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Remifentanilinduced hyperalgesia (RIH) is characterized by the emergence of stimulationinduced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequencespecific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at 24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitationPCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and pNR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dosedependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p)NR2B. Nevertheless, the increased amount of pNR2B by RIH was dosedependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.
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Hiperalgesia , Isoflavonas , Animales , Ratas , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/genética , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Piperidinas/farmacología , Ratas Sprague-Dawley , Remifentanilo/efectos adversos , Factor de Transcripción PAX6/efectos de los fármacos , Factor de Transcripción PAX6/metabolismo , Canales Catiónicos TRPV/efectos de los fármacos , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismoRESUMEN
BACKGROUND: Spinal cord ischemia-reperfusion injury (SCII) is usually caused by spinal surgery, often leading to severe neurological deficits. The ubiquitin-specific protease 18 (USP18) plays a significant role in neurological diseases. OBJECTIVE: The present study was designed to assess the effects and mechanisms of USP18 on SCII. METHODS: By inducing transient aortic occlusion and subsequent reperfusion, a rat model of SCII was successfully established. The Basso-Beattie-Bresnahan scores, the inclined plane test, and hematoxylin and eosin (HE) were used to measure locomotor activity and histological changes in the injured spinal cords. Moreover, the SCII cell model was established using PC12 cells under oxygen-glucose deprivation and reoxygenation (OGD/R). Proinflammatory factors (TNF-α, IL-6, and INF-α) were examined using an ELISA kit. Cell apoptosis was assessed by Annexin V-FITC/PI double-staining and TUNEL assays. Western blot was used to detect the expression levels of proteins related to apoptosis and autophagy. RESULTS: USP18 expression was decreasedin vivo and in vitro SCII models. The upregulation of USP18 ameliorated hind limbs' motor function, inhibiting inflammation and apoptosis after SCII in rats. USP18 overexpression in vitro may protect PC12 cells from OGD/R-induced damage by modulating inflammatory responses and apoptosis. Moreover, Overexpression of USP18 enhanced autophagy to inhibit cell apoptosis induced by SCII in vivo and in vitro. CONCLUSIONS: In summary, USP18 overexpression protects against SCII via regulating autophagy.
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Daño por Reperfusión , Isquemia de la Médula Espinal , Animales , Ratas , Apoptosis , Autofagia , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Médula Espinal/metabolismo , Isquemia de la Médula Espinal/metabolismoRESUMEN
Solanum nigrum Linn., is a common edible medicinal herb of the Solanaceae family which is native to Southeast Asia and is now widely distributed in temperate to tropical regions of Europe, Asia, and America. Traditionally, it has been used to treat various cancers, acute nephritis, urethritis, leucorrhea, sore throat, toothache, dermatitis, eczema, carbuncles, and furuncles. Up to now, 188 chemical constituents have been identified from S. nigrum. Among them, steroidal saponins, alkaloids, phenols, and polysaccharides are the major bioactive constituents. Investigations of pharmacological activities of S. nigrum revealed that this edible medicinal herb exhibits a wide range of therapeutic potential, including antitumor, anti-inflammatory, antioxidant, antibacterial, and neuroprotective activities both in vivo and in vitro. This article presents a comprehensive and systematic overview of the botanical, traditional uses, phytochemical compositions, pharmacological properties, clinical trials, and toxicity of S. nigrum to provide the latest information for further exploitation and applications of S. nigrum in functional foods and medicines.
RESUMEN
STUDY OBJECTIVES: This study aimed to investigate the effects of repeated preoperative intranasal administration of insulin on the incidence of postoperative delirium (POD) and the levels of serum pro-inflammatory markers in elderly patients undergoing laparoscopic radical gastrointestinal surgery. DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical study. SETTING: General Hospital of Western Theater Command from August 2019 to December 2019. PATIENTS: Ninety elderly patients underwent laparoscopic radical gastrointestinal tumor resections under general anesthesia. INTERVENTIONS: Patients were randomly divided into a control group (0.5 mL saline administered intranasally) or an insulin group (20 U/0.5 mL insulin administered intranasally) for 2 days prior to surgery, with 45 patients in each group. MEASUREMENTS: The incidence of delirium was measured at postoperative day 1 (T2), day 3 (T3), and day 5 (T4) using the Confusion Assessment Method for the intensive care unit (CAM-ICU). Plasma levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were measured at T0 (before insulin or saline administration), T1 (at the end of surgery), T2, T3, and T4 by enzyme-linked immunosorbent assay. MAIN RESULTS: Compared with the control group, the insulin group demonstrated a decreased POD incidence (12.5% vs. 47.5%, pâ¯=â¯0.001) within 5 days after surgery. The incidence of POD was significantly lower in the Ins group than in the Con group at T2 (12.5% vs. 32.5%, pâ¯=â¯0.032) and at T3 (2.5% vs. 20%, pâ¯=â¯0.034). The incidence of POD decreased in both groups over time and was similar at T4 (0% vs 10%, pâ¯=â¯0.116). Compared with the baseline value at T0, serum TNF-α, IL-6 and IL-1ß concentrations increased significantly at T1-4 (p <0.05). Compared with the control group at the same time point, the expression levels of TNF-α, IL-6 and IL-1ß in group I at T2 and T3 were significantly reduced (p <0.05). The incidence rates of adverse events were similar in the two groups. CONCLUSIONS: Repeated preoperative intranasal administration of insulin prevented the occurrence of delirium after laparoscopic radical gastrointestinal surgery in elderly patients and reduced TNF-α, IL-1ß, and IL-6 levels.
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Delirio , Procedimientos Quirúrgicos del Sistema Digestivo , Laparoscopía , Administración Intranasal , Anciano , Delirio/epidemiología , Humanos , Incidencia , Insulina , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Estudios ProspectivosRESUMEN
The purpose of our study was to investigate the effect of vaspin on myocardial ischemia reperfusion injury (MIRI) and explore the underlying mechanism. The MIRI model was induced with 30â¯min of left anterior descending (LAD) occlusion followed by 24â¯h of reperfusion. In vivo, the rats were randomly divided into five groups: (1) Sham, (2) MIRI, (3) MIRIâ¯+â¯vaspin (10â¯mg/kg), (4) MIRIâ¯+â¯vaspin (20â¯mg/kg) and (5) MIRIâ¯+â¯vaspin (40â¯mg/kg). In vitro, H9C2 cells were assigned to five groups: (1) control, (2) hypoxia-re-oxygenation (H/R), (3) H/R +â¯vaspin (1⯵g/ml), (4) H/Râ¯+â¯vaspin (2⯵g/ml) and (5) H/Râ¯+â¯vaspin (4⯵g/ml). As a result, vaspin ameliorated MIRI and H/R in a dose-dependent manner, as evidenced by triphenyl tetrazolium chloride (TTC) staining, TUNEL Assay and MTT assay, respectively, meanwhile vaspin decreased the levels of creatine phosphokinase-isoenzyme (CK-MB) and lactate dehydrogenase (LDH) in rat serum, moreover, vaspin could reduce the contents of interleukin-1ß (IL-1ß), IL-18 and tumor necrosis factor alpha (TNF-α) in serum of rats and supernatant of H9C2 cells. Furthermore, vaspin down-regulated the expression of toll-like receptor 4 (TLR4) and the phosphorylation of nuclear factor κB (NF-κB) in MIRI rats and H/R-induced H9C2 cells. In addition, patients with acute myocardial infarction (AMI) had lower levels of vaspin than patients without. In conclusion, vaspin might be a useful predictive biomarker in patients with AMI; furthermore, vaspin exhibits cardioprotective effects on MIRI which might act through inhibiting TLR4/NF-κB signaling pathway in vivo and in vitro.
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Daño por Reperfusión Miocárdica/prevención & control , FN-kappa B/metabolismo , Serpinas/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Ratas , Ratas Sprague-DawleyRESUMEN
High altitude cerebral edema (HACE) is a severe type of acute mountain sickness (AMS) that occurs in response to a high altitude hypobaric hypoxic (HH) environment. GM1 monosialoganglioside can alleviate brain injury under adverse conditions including amyloid-ß-peptide, ischemia and trauma. However, its role in HACE-induced brain damage remains poorly elucidated. In this study, GM1 supplementation dose-dependently attenuated increase in rat brain water content (BWC) induced by hypobaric chamber (7600â¯m) exposurefor 24â¯h. Compared with the HH-treated group, rats injected with GM1 exhibited less brain vascular leakage, lower aquaporin-4 and higher occludin expression, but they also showed increase in Na+/K+-ATPase pump activities. Importantly, HH-incurred consciousness impairment and coordination loss also were ameliorated following GM1 administration. Furthermore, the increased oxidative stress and decrease in anti-oxidant stress system under the HH condition were also reversely abrogated by GM1 treatment via suppressing accumulation of ROS, MDA and elevating the levels of SOD and GSH. Simultaneously, GM1 administration also counteracted the enhanced inflammation in HH-exposed rats by muting pro-inflammatory cytokines IL-1ß, TNF-α, and IL-6 levels in serum and brain tissues. Subsequently, GM1 potentiated the activation of the PI3K/AKT-Nrf2 pathway. Cessation of this pathway by LY294002 reversed GM1-mediated inhibitory effects on oxidative stress and inflammation, and ultimately abrogated the protective role of GM1 in abating brain edema, cognitive and motor dysfunction. Overall, GM1 may afford a protective intervention in HACE by suppressing oxidative stress and inflammatory response via activating the PI3K/AKT-Nrf2 pathway, implying a promising agent for the treatment of HACE.
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Altitud , Edema Encefálico/prevención & control , Gangliósido G(M1)/farmacología , Inflamación/prevención & control , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Mal de Altura/complicaciones , Mal de Altura/metabolismo , Mal de Altura/prevención & control , Animales , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Inflamación/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Tremendous experimental and clinical studies identify that remifentanil anesthesia might elicit postoperative opioid-induced hyperalgesia (OIH) and aggravate nociceptive hypersensitivity, whereas definite mechanisms remain equivocal. WNT signaling and fractalkine pathway have been manifested to participate in varieties of pain pathogenesis, respectively, but no report is on whether they could lead to OIH. This study intended to investigate the effect of WNT3a/ß-catenin on fractalkine and its receptor CX3CR1 in OIH in rats model of incision pain. METHODS: A WNT scavenger Fz-8/Fc and a neutralizing antibody against CX3CR1 (anti-CX3CR1) were injected intrathecally after remifentanil infusion. Exogenous WNT agonist delivery was utilized in naïve rats. PWT and PWL were documented for postsurgical 48h to assess mechanical and thermal hyperalgesia. Also, expressions of WNT3a, FZ1, FZ8, ß-catenin, fractalkine and CX3CR1 in spinal dorsal horn were measured by Western blot and RT-qPCR after nociceptive testing. RESULTS: We found that postsurgical mechanical and thermal hyperalgesia could be engendered after remifentanil exposure, which was accompanied by a dramatical rise of spinal WNT3a, FZ8, ß-catenin, fractalkine and CX3CR1 levels. Moreover, OIH was attenuated by intrathecal application of Fz-8/Fc and anti-CX3CR1. Up-regulation of spinal fractalkine and CX3CR1 expression after remifentanil anesthesia was reversed by Fz-8/Fc. Also, WNT agonist administration could directly generate hypernociception and elevate fractalkine/CX3CR1 level in naïve rats, which was prevented by anti-CX3CR1. CONCLUSION: These present findings demonstrated that the involvement of spinal WNT3a/FZ8/ß-catenin in OIH through modulating fractalkine/CX3CR1 in rats.
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Analgésicos Opioides/efectos adversos , Anestésicos Intravenosos/efectos adversos , Quimiocina CX3CL1/metabolismo , Hiperalgesia/metabolismo , Piperidinas/efectos adversos , Receptores de Quimiocina/metabolismo , Vía de Señalización Wnt , Animales , Receptor 1 de Quimiocinas CX3C , Receptores Frizzled/metabolismo , Hiperalgesia/inducido químicamente , Dolor Postoperatorio/inducido químicamente , Dolor Postoperatorio/metabolismo , Ratas Sprague-Dawley , Remifentanilo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismoRESUMEN
OBJECTIVES: To investigate the protective effect of Tanshinone IIA (TSA) on oxygen-glucose deprivation and reperfusion (OGD/R) injury of BV-2 cell and its NLRP3 inflammatory signaling pathway. METHODS: The highest expression level of NLPR3 in BV-2 cells was detected by Western blot after oxygen-glucose deprivation (OGD) for 3 h and reperfusion for different time, to determine the most suitable reperfusion time. Cell viability of TSA (0-2.5 ug/mL) treatment was detected by CCK8 assay to determine the maximum effect concentration of TSA. In TSA 0 (also called OGD group), 0.5, 1.0, 2.0 ug/mL groups, expression levels of NLRP3 and caspase-1 were detected by Western blot, while IL-1ß and IL-18 in culture medium of those groups were detected by ELISA assay. RESULTS: The highest expression level of NLRP3 came to 12 h of reperfusion. The maximum effective concentration of TSA was 2.0 ug/mL. The expression levels of NLRP3, caspase-1, IL-1ß and IL-18 decreased with the increase of TSA concentration. CONCLUSIONS: TSA can inhibit the expression of protein and cytokines of NLRP3 inflammatory signaling pathway in OGD/R BV-2 cells, which may be one of the molecular mechanisms of the protective effect of TSA on OGD/R cells.
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Abietanos/farmacología , Microglía/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión/metabolismo , Transducción de Señal , Animales , Línea Celular , Citocinas/metabolismo , Glucosa , Ratones , OxígenoRESUMEN
Tetramethylpyrazine (TMP) has been widely used in China as a drug for the treatment of various diseases. Recent studies have suggested that TMP has a protective effect on ischemic neuronal damage. However, the exact mechanism is still unclear. This study aims to investigate the mechanism of TMP mediated ischemic hippocampal neurons injury induced by oxygen-glucose deprivation (OGD). The effect of TMP on hippocampal neurons viability was detected by MTT assay, LDH release assay and apoptosis rate was measured by flow cytometry. TMP significantly suppressed neuron apoptosis in a concentration-dependent manner. TMP could significantly reduce the elevated levels of connexin32 (Cx32) induced by OGD. Knockdown of Cx32 by siRNA attenuated OGD injury. Moreover, our study showed that viability was increased in siRNA-Cx32-treated-neurons, and neuron apoptosis was suppressed by activating Bcl-2 expression and inhibiting Bax expression. Over expression of Cx32 could decrease neurons viability and increase LDH release. Furthermore, OGD increased phosphorylation of ERK1/2 and p38, whose inhibitors relieved the neuron injury and Cx32 up-regulation. Taken together, TMP can reverse the OGD-induced Cx32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathways.
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Conexinas/metabolismo , Glucosa/metabolismo , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxígeno/metabolismo , Pirazinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Conexinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Hipocampo/citología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación , Interferencia de ARN , Ratas Wistar , Proteína beta1 de Unión ComunicanteRESUMEN
AIM: Glycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains. METHODS: Focal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA) in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA). Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains. RESULTS: Pre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1ß, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration. CONCLUSIONS: GL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1.
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Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Ácido Glicirrínico/uso terapéutico , Proteína HMGB1/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Isquemia Encefálica/sangre , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Infarto Cerebral/sangre , Infarto Cerebral/complicaciones , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/patología , Ácido Glicirrínico/farmacología , Proteína HMGB1/metabolismo , Infarto de la Arteria Cerebral Media/sangre , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Inflamación/complicaciones , Inflamación/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/farmacología , Ratas Sprague-Dawley , Daño por Reperfusión/sangre , Daño por Reperfusión/complicaciones , Daño por Reperfusión/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Inhalational anesthetic preconditioning can induce neuroprotective effects, and the notch signaling pathway plays an important role in neural progenitor cell differentiation and the inflammatory response after central nervous system injury. This study evaluated whether the neuroprotective effect of isoflurane preconditioning is mediated by the activation of the notch signaling pathway. Mice were divided into two groups consisting of those that did or did not receive preconditioning with isoflurane. The expression levels of notch-1, notch intracellular domain (NICD), and hairy and enhancer of split (HES-1) were measured in mice subjected to transient global cerebral ischemia-reperfusion injury. The notch signaling inhibitor DAPT and conditional notch-RBP-J knockout mice were used to investigate the mechanisms of isoflurane preconditioning-induced neuroprotection. Immunohistochemical staining, real-time polymerase chain reaction assays, and Western blotting were performed. Isoflurane preconditioning induced neuroprotection against global cerebral ischemia. Preconditioning up-regulated the expression of notch-1, HES-1, and NICD after ischemic-reperfusion. However, these molecules were down-regulated at 72 h after ischemic-reperfusion. The inhibition of notch signaling activity by DAPT significantly attenuated the isoflurane preconditioning-induced neuroprotection, and similar results were obtained using notch knockout mice. Our results demonstrate that the neuroprotective effects of isoflurane preconditioning are mediated by the pre-activation of the notch signaling pathway.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Proteínas de Homeodominio/fisiología , Ataque Isquémico Transitorio/tratamiento farmacológico , Isoflurano/uso terapéutico , Proteínas del Tejido Nervioso/fisiología , Fármacos Neuroprotectores/uso terapéutico , Premedicación , Receptor Notch1/fisiología , Daño por Reperfusión/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis , Ataxia/etiología , Ataxia/prevención & control , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Región CA1 Hipocampal/irrigación sanguínea , Región CA1 Hipocampal/patología , Arteria Carótida Común , Circulación Cerebrovascular/efectos de los fármacos , Dipéptidos/farmacología , Evaluación Preclínica de Medicamentos , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Ataque Isquémico Transitorio/fisiopatología , Isoflurano/administración & dosificación , Isoflurano/farmacología , Ligadura , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Nitrógeno/administración & dosificación , Nitrógeno/farmacología , Estructura Terciaria de Proteína , Distribución Aleatoria , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/biosíntesis , Receptor Notch1/deficiencia , Receptor Notch1/genética , Daño por Reperfusión/etiología , Transducción de Señal/fisiología , Factor de Transcripción HES-1 , Regulación hacia ArribaRESUMEN
AIM: To investigate the neuroprotective effect of glycyrrhizin (Gly) against the ischemic injury of rat spinal cord and the possible role of the nuclear protein high-mobility group box 1 (HMGB1) in the process. METHODS: Male Sprague-Dawley rats were subjected to 45 min aortic occlusion to induce transient lumbar spinal cord ischemia. The motor functions of the animals were assessed according to the modified Tarlov scale. The animals were sacrificed 72 h after reperfusion and the lumbar spinal cord segment (L2-L4) was taken out for histopathological examination and Western blotting analysis. Serum inflammatory cytokine and HMGB1 levels were analyzed using ELISA. RESULTS: Gly (6 mg/kg) administered intravenously 30 min before inducing the transient lumbar spinal cord ischemia significantly improved the hind-limb motor function scores, and reduced the number of apoptotic neurons, which was accompanied by reduced levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the plasma and injured spinal cord. Moreover, the serum HMGB1 level correlated well with the serum TNF-α, IL-1ß and IL-6 levels during the time period of reperfusion. CONCLUSION: The results suggest that Gly can attenuate the transient spinal cord ischemic injury in rats via reducing inflammatory cytokines and inhibiting the release of HMGB1.
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Citocinas/sangre , Ácido Glicirrínico/uso terapéutico , Proteína HMGB1/sangre , Fármacos Neuroprotectores/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Citocinas/inmunología , Ácido Glicirrínico/farmacología , Humanos , Vértebras Lumbares , Masculino , Actividad Motora/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/patologíaRESUMEN
AIM: To explore the protective mechanism of LPS pretreatment in a rat model of cerebral ischemia-reperfusion injury. METHODS: Sixty-six male Spraque-Dawley rats were randomly divided into a sham group (n=22), a control group (n=22) and a LPS group (n=22).The control group and the LPS group were subjected to focal cerebral isehmia induced by middle cerebral artery occlusion (MCAO) for 2 hours. The LPS group was pretreated with LPS for five consecutive days with the last pretreatment at 24 hours before the surgery, while the control group and the sham group were pretreated similarly with normal saline. Seventy-two hours after reperfusion, the rats were examined for neurological behavior scores and then killed to measure the infarct volumes and the brain levels of TNF-α, IL-1ß, IL-6 and IL-10. RESULTS: The brain levels of LRG and IL-10 in the LPS group were significantly higher than those in the control group, while obvious decrease of TNF-α, IL-1ß and IL-6 was observed in the brains of the LPS group. Accordingly, the neurological behavior scores in the LPS group were better than those in the control group, whereas the infarct volumes in the LPS group were significantly smaller than those in the control group (P<0.05). CONCLUSION: LPS pretreatment has neuroprotective effect, which involves LRG upregulation and interference in the dynamic balance of inflammatory reactions.
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Encéfalo/metabolismo , Encéfalo/patología , Endotoxinas/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Endotoxinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/fisiopatología , Daño por Reperfusión/prevención & controlRESUMEN
BACKGROUND: Recent studies suggest that the novel neuropeptide orexin-A may play an essential role during neuronal damage. However, the function of orexin-A during brain ischemia remains unclear. Recently, hypoxia-inducible factor-1α (HIF-1α) was shown to be activated by orexin-A. The aim of the current study is to test the hypothesis that administration of exogenous orexin-A can attenuate ischemia-reperfusion injury through the facilitation of HIF-1α expression. METHODS: Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 120 min. Rats were treated with different doses of orexin-A or vehicle before the ischemia and at the onset of reperfusion. To investigate the action of HIF-1α in the neuroprotective effects of orexin-A, the HIF-1α inhibitor YC-1 was used alone or combined with orexin-A. Neurologic deficit scores and infarct volume were assessed. Brains were harvested for immunohistochemical staining and western blot analysis. RESULTS: Orexin-A significantly ameliorated neurologic deficit scores and reduced infarct volume after cerebral ischemia reperfusion. Administration of 30 µg/kg orexin-A showed optimal neuroprotective effects. This effect was still present 7 days after reperfusion. Furthermore, orexin-A decreased the number of apoptotic cells and significantly enhanced HIF-1α expression after cerebral ischemia reperfusion. Moreover, the facilitation of HIF-1α expression was accompanied with inhibition of von Hippel-Lindau expression. Administration of HIF-1α inhibitor suppressed the increase of HIF-1α and reversed the neuroprotective effects of orexin-A. CONCLUSIONS: Orexin-A has a neuroprotective effect against cerebral ischemia-reperfusion injury. These effects may be mediated through the HIF-1α pathway.
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Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/farmacología , Neuropéptidos/farmacología , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/prevención & control , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Etiquetado Corte-Fin in Situ , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Neuropéptidos/metabolismo , Fármacos Neuroprotectores/metabolismo , Neurotransmisores/metabolismo , Neurotransmisores/farmacología , Orexinas , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismoRESUMEN
BACKGROUND: In this study, we sought to clarify the role of inhibiting ubiquitin-conjugated protein aggregation in the formation of a neuroprotective effect after isoflurane preconditioning using a transient global cerebral ischemia-reperfusion injury mouse model. METHODS: C57BL/6 mice were randomly assigned to 3 groups (isoflurane preconditioning [IsoPC] group, control [Con] group, and sham group, n = 24 in each group). Mice in the IsoPC group and sham group were placed in a chamber and pretreated with isoflurane (1.2% isoflurane, 98% O(2), 1 hour/day) for 5 days. Mice in the Con group were placed in the same chamber but pretreated with oxygen only (98% O(2), 2% N(2), 1 hour/day) for 5 days. Twenty-four hours after the last preconditioning day, bilateral common carotid artery occlusion was performed as a model of global cerebral ischemia for 20 minutes in the IsoPC group and Con group. The total motor scores, number of viable neurons in the CA1 region of the hippocampus, and expression levels of conjugated ubiquitin or free ubiquitin were assessed by neurological assessment, immunohistochemistry, and Western blotting (at 24 and 72 hours) after reperfusion, respectively. RESULTS: The total motor scores in the IsoPC group were better than the Con group (P < 0.05). Morphological observations showed that the IsoPC group had better neuron structure than in the Con group. The numbers of viable neurons in the CA1 region were significantly increased by isoflurane preconditioning compared with those in the Con group (P < 0.05). The numbers of TUNEL-positive neurons in the CA1 region were significantly decreased after isoflurane preconditioning. The density of conjugated ubiquitin staining in the CA1 region of the IsoPC group was significantly lower than in the Con group (P < 0.05) and the expression of conjugated ubiquitin in the IsoPC group was lower than in the Con group (P < 0.05). CONCLUSION: Inhibition of ubiquitin-conjugated protein aggregation may have an essential role in inducing cerebral ischemic tolerance by isoflurane preconditioning in a transient global cerebral ischemia-reperfusion injury mouse model.