spinal cord injury (SCI) is the most commonly seen trauma leading to disability in people worldwide. The purpose of current study was to determine the protective effect of methoxytetrahydro-2H-pyran-2-yl)methyl benzoate (HMPB) on SCI in rat model. TUNEL staining was used to examine apoptotic changes in spinal cord of SCI rats. The ELISA kits were employed to assess inflammatory processes and oxidative factors in the spinal cord tissues. Behavioral changes in SCI rats were assessed using Basso, Beattie, and Bresnahan (BBB) scoring system. Western blotting was used for assessment of proteins. The HMPB treatment of SCI rats reduced apoptotic cell number based on the concentration of dose administered. Treatment of SCI rats with HMPB enhanced BBB score and decreased accumulation of water content in SCI rats significantly. On treatment with HMPB the TNF-α and interleukin-6/1ß/18 levels were suppressed in SCI rats. Treatment with HMPB induced excessive release of SOD, CAT, and GSH molecules and decreased overproduction of MDA. The SCI induced upregulation of caspase-3/9 activity was completely alleviated by HMPB at 2 mg/kg dose. The HMPB treatment of SCI rats promoted peroxisome proliferator-activated receptor γ (PPAR-γ) expression, reduced cyclooxygenase (COX)-2 production and increased expression of p-Akt and phosphoinositide 3-kinase (p-PI3K). The study demonstrated that HMPB suppressed apoptosis, raised BBB score and inhibited inflammation in SCI rats. Moreover, activation of PI3K/Akt in the spinal cord tissues of SCI rats was promoted by HMPB. Therefore, HMPB has protective effect on SCI in the rat model.


Assuntos
PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piranos/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Crataegus , Citocinas/metabolismo , Modelos Animais de Doenças , Marcação In Situ das Extremidades Cortadas , Inflamação , Masculino , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Piranos/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
3.
Life Sci ; 245: 117351, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981629

RESUMO

AIMS: To study the specific therapeutic effect of zinc on spinal cord injury (SCI) and its specific protective mechanism. MAIN METHODS: The effects of zinc ions on neuronal cells were examined in a mouse SCI model and in vitro. In vivo, neurological function was assessed by Basso Mouse Scaleat (BMS) at 1, 3, 5, 7, 10, 14, 21, and 28 days after spinal cord injury. The number of neurons and histomorphology were observed by nissl staining and hematoxylin-eosin staining (HE). The chromatin and mitochondrial structure of neurons were detected by transmission electron microscopy (TEM). The expression of nuclear factor erythroid 2 related factor 2 (Nrf2)-related antioxidant protein and NLRP3 inflammation-related protein were detected in vivo and in vitro by western blot (WB) and immunofluorescence (IF), respectively. KEY FINDINGS: Zinc treatment promoted motor function recovery on days 3, 5, 7, 14, 21 and 28 after SCI. In addition, zinc reduces the mitochondrial void rate in spinal neuronal cells and promotes neuronal recovery. At the same time, zinc reduced the levels of reactive oxygen species (ROS) and malondialdehyde in spinal cord tissue after SCI, while increasing superoxide dismutase activity and glutathione peroxidase production. Zinc treatment resulted in up-regulation of Nrf2/Ho-1 levels and down-regulation of nlrp3 inflammation-associated protein expression in vitro and in vivo. SIGNIFICANCE: Zinc has a protective effect on spinal cord injury by inhibiting oxidative damage and nlrp3 inflammation. Potential mechanisms may include activation of the Nrf 2/Ho-1 pathway to inhibit nlrp3 inflammation following spinal cord injury. Zinc has the potential to treat SCI.


Assuntos
Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Zinco/uso terapêutico , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Imunofluorescência , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Zinco/farmacologia
4.
Oxid Med Cell Longev ; 2020: 9741369, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998447

RESUMO

Spinal cord injury (SCI) is a devastating disease that may lead to lifelong disability. Thus, seeking for valid drugs that are beneficial to promoting axonal regrowth and elongation after SCI has gained wide attention. Metformin, a glucose-lowering agent, has been demonstrated to play roles in various central nervous system (CNS) disorders. However, the potential protective effect of metformin on nerve regeneration after SCI is still unclear. In this study, we found that the administration of metformin improved functional recovery after SCI through reducing neuronal cell apoptosis and repairing neurites by stabilizing microtubules via PI3K/Akt signaling pathway. Inhibiting the PI3K/Akt pathway with LY294002 partly reversed the therapeutic effects of metformin on SCI in vitro and vivo. Furthermore, metformin treatment weakened the excessive activation of oxidative stress and improved the mitochondrial function by activating the nuclear factor erythroid-related factor 2 (Nrf2) transcription and binding to the antioxidant response element (ARE). Moreover, treatment with Nrf2 inhibitor ML385 partially abolished its antioxidant effect. We also found that the Nrf2 transcription was partially reduced by LY294002 in vitro. Taken together, these results revealed that the role of metformin in nerve regeneration after SCI was probably related to stabilization of microtubules and inhibition of the excessive activation of Akt-mediated Nrf2/ARE pathway-regulated oxidative stress and mitochondrial dysfunction. Overall, our present study suggests that metformin administration may provide a potential therapy for SCI.


Assuntos
Axônios/fisiologia , Metformina/farmacologia , Microtúbulos , Estresse Oxidativo/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Traumatismos da Medula Espinal , Animais , Cromonas/farmacologia , Microtúbulos/metabolismo , Microtúbulos/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Morfolinas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Elementos de Resposta , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
5.
BMC Neurol ; 20(1): 20, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941437

RESUMO

BACKGROUND: Persons with spinal cord injury/dysfunction (SCI/D) often take multiple medications to treat their secondary complications and chronic conditions (multimorbidity). Multiple healthcare and service providers are often involved in care, which can result in increased risk of fragmentation of care. Optimal medication therapy management (MTM) is essential to ensure therapeutic benefit from medication regimens. However, little is known about the experiences of providers in supporting persons with SCI/D with MTM. METHODS: Telephone interviews were conducted to explore healthcare and service providers' experiences with MTM for persons with SCI/D. Participants were recruited through clinical organizations and researchers' personal contacts. Participants were purposefully selected for diversity in profession and were required to be English speaking and to have provided care to at least one person with SCI/D. The qualitative interviews followed a semi-structured interview guide. Data display matrices were used in a constant comparative process for descriptive and interpretive analysis. RESULTS: Thirty-two interviews were conducted from April to December 2018. Each profession had distinct views on their roles in facilitating MTM for persons with SCI/D, which aligned with their respective scopes of practice. Shared provider tasks included tailoring medications, providing education, and exploring medication alternatives. Most participants felt that the care they provided for persons with SCI/D was similar to the care that they provided to other patients, with some differences relating to the physical limitations and medical complexity associated with SCI/D. Five factors were identified that impacted participants' abilities to provide MTM for persons with SCI/D: patient self-management skills, provider knowledge and confidence, provider-patient relationships, interprofessional collaboration, and provider funding models including the use of technology-supported consultations. CONCLUSION: While participants described commonalities in the barriers and enablers associated with providing MTM to persons with SCI/D and other populations, there were unique considerations identified. These SCI/D-specific considerations resulted in recommendations for improvements in MTM for this population. Future research should include perspectives from persons with SCI/D.


Assuntos
Pessoal de Saúde , Conduta do Tratamento Medicamentoso , Pesquisa Qualitativa , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Yakugaku Zasshi ; 139(11): 1385-1390, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685734

RESUMO

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


Assuntos
Axônios/fisiologia , Medicina Herbária , Regeneração Nervosa , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/farmacologia , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Estimulação Química
7.
Br J Anaesth ; 123(6): 827-838, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31623841

RESUMO

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Inflamação/tratamento farmacológico , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Microglia/efeitos dos fármacos , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
8.
Neurochem Res ; 44(12): 2746-2754, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630316

RESUMO

Spinal cord ischemia and reperfusion (SCIR) injury can induce autophagy, which is involved in the survival of neurons. However, whether autophagy plays a neuroprotective or a detrimental role in SCIR injury remains controversial. Angiopoietin-1 (Ang-1), an endothelial growth factor, has been shown to have neuroprotective effects. The present study aimed to explore the neuroprotective mechanisms of Ang-1 in neuronal cells in a rat model of SCIR injury in vivo. Ang-1 protein and rapamycin were injected intrathecally. Basso Beattie Bresnahan (BBB) scoring and hematoxylin and eosin staining were used to assess the degree of SCIR injury. Proteins that reflected the level of autophagy expression, such as Beclin-1 and LC3, were evaluated by western blotting. The results indicated that SCIR injury resulted in loss in lower limb motor function. Ang-1 protein inhibited the expression of Beclin-1 and LC3, which improved the BBB score and alleviated spinal cord injury. In contrast, rapamycin, an autophagy activator, caused the opposite effect. This study provides evidence that Ang-1 plays a neuroprotective role by inhibiting of autophagy expression in SCIR injury. Overall, findings could be useful for the treatment of SCIR injury.


Assuntos
Angiopoietina-1/uso terapêutico , Autofagia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Isquemia do Cordão Espinal/tratamento farmacológico , Animais , Masculino , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Sirolimo/farmacologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Isquemia do Cordão Espinal/fisiopatologia
9.
Mol Immunol ; 116: 56-62, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31605961

RESUMO

Macrophages can be polarized towards either a classically activated pro-inflammatory (M1) state, or alternatively towards an activated anti-inflammatory (M2) state. M1 cells are activated by ligands of toll-like receptor (TLR) or interferon (IFN)-γ and have a toxic effect, whereas M2 cells are activated by interleukin (IL)-4, IL-10, and IL-13 and have a regenerative effect in vitro and in vivo. Previously studies have shown that these cells play an important role in the inflammatory responses following spinal cord injury (SCI). Mechanistically, the role of PTEN in the regulation of macrophage polarization has yet to be fully elucidated. In the present study, we first evaluated the expression of PTEN in macrophages after SCI. We found that PTEN expression was accumulated in the macrophages after the SCI surgery. Knock-down of PTEN or inhibition of phospho-PTEN with bpV(pic) in RAW264.7 cells resulted in increased M2 polarization and decreased M1 polarization. In a rat model of SCI, grafts containing bpV(pic) reduced spinal tissue cavitation and promoted locomotor improvement, while combining grafts of bpV(pic) and acellular spinal cord (ASC) scaffolds showed a better effect. Moreover, grafts containing bpV(pic) enhanced M2 polarization and decreased M1 polarization in the macrophages during SCI. Thus, we have established that PTEN is critical for the polarization of macrophages and the functional recovery of SCI. Targeting PTEN enhances the macrophages towards to M2 polarization and promoting the functional recovery in SCI, and this suggest that PTEN may be a future therapeutic target for SCI treatment.


Assuntos
Macrófagos/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Compostos de Vanádio/farmacologia , Animais , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Receptores Toll-Like/metabolismo
12.
Mol Med Rep ; 20(4): 3433-3439, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432160

RESUMO

Icariin is a type of flavonoid derived from the Chinese herbal plant Epimedium sagittatum Maxim. Mounting evidence has confirmed the beneficial effects of icariin in neurological diseases, including spinal cord injury (SCI). The aim of the present study was to investigate the neuroprotective effects of icariin in SCI and the precise underlying mechanism. The weight­drop injury technique was applied to construct an SCI model in Sprague­Dawley rats. Icariin (35 µmol/kg) was administered orally once daily for 7 consecutive days to examine its neuroprotective effects. The Basso, Beattie and Bresnahan scoring system was used for neurobehavioral evaluation. The water content of the injured spinal cord was measured via the dry­wet weight method. Biochemical indices were examined by colorimetric assay using commercially available kits. Western blot analysis was used to detect protein expression. Icariin significantly accelerated the recovery of the locomotor function of SCI rats and decreased spinal cord water content. Icariin also attenuated SCI­induced pro­apoptotic protein expression and activity, while it increased anti­apoptotic protein levels. In addition, icariin alleviated oxidative stress in SCI rats and decreased the levels of inflammatory molecules, including interleukin (IL)­1ß, IL­6, tumor necrosis factor­α, nitric oxide, nuclear factor­κB and inducible nitric oxide synthase, and increased the expression of anti­inflammatory proteins, including NADPH­quinone oxidoreductase­1, heme oxygenase­1 and nuclear factor erythroid 2­related factor 2 in the injured spinal cord. Therefore, icariin treatment accelerated locomotor function recovery in SCI, and its protective effects may be mediated via its antioxidant, anti­inflammatory and anti­apoptotic bioactivity.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
13.
Clinics (Sao Paulo) ; 74: e674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31433044

RESUMO

OBJECTIVE: To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS: Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: "Group EPO", treated with erythropoietin only; "Group EPO + IL-6", treated with both substances; "Group IL-6", receiving IL-6 administration only; "Group Placebo", receiving a placebo solution; and "Group Sham", submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS: The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS: Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.


Assuntos
Eritropoetina/uso terapêutico , Potencial Evocado Motor/efeitos dos fármacos , Interleucina-6/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Modelos Animais de Doenças , Eritropoetina/farmacologia , Interleucina-6/farmacologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia
14.
Med Sci Monit ; 25: 6359-6366, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31444877

RESUMO

BACKGROUND Brilliant blue G (BBG) is a P2X7 receptor inhibitor that has been reported to improve spinal cord injury (SCI) in previous studies, but the specific mechanism has been unclear. In this study, we investigated the effects of BBG on inflammasomes and blood-spinal cord barrier (BSCB) permeability after SCI. MATERIAL AND METHODS The experimental rats were randomly divided into 3 groups: sham, SCI, and SCI+BBG. The expression of P2X7 and inflammasome-related proteins was measured by Western blot and immunohistochemistry, while IL-1ß and IL-18 levels were measured by using an enzyme-linked immunosorbent assay (ELISA) kit. The permeability of the BSCB was evaluated by Evans Blue (EB) exosmosis, and histological alterations were observed by hematoxylin-eosin staining. Motor function recovery was assessed by the Basso, Beattie, Bresnahan (BBB) scale after SCI. RESULTS The expression levels of P2X7, NLRP3, ASC, cleaved XIAP, caspase-1, caspase-11, IL-1ß, and IL-18 were increased significantly after SCI, and BBG administration inhibited this increase at 72 h after SCI. BBG administration significantly reduced EB leakage at 24 h after SCI. Furthermore, treatment with BBG significantly attenuated histological alterations and improved motor function recovery after SCI. CONCLUSIONS BBG administration promoted motor function recovery and alleviated tissue injury, and these effects might be related to the suppression of inflammasomes and the maintenance of BSCB integrity.


Assuntos
Inflamassomos/efeitos dos fármacos , Corantes de Rosanilina/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Masculino , Fármacos Neuroprotetores/farmacologia , Antagonistas do Receptor Purinérgico P2X/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Coluna Vertebral/patologia
15.
Neurol Res ; 41(11): 991-1000, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31397222

RESUMO

Objectives: The aim of the study was to determine the relationships between microRNA-20a and microRNA-125b expression and apoptosis and inflammation in a rat model of spinal cord injury (SCI) using microscopy, immunohistochemistry, and molecular biology. Methods: Sixty-one rats were divided into three groups: a control group that was not subjected to any operation; a sham-operated group; and an experimental group that was subjected to spinal cord compression. The experimental group was further subdivided into two subgroups: the experimental control group, which did not receive any drug treatment; and the methylprednisolone treatment group, which received 30 mg/kg methylprednisolone on day 0 followed by 10 mg/kg/day methylprednisolone from days 1-14. Results: Tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 levels increased in the experimental control group on days 1 and 3, and decreased in the experimental control group and methylprednisolone treatment group on days 7 and 14. Caspase-3 levels increased in the experimental control group on day 1, and decreased in the experimental control group and methylprednisolone treatment group on days 3, 7, and 14. MicroRNA-20a expression was upregulated in the experimental control group on days 1 and 3, and microRNA-125b expression was downregulated on days 3 and 7. Conclusions: After SCI, upregulated microRNA-20a expression and increased proinflammatory cytokines may lead to an increase in inflammation. MicroRNA-125b may be associated with caspase-3, and microRNA-125b downregulation may inhibit apoptosis. Although the results of this study suggest potential relationships between microRNA-20a and microRNA-125b expression and apoptosis and inflammation in SCI, further studies are needed to confirm microRNA-20a and microRNA-125b as biomarkers in SCI and to develop new strategies for the treatment of SCI.


Assuntos
Apoptose/genética , MicroRNAs/genética , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Metilprednisolona/uso terapêutico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Biomed Res Int ; 2019: 9628065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467921

RESUMO

The reparative process following spinal cord injury (SCI) is extremely complicated. Cells in the microenvironment express multiple inhibitory factors that affect axonal regeneration over a prolonged period of time. The axon growth inhibitory factor glycogen synthase kinase-3 (GSK-3) is an important factor during these processes. TDZD-8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) is the most effective and specific non-ATP-competitive inhibitor of GSK-3. Here, we show that administering TDZD-8 after SCI was associated with significantly inhibited neuronal apoptosis, upregulated GAP-43 expression, increased density of cortical spinal tract fibers around areas of injury, and increased Basso, Beattie, and Bresnahan (BBB) scores in the lower limbs. These findings support the notion that GSK-3 inhibitors promote neuronal cell regeneration and lower limb functional recovery.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Tiadiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Axônios/efeitos dos fármacos , Modelos Animais de Doenças , Proteína GAP-43/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/genética , Humanos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia
17.
World Neurosurg ; 132: 138-147, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31470153

RESUMO

BACKGROUND: The infliction of a traumatic spinal cord injury (SCI) propagates damage that occurs in 2 stages. The first phase of trauma develops from the initial mechanical insult. The second phase involves the degradation of nervous tissue but is likely not affected by the initial insult. Thus, therapeutic targets with a high specificity for these secondary injury processes have been of increasing interest. We reviewed the pathophysiologic cascades of inflammation after SCI and potential therapeutic targets. METHODS: The PubMed and EMBASE databases were queried using appropriate medical subject headings for studies involving tumor necrosis factor (TNF)-α), nuclear factor (NF)-κB, inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, and/or Fas ligand (FasL) targets. The relevant studies found were graded into 3 levels (i.e., A, B, C) according to the quality of evidence. RESULTS: We have summarized the basis of the neurological damage for TNF-α, NF-κB, iNOS, IL-1ß, and FasL after SCI. A total of 17 studies were rated, each of which had reported histological, biochemical, physiological, and behavioral outcomes according to the treatment that had focused on TNF-α, NF-κB, iNOS, IL-1ß, and FasL. CONCLUSION: The TNF-α, iNOS, NF-κB, IL-1ß, and FasL will become active within minutes after SCI. The adverse effects from the activity of these receptors include inflammation and other important neurological damage. Each of these targets can be modulated by specific agents with differing degrees of efficacy according to the reported data.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Citocinas/metabolismo , Humanos , Receptores de Citocinas/efeitos dos fármacos
18.
J Neuroinflammation ; 16(1): 160, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358003

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a catastrophic trauma accompanied by intralesional bleeding and neuroinflammation. Recently, there is increasing interest in tranexamic acid (TXA), an anti-fibrinolytic drug, which can reduce the bleeding volume after physical trauma. However, the efficacy of TXA on the pathology of SCI remains unknown. METHODS: After producing a contusion SCI at the thoracic level of mice, TXA was intraperitoneally administered and the bleeding volume in the lesion area was quantified. Tissue damage was evaluated by immunohistochemical and gene expression analyses. Since heme is one of the degraded products of red blood cells (RBCs) and damage-associated molecular pattern molecules (DAMPs), we examined the influence of heme on the pathology of SCI. Functional recovery was assessed using the open field motor score, a foot print analysis, a grid walk test, and a novel kinematic analysis system. Statistical analyses were performed using Wilcoxon's rank-sum test, Dunnett's test, and an ANOVA with the Tukey-Kramer post-hoc test. RESULTS: After SCI, the intralesional bleeding volume was correlated with the heme content and the demyelinated area at the lesion site, which were significantly reduced by the administration of TXA. In the injured spinal cord, toll-like receptor 4 (TLR4), which is a DAMP receptor, was predominantly expressed in microglial cells. Heme stimulation increased TLR4 and tumor necrosis factor (TNF) expression levels in primary microglial cells in a dose-dependent manner. Similarly to the in vitro experiments, the injection of non-lysed RBCs had little pathological influence on the spinal cord, whereas the injection of lysed RBCs or heme solution significantly upregulated the TLR4 and TNF expression in microglial cells. In TXA-treated SCI mice, the decreased expressions of TLR4 and TNF were observed at the lesion sites, accompanied by a significant reduction in the number of apoptotic cells and better functional recovery in comparison to saline-treated control mice. CONCLUSION: The administration of TXA ameliorated the intralesional cytotoxicity both by reducing the intralesional bleeding volume and preventing heme induction of the TLR4/TNF axis in the SCI lesion. Our findings suggest that TXA treatment may be a therapeutic option for acute-phase SCI.


Assuntos
Heme/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Ácido Tranexâmico/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Animais , Feminino , Camundongos , Atividade Motora/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Vértebras Torácicas , Ácido Tranexâmico/farmacologia
19.
Int Immunopharmacol ; 74: 105726, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276973

RESUMO

Pharmacological therapy options for spinal cord injury (SCI) in acute phase have so far been limited, thus we focused on Calcitriol, FDA-approved biologically active form of vitamin D whose neuroprotective effects are increasingly recognized, to ameliorating damage following acute SCI in rats. Calcitriol (1 µg/kg) treatment for 7 consecutive days after SCI was compared SCI control and Sham control rat groups. Calcitriol-treated group had significantly improved outcome in standard functional recovery evaluation test (BBB) 12 weeks after SCI compared to SCI control, which was confirmed by increased ventral horn motor neurons in Calcitriol-treated group. In addition, proliferation test performed on lymphocytes from spleen and lymph nodes one week after SCI showed that calcitriol injection has a significant regulatory effect on Division Index (DI) in response to MBP stimulation compared to control SCI groups, which was associated with significant reduction in IFN-γ and IL-17A secretion and leukocyte infiltration into injury site. Along with confirmation of immunoregulatory aspects of Calcitriol treatment against myelin antigens in SCI, this study has shown that reducing the extent of progressive tissue loss by Calcitriol therapy in acute phase, could result in better recovery after SCI.


Assuntos
Calcitriol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Doença Aguda , Animais , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Imunomodulação , Interferon gama/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária , Ratos , Ratos Sprague-Dawley , Estados Unidos , United States Food and Drug Administration
20.
Neurochem Res ; 44(8): 2007-2019, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31325156

RESUMO

Spinal cord injury (SCI) leads to neuronal death resulting in central nervous system (CNS) dysfunction; however, the pathogenesis is still poorly understood. Melatonin (MT), a hormone secreted mainly by the pineal gland, is associated with neuroprotective effects against SCI. Enhanced autophagy can promote the recovery of locomotor function and reduce apoptosis after SCI. Interestingly, MT increases autophagy in SCI in vivo. Nevertheless, the ability of MT to increase autophagy and decrease apoptosis, and the potential effects on the recovery of motor neurons in the anterior horn after SCI remain to be clarified. In this study, we discovered that MT treatment improved motor function recovery in a rat SCI model. Indeed, MT upregulated the expression of the phosphatidylinositol 3-kinase (PI3K), while expression of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) was downregulated after SCI. Additionally, MT increased the expression of autophagy-activating proteins, while the expression of apoptosis-activating proteins in neurons was decreased following SCI. Furthermore, autophagy was inhibited, while apoptosis was induced in SCI model rats and lipopolysaccharide (LPS)-stimulated primary neurons by treatment with MT, the PI3K inhibitor 3-methyladenine (3-MA) and mTOR inhibitor Rapamycin (Rapa). Collectively, our results suggest that MT can improve the recovery of locomotor function by enhancing autophagy as well as reducing apoptosis after SCI in rats, probably via the PI3K/AKT/mTOR signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Melatonina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Locomoção/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Serina-Treonina Quinases TOR/metabolismo
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