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1.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800907

RESUMO

BACKGROUND: In the present study, we examined superoxide-mediated excitatory nociceptive transmission on at-level neuropathic pain following spinal thoracic 10 contusion injury (SCI) in male Sprague Dawley rats. METHODS: Mechanical sensitivity at body trunk, neuronal firing activity, and expression of superoxide marker/ionotropic glutamate receptors (iGluRs)/CamKII were measured in the T7/8 dorsal horn, respectively. RESULTS: Topical treatment of superoxide donor t-BOOH (0.4 mg/kg) increased neuronal firing rates and pCamKII expression in the naïve group, whereas superoxide scavenger Tempol (1 mg/kg) and non-specific ROS scavenger PBN (3 mg/kg) decreased firing rates in the SCI group (* p < 0.05). SCI showed increases of iGluRs-mediated neuronal firing rates and pCamKII expression (* p < 0.05); however, t-BOOH treatment did not show significant changes in the naïve group. The mechanical sensitivity at the body trunk in the SCI group (6.2 ± 0.5) was attenuated by CamKII inhibitor KN-93 (50 µg, 3.9 ± 0.4) or Tempol (1 mg, 4 ± 0.4) treatment (* p < 0.05). In addition, the level of superoxide marker Dhet showed significant increase in SCI rats compared to the sham group (11.7 ± 1.7 vs. 6.6 ± 1.5, * p < 0.05). CONCLUSIONS: Superoxide and the pCamKII pathway contribute to chronic at-level neuropathic pain without involvement of iGluRs following SCI.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Hiperalgesia/tratamento farmacológico , Proteínas do Tecido Nervoso/fisiologia , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Superóxidos/metabolismo , Animais , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Contusões/fisiopatologia , Óxidos N-Cíclicos/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Hiperalgesia/etiologia , Masculino , Modelos Animais , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neuralgia/etiologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Marcadores de Spin , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologia , Sulfonamidas/farmacologia , Transmissão Sináptica
2.
AAPS PharmSciTech ; 22(3): 101, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712968

RESUMO

There is an increasing need to develop improved and non-invasive strategies to treat spinal cord injury (SCI). Nanoparticles (NPs) are an enabling technology to improve drug delivery, modulate inflammatory responses, and restore functional responses following SCI. However, the complex pathophysiology associated with SCI presents several distinct challenges that must be overcome for sufficient NP drug delivery to the spinal cord. The objective of this mini-review is to highlight the physiological challenges and cell types available for modulation and discuss several promising advancements using NPs to improve SCI treatment. We will focus our discussion on recent innovative approaches in NP drug delivery and how the implementation of multifactorial approaches to address the proinflammatory and complex immune dysfunction in SCI offers significant potential to improve outcomes in SCI.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Humanos
3.
J Med Food ; 24(3): 218-225, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33739882

RESUMO

Spinal cord ischemia-reperfusion injury (SCII) easily causes unalterable neurological deficits. We previously demonstrated that the flavonoid luteolin (LU) has strong antioxidant, anti-inflammatory, and other neuroprotective efficacies against SCII. In our current study, we examined the contributions of the NF-E2-related factor 2 (Nrf2)/glutamate-cysteine ligase (GCL) pathway to LU-mediated neuroprotection in the transient abdominal aorta occlusion rat model of SCII. Rats were divided into four groups: Sham surgery, SCII alone, SCII plus LU pretreatment (SCII + LU), and SCII plus cotreatment with LU and the Nrf2 inhibitor ML385 (SCII + LU + ML385). The Basso-Beattie-Bresnahan (BBB) scale was used to assess neurological function, hematoxylin and eosin staining to evaluate pathological change to the spinal cord, and enzyme-linked immunosorbent assay to measure tissue markers of oxidative stress and inflammation induced by SCII. Mitochondrial injury and apoptosis were examined by flow cytometry and expression levels of Nrf2, GCL catalytic subunit (GCLc), and GCL modifier subunit (GCLm) by real-time quantitative polymerase chain reaction. LU pretreatment significantly enhanced recovery of motor function as evidenced by the BBB score and attenuated the pathological damage. Furthermore, LU effectively enhanced the antioxidative activity, alleviated mitochondrial swelling, decreased the expression levels of several proinflammatory cytokines after SCII, and significantly upregulated Nrf2, GCLc, and GCLm expression levels. Cotreatment with ML385 reversed all these protective effects of LU except the anti-inflammatory response. Collectively, these findings indicate that the neuroprotective efficacy of LU depends on suppression of oxidative stress and preservation of mitochondrial function through signaling pathways involving Nrf2 activation and downstream gene expression.


Assuntos
Traumatismo por Reperfusão , Traumatismos da Medula Espinal , Animais , Glutamato-Cisteína Ligase/genética , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/genética
4.
Acta Biomater ; 126: 211-223, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33722788

RESUMO

Spinal cord injury (SCI) causes immune activation of resident macrophages/microglia. Activated macrophages/microglia have two different phenotypes, the pro-inflammatory classically activated (M1) phenotype and the anti-inflammatory alternatively activated (M2) phenotype. M1 phenotype macrophages/microglia are the key factor in inflammation. The treatment of SCI remains a huge challenge due to the nontargeting and inefficiency of anti-inflammatory drugs through the blood-brain barrier (BBB). The purpose of this experiment was to design M2-type primary peritoneal macrophages exosomes (Exos) as a drug carrier for berberine (Ber), which can be efficiently targeted to deliver drugs to the injured spinal cord due to the natural advantage of Exos across the BBB. The Exos with particle size of 125±12 nm were loaded with by an ultrasonic method and the drug loading reached 17.13 ±1.64%. The Ber release experiment showed that the loaded sample (Exos-Ber) exhibited sustained release effect, and the cumulative release amount reached 71.44±2.86% within 48 h. In vitro and in vivo experiments confirmed that the Exos-Ber could decrease the M1 protein marker iNOS, elevate the M2 protein marker CD206 and reduce inflammatory and apoptotic cytokines (TNF-α, IL-1ß, IL-6, Caspase 9, Caspase 8), which showed that Exos-Ber had a good anti-inflammatory and anti-apoptotic effect by inducing macrophages/microglia from the M1 phenotype to M2 phenotype polarization. Moreover, the motor function of SCI mice was significantly improved after Exos-Ber treatment, indicating that Exos-Ber is a potential agent for SCI therapy. STATEMENT OF SIGNIFICANCE: Efficient targeting strategy for drug delivery. In addition to good biocompatibility and stealth ability, M2 macrophage-derived Exosomes present natural inflammatory targeting ability. The inflammatory microenvironment after spinal cord injury provides motivation for the targeting of exosomes. Natural drug carrier with higher safety. With the rapid development of nanomaterials, drug carriers have become more selective. However, due to the special microenvironment after central nervous system damage, some non-degradable inorganic materials will increase the pressure of self-healing and even secondary damage to neurons, which has been solved by the emergence of exosomes. Some previous studies used tumor cell line exosomes as drug carriers, but the carcinogenic factors carried by themselves have extremely high hidden dangers, and endogenous macrophage exosomes have absolute advantages over their safety.


Assuntos
Berberina , Exossomos , Traumatismos da Medula Espinal , Animais , Berberina/farmacologia , Macrófagos , Camundongos , Microglia , Traumatismos da Medula Espinal/tratamento farmacológico
5.
ACS Chem Neurosci ; 12(6): 1031-1038, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33621043

RESUMO

Bradykinin and bradykinin B2 receptors (B2R) play important roles in both the peripheral and central nervous systems. The aim of this study was to explore the changes of bradykinin and B2R in spinal cord ischemic injury (SCII) and whether bradykinin treatment would improve the neurologic function of SCII rats. The rats were divided into the sham group, the SCII group, and three doses of bradykinin (50, 100, 150 µg/kg) groups. The neurologic function was assessed by the Basso, Beattie, and Bresnahan (BBB) score at -1, 1, 3, 5, and 7 days postsurgery. Bradykinin concentration in serum and IL-6, TNF-α, and MCP-1 levels in the spinal cord were detected by ELISA. The mRNA expressions of B2R, IL-6, TNF-α, MCP-1, COX-2, and iNOS in the spinal cord were determined by RT-PCR. The protein expressions of B2R, COX-2, iNOS, p65, and p-p65 were detected by Western blot. Immunohistochemical staining was used to examine B2R expression in the L4-6 segments of the spinal cord. Bradykinin levels in serum and B2R expression in the spinal cord were downregulated in SCII rats. Bradykinin treatment significantly improved the hind limb motor function of SCII rats and increased B2R expression, inhibiting COX-2, iNOS, and p-p65 expression in the spinal cord of SCII rats together with a decrease of the inflammatory mediators of IL-6, TNF-α, and MCP-1 levels. Bradykinin administration activated B2R in the spinal cord of SCII rats, which may improve hind limb locomotor recovery by regulating the NF-κB signaling pathway to inhibit the inflammatory response. These findings may provide a theoretical basis for the clinical application of bradykinin in SCII.


Assuntos
Traumatismo por Reperfusão , Traumatismos da Medula Espinal , Animais , Bradicinina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor B2 da Bradicinina , Traumatismo por Reperfusão/tratamento farmacológico , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico
6.
BMC Complement Med Ther ; 21(1): 69, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607999

RESUMO

BACKGROUND: Endoplasmic reticulum stress (ERS) is one of the main mechanisms of spinal cord injury (SCI) pathology and can affect the physiological state of neurons. Icariin (ICA), the main pharmacological component of Epimedium, can relieve the symptoms of patients with SCI and has obvious protective effects on neurons through ERS. METHODS: PC12 cells were induced to differentiate into neurons by nerve growth factor and identified by flow cytometry. Cell proliferation was detected by CCK8 method, cell viability was detected by SRB assay, apoptosis was detected by flow cytometry and microstructure of ER was observed by transmission electron microscope. Western blot was used to detect the protein expression of CHOP and Grp78, and qPCR was used to detect the mRNA expression of CHOP and Grp78. RESULTS: The results of CCK8, SRB and flow cytometry showed that ICA could relieve ERS and reduce apoptosis of PC12 cells. The results of transmission microscope showed that ICA could reduce apoptosis of PC12 cells caused by ERS. The results of Western blot and q-PCR showed that ICA could inhibit ERS by down-regulating the expression of CHOP and Grp78. CONCLUSIONS: ICA can inhibit ERS and promote the repair of PC12 cells by down-regulating the expression of CHOP and Grp78. ICA has the potential to promote the recovery of spinal cord injury.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Epimedium/química , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Traumatismos da Medula Espinal/patologia , Animais , Apoptose , Proteínas de Transporte/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Flavonoides/uso terapêutico , Células PC12 , Extratos Vegetais/uso terapêutico , Ratos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Fator de Transcrição CHOP/metabolismo
7.
Biomater Sci ; 9(8): 2955-2971, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33634811

RESUMO

The limited regrowth of transected axons and insufficient regeneration of lost neurons in adult mammals collectively hinder complete spinal cord injury (SCI) repair. Hence, designing an ideal bio-scaffold which could coordinate the regeneration of axons and neurons in situ might be able to effectively facilitate the reconstruction of neural circuits and the recovery of nerve function after complete SCI. In this study, a sponge-like collagen scaffold with good drug release characteristics and good nerve cell compatibility was prepared and used as a drug delivery platform. When doubly modified with Taxol liposomes and collagen-binding neurotrophic factor 3, the scaffold dually alleviated myelin-derived inhibition on neurite outgrowth of neurons and neuronal differentiation of neural stem cells in vitro. Meanwhile, the binary-drug modified scaffold was also able to simultaneously promote both axonal and neuronal regeneration when implanted into a complete transected SCI model. Additionally, the regenerated axons and neurons throughout the lesion site formed extensive synaptic connections. Finally, complete SCI rats that received binary scaffold implantation exhibited optimal neuroelectrophysiological recovery and hindlimb locomotor improvement. Taken together, implantation of the binary scaffold can establish neural bridging networks for functional recovery, representing a clinically promising strategy for complete SCI repair.


Assuntos
Traumatismos da Medula Espinal , Regeneração da Medula Espinal , Animais , Axônios , Regeneração Nervosa , Neurônios , Ratos , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Tecidos Suporte
8.
Adv Healthc Mater ; 10(8): e2001896, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33522126

RESUMO

Spinal cord injury (SCI) is plaguing medical professionals globally due to the complexity of injury progression. Based on tissue engineering technology, there recently emerges a promising way by integrating drugs with suitable scaffold biomaterials to mediate endogenous neural stem cells (NSCs) to achieve one-step SCI repair. Herein, exosomes extracted from human umbilical cord-derived mesenchymal stem cells (MExos) are found to promote the migration of NSCs in vitro/in vivo. Utilizing MExos as drug delivery vehicles, a NSCs migration promoted and paclitaxel (PTX) delivered MExos-collagen scaffold is designed via a novel dual bio-specificity peptide (BSP) to effectively retain MExos within scaffolds. By virtue of the synergy that MExos recruit endogenous NSCs to the injured site, and PTX induce NSCs to give rise to neurons, this multifunctional scaffold has shown superior performance for motor functional recovery after complete SCI in rats by enhancing neural regeneration and reducing scar deposition. Besides, the dual bio-specific peptide demonstrates the capacity of tethering other cells-derived exosomes on collagen scaffold, such as erythrocytes-derived or NSCs-derived exosomes on collagen fibers or membranes. The resulting exosomes-collagen scaffold may serve as a potential multifunctional therapy modality for various disease treatments including SCI.


Assuntos
Exossomos , Células-Tronco Neurais , Preparações Farmacêuticas , Traumatismos da Medula Espinal , Animais , Colágeno , Células-Tronco Neurais/transplante , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Tecidos Suporte
9.
Neurosci Lett ; 748: 135690, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33540059

RESUMO

Polysialic acid (PolySia) is a critical post-translational modification on the neural cell adhesion molecule (NCAM, a.k.a., CD56), important for cell migration and axon growth during nervous system development, plasticity and repair. PolySia induction on Schwann cells (SCs) enhances their migration, axon growth support and ability to improve functional recovery after spinal cord injury (SCI) transplantation. In the current investigation two methods of PolySia induction on SCs, lentiviral vector transduction of the mouse polysialytransferase gene ST8SIA4 (LV-PST) or enzymatic engineering with a recombinant bacterial PST (PSTNm), were examined comparatively for their effects on PolySia induction, SC migration, the innate immune response and axon growth after acute SCI. PSTNm produced significant PolySia induction and a greater diversity of surface molecule polysialylation on SCs as evidenced by immunoblot. In the scratch wound assay, PSTNm was superior to LV-PST in the promotion of SC migration and gap closure. At 24 h after SCI transplantation, PolySia induction on SCs was most pronounced with LV-PST. Co-delivery of PSTNm with SCs, but not transient cell exposure, led to broader induction of PolySia within the injured spinal cord due to polysialylation upon both host cells and transplanted SCs. The innate immune response after SCI, measured by CD68 immunoreactivity, was similar among PolySia induction methods. LV-PST or PSTNm co-delivery with SCs provided a similar enhancement of SC migration and axon growth support above that of unmodified SCs. These studies demonstrate that LV-PST and PSTNm provide comparable acute effects on SC polysialation, the immune response and neurorepair after SCI.


Assuntos
Movimento Celular/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Ácidos Siálicos/farmacologia , Sialiltransferases/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Movimento Celular/fisiologia , Modelos Animais de Doenças , Camundongos , Moléculas de Adesão de Célula Nervosa , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Células de Schwann/metabolismo , Sialiltransferases/genética , Traumatismos da Medula Espinal/fisiopatologia
10.
eNeuro ; 8(2)2021.
Artigo em Inglês | MEDLINE | ID: mdl-33632814

RESUMO

Secondary damage after spinal cord injury (SCI) occurs because of a sequence of events after the initial injury, including exacerbated inflammation that contributes to increased lesion size and poor locomotor recovery. Thus, mitigating secondary damage is critical to preserve neural tissue and improve neurologic outcome. In this work, we examined the therapeutic potential of a novel antisense oligonucleotide (ASO) with special chemical modifications [2'-deoxy-2-fluoro-D-arabinonucleic acid (FANA) ASO] for specifically inhibiting an inflammatory molecule in the injured spinal cord. The chemokine CCL3 plays a complex role in the activation and attraction of immune cells and is upregulated in the injured tissue after SCI. We used specific FANA ASO to inhibit CCL3 in a contusive mouse model of murine SCI. Our results show that self-delivering FANA ASO molecules targeting the chemokine CCL3 penetrate the spinal cord lesion site and suppress the expression of CCL3 transcripts. Furthermore, they reduce other proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1ß after SCI. In summary, we demonstrate for the first time the potential of FANA ASO molecules to penetrate the spinal cord lesion site to specifically inhibit CCL3, reducing proinflammatory cytokines and improve functional recovery after SCI. This novel approach may be used in new treatment strategies for SCI and other pathologic conditions of the CNS.


Assuntos
Oligonucleotídeos , Traumatismos da Medula Espinal , Animais , Modelos Animais de Doenças , Inflamação , Camundongos , Recuperação de Função Fisiológica , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico
11.
ACS Chem Neurosci ; 12(6): 959-965, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33635633

RESUMO

17ß-Estradiol (E2) confers neuroprotection in preclinical models of spinal cord injury when administered systemically. The goal of this study was to apply E2 locally to the injured spinal cord for a sustained duration using poly(pro-E2) film biomaterials. Following contusive spinal cord injury in adult male mice, poly(pro-E2) films were implanted subdurally and neuroprotection was assessed using immunohistochemistry 7 days after injury and implantation. In these studies, poly(pro-E2) films modestly improved neuroprotection without affecting the inflammatory response when compared to the injured controls. To increase the E2 dose released, bolus-releasing poly(pro-E2) films were fabricated by incorporating unbound E2 into the poly(pro-E2) films. However, compared to the injured controls, bolus-releasing poly(pro-E2) films did not significantly enhance neuroprotection or limit inflammation at either 7 or 21 days post-injury. Future work will focus on developing poly(pro-E2) biomaterials capable of more precisely releasing therapeutic doses of E2.


Assuntos
Contusões , Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Animais , Estradiol , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/tratamento farmacológico
12.
Osteoporos Int ; 32(7): 1321-1332, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33443609

RESUMO

Twenty men with spinal cord injury (SCI) were randomized into two 16-week intervention groups receiving testosterone treatment (TT) or TT combined with resistance training (TT + RT). TT + RT appears to hold the potential to reverse or slow down bone loss following SCI if provided over a longer period. INTRODUCTION: Persons with SCI experience bone loss below the level of injury. The combined effects of resistance training and TT on bone quality following SCI remain unknown. METHODS: Men with SCI were randomized into 16-week treatments receiving TT or TT + RT. Magnetic resonance imaging (MRI) of the right lower extremity before participation and post-intervention was used to visualize the proximal, middle, and distal femoral shaft, the quadriceps tendon, and the intermuscular fascia of the quadriceps. For the TT + RT group, MRI microarchitecture techniques were utilized to elucidate trabecular changes around the knee. Individual mixed models were used to estimate effect sizes. RESULTS: Twenty participants completed the pilot trial. A small effect for yellow marrow in the distal femur was indicated as increases following TT and decreases following TT + RT were observed. Another small effect was observed as the TT + RT group displayed greater increases in intermuscular fascia length than the TT arm. Distal femur trabecular changes for the TT + RT group were generally small in effect (decreased trabecular thickness variability, spacing, and spacing variability; increased network area). Medium effects were generally observed in the proximal tibia (increased plate width, trabecular thickness, and network area; decreased trabecular spacing and spacing variability). CONCLUSIONS: This pilot suggests longer TT + RT interventions may be a viable rehabilitation technique to combat bone loss following SCI. CLINICAL TRIAL REGISTRATION: Registered with clinicaltrials.gov : NCT01652040 (07/27/2012).


Assuntos
Treinamento de Força , Traumatismos da Medula Espinal , Densidade Óssea , Osso e Ossos , Humanos , Masculino , Traumatismos da Medula Espinal/tratamento farmacológico , Testosterona , Tíbia
13.
Biomed Pharmacother ; 134: 111168, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33395598

RESUMO

Axonal demyelination is a consistent pathological characteristic of Spinal cord injury (SCI). Promoting differentiation of oligodendrocytes is of importance for remyelination. Conversion of reactive astrocytes with stem cell potential to oligodendrocytes is proposed as an innovative strategy for SCI repair. Neuregulin-1 (Nrg1) plays an essential role in the differentiation of oligodendrocytes. Therefore, it's a potential treatment for demyelination in SCI that using Nrg1 to drive reactive astrocytes toward oligodendrocyte lineage cells. In this study, tumor necrosis factor-α (TNF-α) was used to induce dedifferentiation of primary rat spinal cord astrocytes into reactive astrocytes and Nrg1 was used to induce astrocytes in vitro and in vivo. The results showed that astrocytes treated with TNF-α expressed immaturity markers CD44 and Musashi1 at mRNA and protein levels, indicating that TNF-α induced the stem cell state of astrocytes. Nrg1 induced reactive astrocytes to express oligodendrocyte markers PDGFR-α and O4 at mRNA and protein levels, indicating that Nrg1 directly converts reactive astrocytes toward oligodendrocyte lineage cells. Moreover, upregulation of PI3K-AKT-mTOR signaling activation in response to Nrg1 was observed. In rats with SCI, intrathecal treatment with Nrg1 converted reactive astrocytes to oligodendrocyte lineage cells, inhibited astrogliosis, promoted remyelination, protected axons and eventually improved BBB score. All the biological effects of Nrg1 were significantly reversed by the co-administration of Nrg1 and ErbB inhibitor, suggesting that Nrg1 functioned through the receptor ErbB. Our findings indicate that Nrg1 is sufficient to trans-differentiate reactive astrocytes to oligodendrocytes via the PI3K-AKT-mTOR signaling pathway and repair SCI. Delivery of Nrg1 for the remyelination processes could be a promising strategy for spinal cord repair.


Assuntos
Astrócitos/efeitos dos fármacos , Linhagem da Célula , Transdiferenciação Celular/efeitos dos fármacos , Neuregulina-1/farmacologia , Oligodendroglia/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Astrócitos/enzimologia , Astrócitos/patologia , Células Cultivadas , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Bainha de Mielina/metabolismo , Oligodendroglia/enzimologia , Oligodendroglia/patologia , Ratos Sprague-Dawley , Transdução de Sinais , Medula Espinal/enzimologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/enzimologia , Traumatismos da Medula Espinal/patologia , Fator de Necrose Tumoral alfa/farmacologia
14.
Turk Neurosurg ; 31(1): 93-98, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33491171

RESUMO

AIM: To examine the effect of propolis on the healing process in terms of both electrophysiological and ultrastructural parameters in a rat model of experimental spinal cord injury. MATERIAL AND METHODS: Thirty rats were divided into control, spinal cord trauma, and treated trauma groups with 10 rats per group. The rats were sacrificed after 10 days. Before sacrifice, all rats were neurologically assessed by electrophysiological monitoring, and immediately after sacrifice, the spinal cord was examined ultrastructurally by transmission electron microscopy (TEM). RESULTS: According to the electrophysiological examination, the treatment group was statistically significantly different from the trauma group. However, no statistically significant difference was found between the control and treatment groups. In terms of the TEM examination, the treatment group was significantly different from the trauma group. CONCLUSION: In this study, propolis was administered just before the induction of trauma, and the findings suggest that the use of propolis has a positive effect on the healing process. This implies that in order to prevent postoperative deficits, this treatment may be preferably applied before spinal cord surgery for trauma.


Assuntos
Própole/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Masculino , Própole/farmacologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Traumatismos da Medula Espinal/patologia , Resultado do Tratamento
15.
Phytomedicine ; 82: 153452, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33418139

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a refractory neurodegenerative disease caused by inflammation. M1 microglia induce inflammation, whereas M2 suppress inflammation and exhibit neuroprotective effects. Following SCI, M1 cells are more predominant than M2 cells, and hence, increasing the predominance of M2 microglia may improve SCI. PURPOSE: We aimed to evaluate the active constituents of herbal medicine that induce M2 predominance and to investigate their effects using SCI model mice. METHODS: Herbal medicine inducing M2 were screened using cultured microglia. After orally administering the active herbal medicine, Polygalae Radix (PR), to SCI model mice, motor function was evaluated. Compounds in the spinal cord following treatment were assessed using liquid chromatography-mass spectrometry. The effects of compounds detected in the spinal cord were investigated in cultured microglia. RESULTS: PR induced M2 predominance in cultured microglia, improved motor function in SCI model mice, and showed a tendency to increase M2 microglia and protect against axonal degeneration in the inured spinal cord. Sibiricose A5 and 3,6'-disinapoyl sucrose were identified as active constituents in PR. CONCLUSION: PR may be a promising candidate for the treatment of SCI by inducing M2 predominance.


Assuntos
Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Plantas Medicinais/química , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Masculino , Camundongos
16.
J Neurosci ; 41(5): 845-854, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472820

RESUMO

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.


Assuntos
Interneurônios/metabolismo , Doenças do Sistema Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/patologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
17.
Cell Prolif ; 54(3): e12992, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33506613

RESUMO

Spinal cord injury (SCI) always leads to functional deterioration due to a series of processes including cell death. In recent years, programmed cell death (PCD) is considered to be a critical process after SCI, and various forms of PCD were discovered in recent years, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis. Unlike necrosis, PCD is known as an active cell death mediated by a cascade of gene expression events, and it is crucial for elimination unnecessary and damaged cells, as well as a defence mechanism. Therefore, it would be meaningful to characterize the roles of PCD to not only enhance our understanding of the pathophysiological processes, but also improve functional recovery after SCI. This review will summarize and explore the most recent advances on how apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis are involved in SCI. This review can help us to understand the various functions of PCD in the pathological processes of SCI, and contribute to our novel understanding of SCI of unknown aetiology in the near future.


Assuntos
Apoptose/genética , Morte Celular/efeitos dos fármacos , Necrose/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Morte Celular/fisiologia , Humanos , Necroptose/efeitos dos fármacos , Necrose/metabolismo , Traumatismos da Medula Espinal/patologia
18.
Eur J Pharmacol ; 895: 173878, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453223

RESUMO

Spinal cord injury (SCI), mostly caused by sports injuries, falls, or traffic accidents, is a major cause of disability. The aim of current work was to investigate the therapeutic effect of isorhamnetin (ISO) on functional recovery in rats with SCI. The male adult rats were exposed to a clip-compression SCI and treated with ISO. ISO treatment improved locomotor function and reduced the loss of motor neurons in SCI rats. Treatment with ISO markedly relieved SCI-induced hypersensitivities to mechanical and thermal stimulation in rats. ISO treatment activated nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and abated oxidative stress in injured spinal cords. ISO treatment partly suppressed microglial and glial activation and reduced expression of inflammatory cytokines including TNF-α, monocyte chemotactic protein-1 (MCP-1), and IL-1ß in injured spinal cords. More importantly, ISO treatment promoted M2 macrophage activation in the injured region. lipopolysaccharide (LPS) or IL-4 was employed to stimulate macrophages/microglia into M1 or M2 phenotype in cultured BV2 cells in vitro. ISO treatment enhanced the expression of characteristic microglial anti-inflammatory polarization markers in BV2 cells. In conclusions, ISO treatment promotes functional recovery in rats with SCI by abating oxidative stress and modulating M1/M2 macrophage polarization.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/análogos & derivados , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Locomoção/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Microglia/metabolismo , Microglia/patologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Limiar da Dor/efeitos dos fármacos , Fenótipo , Quercetina/farmacologia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
19.
Turk Neurosurg ; 31(2): 211-216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33372253

RESUMO

AIM: To evaluate the protective effects of azathioprine, a macrophage-inhibiting agent, on secondary injury in spinal cord trauma. MATERIAL AND METHODS: A total of 40 Wistar rats were randomly divided into 4 groups. All the animals had undergone T8-10 laminectomy. Except in group I (control), all the animals were exposed to spinal cord trauma at the T9 level. Animals in group II (trauma) received no treatment following trauma. Animals in group 3 (treatment) and group IV (vehicle) were given intraperitoneal azathioprine 4 mg/kg and saline 2 ml, respectively, 30 minutes after the trauma. Half of the animals in each group were sacrificed 24 hours after injury and specimens were used for biochemical and immunohistochemical evaluations. The rest of the animals were followed-up for 4 weeks in terms of neurological functions and were also sacrificed to perform the histopathological analysis. RESULTS: Significant decrease in apoptotic cells and improved neurological function were observed in the animals treated with azathioprine. Biological and immunohistochemical analysis also showed less oxidative stress in this group compared to those without treatment. CONCLUSION: Azathioprine, a potent macrophage-inhibiting agent, has been shown to decrease the extent of secondary injury following spinal cord trauma.


Assuntos
Azatioprina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Vértebras Torácicas/lesões , Animais , Azatioprina/farmacologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Laminectomia/efeitos adversos , Masculino , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/patologia , Vértebras Torácicas/patologia
20.
Methods Mol Biol ; 2225: 227-239, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108666

RESUMO

Severe inflammatory disease initiated by neurotrauma and stroke is of primary concern in these intractable pathologies as noted in recent studies and understanding of the pathogenesis of spinal cord injury (SCI) in the rat model. Successful anti-inflammatory treatments should result in neuroprotection and limit the loss of neurological function to injury caused by the initial damage. Continuous subdural infusion offers direct access to the cavity of injury (COI) that forms after balloon crush SCI deep in the spinal cord. Some anti-inflammatory compounds are not likely capable of crossing the blood-spinal cord barrier. Subdural infusion of myxoma virus-derived Serp-1, an anti-thrombotic/anti-thrombolytic, and also of M-T7, a chemokine inhibitor, improved the locomotor scores and pain sensation scores as well as reduced the numbers of macrophages in the COI by 50 and 80%, respectively, while intraperitoneal infusion of either protein had little effect. Injection of a chitosan hydrogel loaded with Serp-1 into the dorsal spinal column crush also resulted in improved neurological deficits and in reduction of the size of the crush lesion 4 weeks after injury. While neurological scores in a simplified hind-end (HE) locomotor test together with a toe-pinch withdrawal test demonstrated improvement in all balloon crush injury and dorsal spinal crush injury rats, a severe inflammation is induced by the injury indicating additional damage to the spinal cord. Thus neurological function testing can be contradictory, rather than corresponding, to the pathogenesis of SCI. The count of macrophages in the COI offers a precise, reliable method of measuring the effectiveness of a neuroprotective treatment of SCI in preclinical studies.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores Imunológicos/farmacologia , Myxoma virus/química , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Proteínas Virais/farmacologia , Animais , Anti-Inflamatórios/imunologia , Quitosana/química , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Fatores Imunológicos/imunologia , Injeções Epidurais , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/imunologia , Ratos , Ratos Long-Evans , Receptores de Interferon/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Proteínas Virais/imunologia
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