RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Aralia taibaiensis is known for its ability to promote blood circulation and dispel blood stasis, activate meridians and remove arthralgia. The saponins of Aralia taibaiensis (sAT) are the main active components that are often used to treat cardiovascular and cerebrovascular diseases. However, it has not been reported whether sAT can improve ischemic stroke (IS) by promoting angiogenesis. AIM OF THE STUDY: In this study, we investigated the potential of sAT to promote post-ischemic angiogenesis in mice and determined the underlying mechanism through in vitro experiments. METHODS: To establish the middle cerebral artery occlusion (MCAO) mice model in vivo. First of all, we examined the neurological function, brain infarct volume, and degree of brain swelling in MCAO mice. We also observed pathological changes in brain tissue, ultrastructural changes in blood vessels and neurons, and the degree of vascular neovascularization. Additionally, we established the oxygen-glucose deprivation/reoxygenation (OGD/R) -human umbilical vein endothelial cells (HUVECs) model in vitro to detect the survival, proliferation, migration and tube formation of OGD/R HUVECs. Finally, we verified the regulatory mechanism of Src and PLCγ1 siRNA on sAT promoting angiogenesis by cell transfection technique. RESULTS: In the cerebral ischemia-reperfusion mice, sAT distinctly improved the cerebral infarct volume, brain swelling degree, neurological dysfunction, and brain histopathological morphology due to cerebral ischemia/reperfusion injury. It also increased the double positive expression of BrdU and CD31 in brain tissue, promoted the release of VEGF and NO and decreased the release of NSE and LDH. In the OGD/R HUVECs, sAT significantly improved cell survival, proliferation, migration and tube formation, promoted the release of VEGF and NO, and increased the expression of VEGF, VEGFR2, PLCγ1, ERK1/2, Src and eNOS. Surprisingly, the effect of sAT on angiogenesis was inhibited by Src siRNA and PLCγ1 siRNA in OGD/R HUVECs. CONCLUSION: The results proved that sAT promotes angiogenesis in cerebral ischemia-reperfusion mice and its mechanism is to regulate VEGF/VEGFR2 and then regulate Src/eNOS and PLCγ1/ERK1/2.
Assuntos
Aralia , Edema Encefálico , Isquemia Encefálica , Saponinas , Camundongos , Humanos , Animais , Aralia/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Saponinas/metabolismo , Células Endoteliais , Edema Encefálico/metabolismo , Transdução de Sinais , Isquemia Encefálica/metabolismo , Glucose/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , RNA Interferente PequenoRESUMO
Cannabidiol is a natural herbal medicine known to protect the brain from traumatic brain injury (TBI). Here, a TBI rat model was established, with cannabidiol administered intraperitoneally at doses of 5, 10, or 20 mg/kg, 30 min before surgery and 6 h after surgery until sacrifice. Brain water content, body weight, and modified neurological severity scores were determined, and enzyme-linked immunosorbent assay, immunofluorescence staining, hematoxylin and eosin staining, Nissl staining, Evans-blue dye extravasation, and western blotting were performed. Results showed that cannabidiol decreased the number of aquaporin-4-positive and glial fibrillary acidic protein-positive cells. Cannabidiol also significantly reduced the protein levels of proinflammatory cytokines (TNF-α and IL-1ß) and significantly increased the expression of tight junction proteins (claudin-5 and occludin). Moreover, cannabidiol administration significantly mitigated water content in the brain after TBI and blood-brain barrier disruption and ameliorated the neurological deficit score after TBI. Cannabidiol administration improved the integrity and permeability of the blood-brain barrier and reduced edema in the brain after TBI.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Canabinoides/farmacologia , Animais , Aquaporina 4/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Canabinoides/metabolismo , Claudina-5/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-1beta/metabolismo , Masculino , Modelos Animais , Fármacos Neuroprotetores/farmacologia , Ocludina/metabolismo , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: The 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1H) is an effective novel drug for the treatment of ischemic cerebrovascular disease derived from Ginkgolide B, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, whether XQ-1H exerts neuroprotective effect via regulating neuronal apoptosis and the underlying mechanism remain to be elucidated. MATERIALS AND METHODS: This study was aimed to investigate the neuroprotective effect of XQ-1H in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and the oxygen glucose deprivation/reoxygenation (OGD/R) induced neuronal apoptosis on pheochromocytoma (PC-12) cells. RESULTS: The results showed that administration of XQ-1H at different dosage (7.8, 15.6, 31.2 mg/kg) reduced the brain infarct and edema, attenuated the neuro-behavioral dysfunction, and improved cell morphology in brain tissue after MCAO/R in rats. Moreover, incubation with XQ-1H (1 µM, 3 µM, 10 µM, 50 µM, 100 µM) could increase the cell viability, and showed no toxic effect to PC-12 cells. XQ-1H at following 1 µM, 10 µM, 100 µM decreased the lactate dehydrogenase (LDH) activity and suppressed the cell apoptosis in PC-12 cells exposed to OGD/R. In addition, XQ-1H treatment could significantly inhibit caspase-3 activation both in vivo and in vitro, reciprocally modulate the expression of apoptosis related proteins, bcl-2, and bax via activating PI3K/Akt signaling pathway. For mechanism verification, LY294002, the inhibitor of PI3K/Akt pathway was introduced the expressions of bcl-2 and phosphorylated Akt were down-regulated, the expression of bax was up-regulated, indicating that XQ-1H could alleviate the cell apoptosis through activating the PI3K/Akt pathway. CONCLUSIONS: Our findings demonstrated that XQ-1H treatment could provide a neuroprotective effect against ischemic stroke induced by cerebral ischemia/reperfusion injury in vivo and in vitro through regulating neuronal survival and inhibiting apoptosis. The findings of the study confirmed that XQ-1H could be develop as a potential drug for treatment of cerebral ischemic stroke.
Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Lactonas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de SinaisRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Activation of autophagy has been implicated in cerebral ischiemia/reperfusion (I/R) injury. Salvianolate lyophilized injection (SLI) has been widely used in the clinical treatment of cerebrovascular disease in China. Whether SLI has any influence on the activation of autophagy in cerebral I/R injury remains elusive. AIM OF THE STUDY: The aim of this study were to assess whether SLI attenuates I/R-induced brain injury and evaluate its associated mechanisms. MATERIALS AND METHODS: Focal cerebral ischaemia was induced by middle cerebral artery occlusion (MCAO). SLI (21 mg/kg) was injected intravenously at the beginning of the reperfusion period and 24 and 48 h after ischaemia. The effects of SLI on brain injury were detected according to infarct volume, neurological score, brain oedema, and HE and TUNEL staining at 72 h post-MCAO. Western blotting was used to detect alterations in the autophagy-relevant proteins LC3, Beclin-1, mTOR, p62, Lamp-1, and CTSD in the ipsilateral cortex at 24 or 72 h post-MCAO. RESULTS: We first demonstrated that SLI significantly alleviated the infarct volume, neurological deficits, and brain oedema, and reduced the number of TUNEL-positive cells in rats with cerebral I/R injury. Next, we found that SLI has a bidirectional regulatory effect on autophagy: early-stage (24 h) cerebral ischaemia promotes the activation of autophagy and developmental-stage (72 h) cerebral ischaemia has an inhibitory effect. SLI enhanced I/R-induced autophagy as evidenced by the increased expression level of the autophagy marker protein LC3â ¡, as well as the decreased expression of mTOR and the autophagy substrate protein p62, but there was no change in lysosomal activity at 24 h after I/R-induced injury. Moreover, SLI also inhibited excessive activation of autophagy at 72 h after I/R-induced injury, which manifested as downregulating LC3â ¡ expression, upregulating mTOR and p62 expression, and inhibiting lysosomal activity. CONCLUSION: SLI has a protective effect on cerebral ischaemia/reperfusion injury, which may be mediated by the autophagy-lysosome pathway.
Assuntos
Autofagia/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Administração Intravenosa , Animais , Apoptose/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Lisossomos/química , Lisossomos/metabolismo , Masculino , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Ischemic stroke is a leading cause of mortality worldwide that occurs following the reduction or interruption of blood brain supply, characterized by a cascade of early events as oxidative stress and ensuing neuro-inflammation, energy failure and the burst of intracellular Ca++ resulting in activation of phospholipases and large increase in FFA including arachidonic acid, ultimately leading to nervous cell death. Grape Seed Flour (GSF) is a complex polyphenolic mixture harboring antioxidant, anti-inflammatory and neuroprotective properties. Orlistat (Xenical ™,Xe) is a gastro-intestinal lipase inhibitor and an anti-obesity agent. In an earlier study we reported the higher efficiency in neuroprotection against HFD-induced brain lipotoxicity when combining the two drugs (GSF + Xe). As a result repurposing Xe as an adjunct to GSF therapy against stroke appeared relevant and worthy of investigation. I/R insult disrupted the blood brain barrier (BBB) as assessed by EB dye extravasation, increased water and Na+ within the brain. Ultrastructurally I/R altered the brain blood capillaries at the vicinity of hippocampus dentate gyrus area as assessed by transmission and scanning electron microscopy. I/R altered lipid metabolism as revealed by LDL/HDL ratio, lipase activity, and FFA profiles. Moreover, I/R induced neuro-inflammation as assessed by down-regulation of anti-inflammatory CD 56 and up-regulation of pro-inflammatory CD 68 antigen. Importantly almost all I/R-induced disturbances were retrieved partially upon Xe or GSF on their own, and optimally when combining the two drugs. Xe per se is protective against I/R injury and the best neuroprotection was obtained when associating low dosage Xe with high dosage GSF, enabling neuroprevention and cell survival within hippocampus dentate gyrus area as revealed by increased staining of Ki 67 proliferation biomarker.
Assuntos
Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/prevenção & controle , Permeabilidade Capilar/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Reguladores do Metabolismo de Lipídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Orlistate/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/ultraestrutura , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Masculino , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
The lack of inclusion of comorbidities in animal models of stroke may underlie the limited development of therapy in stroke. Previous studies in mice deficient of CD36, an immune receptor, indicated its contribution to stroke-induced inflammation and injury in hyperlipidemic conditions. The current study, therefore, tested whether pharmacological inhibition of CD36 provides neuroprotection in hyperlipidemic stroke. The hyperlipidemic mice subjected to stroke showed an exacerbation of infarct size and profound brain swelling. However, post-stroke treatment with CD36 inhibitors did not reduce, and in some cases worsened, acute stroke outcome, suggesting potential benefits of elevated CD36 in the post-stroke brain in a hyperlipidemic condition. On the other hand, chronic treatment of a CD36 inhibitor prior to stroke significantly reduced stroke-induced brain swelling. There was a trend toward infarct reduction, although it did not reach statistical significance. The observed benefit of preventative CD36 inhibition is in line with previously reported smaller infarct volume and swelling in CD36 KO mice. Thus, the current findings suggest that insights gained from the genetic models should be carefully considered before the implementation of pharmacological interventions, as a potential therapeutic strategy may depend on preventative treatment or a post-stroke acute treatment paradigm.
Assuntos
Benzofuranos/administração & dosagem , Edema Encefálico/prevenção & controle , Antígenos CD36/antagonistas & inibidores , Hiperlipidemias/metabolismo , Substâncias Protetoras/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Animais , Apolipoproteínas E/genética , Benzofuranos/farmacologia , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Medicamentos de Ervas Chinesas , Hiperlipidemias/complicações , Inflamação , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/farmacologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismoRESUMO
Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in cognitive impairment and acquisition of new functional limitations in sepsis survivors. However, the exact nature of brain injury in this setting is often subtle and remains to be fully characterized both in preclinical studies and at the bedside. Given the translation potential for the use of magnetic resonance imaging (MRI) to define sepsis-induced brain injury, we sought to determine and correlate the cellular changes with neuroradiographic presentations in a classic murine model of sepsis induced by cecal ligation and puncture (CLP). Sepsis was induced in 6-10-week-old male C57/BL6 mice by CLP. We used immunohistochemistry (IHC) to define neuropathology in a mouse model of sepsis along with parallel studies using MRI, focusing on cerebral edema, blood-brain barrier (BBB) disruption, and microglial activation on days 1 and 4 days after CLP. We demonstrate that septic mice had evidence of early axonal injury, inflammation, and robust microglial activation on day 1 followed by cytotoxic edema on day 4 in the cortex, thalamus, and hippocampus in the absence of BBB disruption. We note the superiority of the MRI to detect subtle brain injury and cytotoxic cerebral edema in comparison with the traditional gold standard assessment, i.e., percent brain water (wet-dry weight method). We conclude that inflammatory changes in the septic brain can be detected in real time, and further studies are needed to understand axonal injury and the impact of inhibition of microglial activation on the development of cerebral edema.
Assuntos
Edema Encefálico/patologia , Sepse/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Ceco/lesões , Corpo Caloso/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Sepse/metabolismo , Tálamo/metabolismoRESUMO
Cerebral hemorrhage (ICH) is a common cerebrovascular condition with high mortality, disability and recurrence rates. TLR4-mediated acute inflammatory injury plays a pivotal role in ICH. Verbascoside (VB) is an active component of multiple medicinal plants, and exerts neuroprotective effects in ischemic stroke by targeting the inflammatory response. However, the effects of VB on ICH and the underlying mechanisms remain unclear. In this study, we analyzed the therapeutic effects of VB on acute ICH, and the possible involvement of TLR4-mediated inflammation. VB improved the behavioral score and reduced the hematoma volume, brain edema and neuronal apoptosis in a murine model of acute ICH. Mechanistically, VB attenuated macroglia activation and decreased inflammatory factor levels, which in turn protected the neurons. Furthermore, TLR4 knockout abolished the effects of VB both in vivo and in vitro. Taken together, VB attenuates the symptoms of ICH by targeting the TLR4-mediated acute inflammatory response.
Assuntos
Edema Encefálico/prevenção & controle , Hemorragia Cerebral/prevenção & controle , Glucosídeos/farmacologia , Inflamação/prevenção & controle , Fenóis/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Edema Encefálico/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Plantas Medicinais/química , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10â¯mg/kg) daily at 10:00â¯a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1ß, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Indenos/farmacologia , Fator 2 Relacionado a NF-E2/genética , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Edema Encefálico/genética , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Inflamação , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/agonistas , Receptor MT2 de Melatonina/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.
Assuntos
Edema Encefálico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Hipóxia Encefálica , Imageamento por Ressonância Magnética , Nimodipina/administração & dosagem , Tálamo , Adulto , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Feminino , Humanos , Hipóxia Encefálica/complicações , Hipóxia Encefálica/diagnóstico por imagem , Hipóxia Encefálica/tratamento farmacológico , Hipóxia Encefálica/metabolismo , Masculino , Tálamo/diagnóstico por imagem , Tálamo/metabolismoRESUMO
Intracerebral hemorrhage (ICH) is the most severe form of stroke. Catheter-delivered thrombolysis with recombinant tissue-type plasminogen activator (rtPA) for the drainage of ICH is currently under evaluation in a phase III clinical trial (MISTIE III). However, in a pig model of ICH, in situ fibrinolysis with rtPA was reported to increase peri-lesional edema by promoting N-methyl-D-aspartate (NMDA)-dependent excitotoxicity. In the present study, we engineered a non-neurotoxic tPA variant, OptPA, and investigated its safety and efficacy for in situ fibrinolysis in a rat model of ICH. Magnetic resonance imaging analyses of hematoma and edema volumes, behavioral tasks and histological analyses were performed to measure the effects of treatments. In vitro, OptPA was equally fibrinolytic as rtPA without promoting NMDA-dependent neurotoxicity. In vivo, in situ fibrinolysis using OptPA reduced hematoma volume, like rtPA, but it also reduced the evolution of peri-hematomal neuronal death and subsequent edema progression. Overall, this preclinical study demonstrates beneficial effects of OptPA compared to rtPA for the drainage of ICH.
Assuntos
Edema Encefálico/tratamento farmacológico , Hemorragia Cerebral/tratamento farmacológico , Fibrinolíticos/farmacologia , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Ensaios Clínicos Fase III como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Engenharia de Proteínas , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Suínos , Ativador de Plasminogênio Tecidual/genéticaRESUMO
BACKGROUND: Aquaporin 4 (AQP4) is a water-selective transport protein expressed in astrocytes throughout the central nervous system. AQP4 level increases after cerebral ischemia and results in ischemic brain edema. Brain edema markedly influences mortality and motor function by elevating intracranial pressure that leads to secondary brain damage. Therefore, AQP4 is an important target to improve brain edema after cerebral ischemia. The Japanese herbal Kampo medicine, goreisan, is known to inhibit AQP4 activity. Here, we investigated whether goreisan prevents induction of brain edema by cerebral ischemia via AQP4 using 4-hour middle cerebral artery occlusion (4h MCAO) mice. METHODS: Goreisan was orally administered at a dose of 500 mg/kg twice a day for 5 days before MCAO. AQP4 expression and motor coordination were measured by Western blotting and rotarod test, respectively. RESULTS: Brain water content of 4h MCAO mice was significantly increased at 24 hours after MCAO. Treatment with goreisan significantly decreased both brain water content and AQP4 expression in the ischemic brain at 24 hours after MCAO. In addition, treatment with goreisan alleviated motor coordination deficits at 24 hours after MCAO. CONCLUSIONS: The results of this study suggested that goreisan may be a useful new therapeutic option for ischemic brain edema.
Assuntos
Aquaporina 4/metabolismo , Edema Encefálico/prevenção & controle , Encéfalo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Água Corporal/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Medicina Kampo , Camundongos , Atividade Motora/efeitos dos fármacos , Fatores de Tempo , Regulação para CimaRESUMO
Growing evidence has demonstrated that the nucleotidebinding oligomerization domainlike receptor family pyrin domain containing 3 (NLRP3) inflammasomemediated inflammatory pathways have been involved in the secondary injury of traumatic brain injury (TBI). In the present study, the authors investigated the effects of hyperbaric oxygen (HBO) therapy on the NLRP3 inflammasome pathway following TBI. Following the evaluation of motor deficits and brain edema, the therapeutic effects of HBO on interleukin (IL)1ß and IL18 expression were assessed, as well as NLRP3 inflammasome activation following TBI. HBO may improve motor score and reduce brain edema, accompanied with the reduction of IL1ß and IL18 during the 7day observation period. Furthermore, HBO suppressed mRNA and protein expression of NLRP3inflammasome components, especially reducing NLRP3 expression in microglia. Thus, these results suggested that HBO alleviates the inflammatory response in experimental TBI via modulating microglial NLRP3inflammasome signaling.
Assuntos
Lesões Encefálicas Traumáticas/terapia , Oxigenoterapia Hiperbárica , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/metabolismo , Edema Encefálico/terapia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microscopia de Fluorescência , Atividade Motora , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de SinaisRESUMO
BACKGROUND: Reduction of permanent or transient cerebral blood flow may lead to some structural and functional changes of the brain, causing high mortality and morbidity. The aim of this experimental study was to investigate the effects of hydroalcoholic extract of Nigella sativa (NS) on markers of cerebral angiogenesis in rats induced by global brain ischemia. METHODS: Thirty-two male Wistar rats (250 ± 20 g) were randomly divided into 4 groups: group 1, control group receiving only normal saline; group 2, sham group undergoing surgery and stroke induction without treatment; and groups 3 and 4 treated with 10 and 20 mg/kg NS, respectively, after induction of stroke. Global ischemia was induced by ligation of the right carotid artery for 20 minutes. RESULTS: According to the results of this study, brain edema and infarct volume were significantly decreased in the group treated with 20 mg/kg NS compared with the group treated with 10 mg/kg NS (P < .05). Global ischemia caused a significant reduction in gene expression of vasoactive endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF) in the sham group compared with the control group (P < .05), but NS groups, in led to a significant increase in gene expression of VEGF and HIF compared with the sham group (P < .05). In addition, the activity level of matrix metallopeptidase-9 was decreased among NS groups compared with the control group (P < .05). CONCLUSIONS: Application of NS extract among rats with brain ischemia is associated with increase of VEGF and HIF as angiogenic markers and inhibition of matrix metallopeptidase-9 activities.
Assuntos
Indutores da Angiogênese/farmacologia , Infarto Encefálico/prevenção & controle , Isquemia Encefálica/tratamento farmacológico , Encéfalo/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Nigella sativa , Extratos Vegetais/farmacologia , Indutores da Angiogênese/isolamento & purificação , Animais , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Edema Encefálico/prevenção & controle , Infarto Encefálico/metabolismo , Infarto Encefálico/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Nigella sativa/química , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Inflammatory damage plays an important role in ischemic stroke and provides potential targets for therapy. Ulinastatin (UTI), a drug used to treat shock and acute pancreatitis in clinic, has attracted attention for its protective effects through immunomodulatory and anti-inflammatory properties. However, the effect of UTI in the acute phase of cerebral ischemia/reperfusion (I/R) is not clear. This study is to investigate the potential neuroprotective effect of UTI and explore its underlying mechanisms. METHODS: Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly assigned into four groups: Sham (sham-operated) group, tMCAO (tMCAO + 0.9% saline) group, UTI-L (tMCAO + UTI 1500 U/100 g), and UTI-H (tMCAO + UTI 3000 U/100 g) group. UTI was administered immediately after reperfusion in the UTI-L and UTI-H groups. About 24 h after the reperfusion, the neurological deficit, brain water content, and infarct volume were detected. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to detect the expression of TLR4 and NF-κB in the ischemic cerebral cortex. RESULTS: Compared with tMCAO group, both UTI-L and UTI-H groups dramatically ameliorated neurological deficit (p < 0.05), lessened the brain water content (p < 0.05) and infarct volume (p < 0.05), and decreased the expression of TLR4 and NF-κB. CONCLUSION: These results showed that UTI protected the brain against ischemic injury which may be due to the alleviation of inflammation reaction in early stage through downregulating TLR4 and NF-κB expression.
Assuntos
Encéfalo/efeitos dos fármacos , Glicoproteínas/farmacologia , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , RNA Mensageiro/metabolismo , Distribuição Aleatória , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND: Early brain injury, one of the most important mechanisms underlying subarachnoid hemorrhage (SAH), comprises edema formation and blood-brain barrier (BBB) disruption. Curcumin, an active extract from the rhizomes of Curcuma longa, alleviates neuroinflammation by as yet unknown neuroprotective mechanisms. In this study, we examined whether curcumin treatment ameliorates SAH-induced brain edema and BBB permeability changes, as well as the mechanisms underlying this phenomenon. METHODS: We induced SAH in mice via endovascular perforation, administered curcumin 15 min after surgery and evaluated neurologic scores, brain water content, Evans blue extravasation, Western blot assay results, and immunohistochemical analysis results 24 h after surgery. RESULTS: Curcumin significantly improved neurologic scores and reduced brain water content in treated mice compared with SAH mice. Furthermore, curcumin decreased Evans blue extravasation, matrix metallopeptidase-9 expression, and the number of Iba-1-positive microglia in treated mice compared with SAH mice. At last, curcumin treatment increased the expression of the tight junction proteins zonula occludens-1 and occludin in treated mice compared with vehicle-treated and sample SAH mice. CONCLUSIONS: We demonstrated that curcumin inhibits microglial activation and matrix metallopeptidase-9 expression, thereby reducing brain edema and attenuating post-SAH BBB disruption in mice.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/prevenção & controle , Curcumina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Barreira Hematoencefálica/metabolismo , Western Blotting , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Curcumina/farmacologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/metabolismo , Resultado do TratamentoRESUMO
Oxidative stress chiefly contributes to the disruption of the BBB following traumatic brain injury (TBI). The Chinese herbal medicine rhubarb is a promising antioxidant in treating TBI. Here we performed in vivo and in vitro experiments to determine whether rhubarb and its absorbed bioactive compound protected the BBB after TBI by increasing ZO-1 expression through inhibition of gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 pathway. Rats were subjected to the controlled cortical impact (CCI) model, and primary rat cortical astrocytes were exposed to scratch-wound model. The liquid chromatography with tandem mass spectrometry method showed that rhein was the compound absorbed in the brains of CCI rats after rhubarb administration. The wet-dry weights and Evans blue measurements revealed that rhubarb and rhein ameliorated BBB damage and brain edema in CCI rats. Western blots showed that rhubarb and rhein downregulated GFAP in vitro. RT-PCR, immunohistochemistry, Western blot and dichlorodihydrofluorescein diacetate analysis indicated that rhubarb prevented activation of gp91phox subunit of NADPH oxidase induced ROS production, subsequently inhibited ERK/MMP-9 pathway in vivo and in vitro. Interestingly, rhein and rhubarb similarly protected the BBB by inhibiting this signaling cascade. The results provide a novel herbal medicine to protect BBB following TBI via an antioxidative molecular mechanism.
Assuntos
Antraquinonas/administração & dosagem , Antioxidantes/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/metabolismo , NADPH Oxidase 2/metabolismo , Rheum/química , Transdução de Sinais/efeitos dos fármacos , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Antraquinonas/farmacocinética , Antioxidantes/farmacocinética , Barreira Hematoencefálica/metabolismo , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
BACKGROUND: Astaxanthin is a carotenoid pigment that possesses potent antioxidative, anti-inflammatory, antitumor, and immunomodulatory activities. Previous studies have demonstrated that astaxanthin displays potential neuroprotective properties for the treatment of central nervous system diseases, such as ischemic brain injury and subarachnoid hemorrhage. This study explored whether astaxanthin is neuroprotective and ameliorates neurological deficits following traumatic brain injury (TBI). RESULTS: Our results showed that, following CCI, treatment with astaxanthin compared to vehicle ameliorated neurologic dysfunctions after day 3 and alleviated cerebral edema and Evans blue extravasation at 24 h (p < 0.05). Astaxanthin treatment decreased AQP4 and NKCC1 mRNA levels in a dose-dependent manner at 24 h. AQP4 and NKCC1 protein expressions in the peri-contusional cortex were significantly reduced by astaxanthin at 24 h (p < 0.05). Furthermore, we also found that bumetanide (BU), an inhibitor of NKCC1, inhibited trauma-induced AQP4 upregulation (p < 0.05). CONCLUSIONS: Our data suggest that astaxanthin reduces TBI-related injury in brain tissue by ameliorating AQP4/NKCC1-mediated cerebral edema and that NKCC1 contributes to the upregulation of AQP4 after TBI.
Assuntos
Aquaporina 4/metabolismo , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Bumetanida/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Distribuição Aleatória , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Xantofilas/farmacologiaRESUMO
PRIMARY OBJECTIVE: Essential oil (EO) of Kelussia odoratissima Mozaff, whose main composition is Z-ligustilide, has been shown to have strong antioxidant and anti-inflammatory effects and potent neuroprotective properties. RESEARCH DESIGN: This study examined whether or not the EO could ameliorate brain damage and behavioural dysfunction in a thromboembolic model of stroke in rats and compare its effects to that of the purified Z-ligustilide. METHODS AND PROCEDURES: Stroke was induced in rats by middle cerebral artery occlusion using an autologous pre-formed clot. EO (10 mg kg(-1) and 45 mg kg(-1)) and Z-ligustilide (20 mg kg(-1)) were injected intraperitoneally 1 h prior to embolization. Behavioural scores, infarct size and brain oedema, as well as the level of tumour necrosis factor-alpha (TNF-α), malondialdehyde, glutathione, catalase and superoxide dismutase activity were determined in the ipsilateral cortex 24 hours following stroke induction. MAIN OUTCOMES AND RESULTS: EO (45 mg kg(-1)), statistically similar to Z-ligustilide (20 mg kg(-1)), curtailed brain infarction and oedema, improved behavioural scores and prevented enhanced oxidative stress and TNF-α level in the ischaemic brain tissues. CONCLUSIONS: The findings provide the first evidence of effectiveness of the extract in a thromboembolic model of stroke, whose action can be mediated, at least in part, by the antioxidative and anti-inflammatory mechanisms.
Assuntos
4-Butirolactona/análogos & derivados , Antioxidantes/uso terapêutico , Apiaceae , Infarto da Artéria Cerebral Média/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Antioxidantes/farmacologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Glutationa/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The therapeutic effects of atorvastatin on early brain injury (EBI), cerebral edema and its association with aquaporin 4 (AQP4) were studied in rabbits after subarachnoid hemorrhage (SAH) using western blot analysis and the dry-wet method. Seventy-two healthy male New Zealand rabbits weighing between 2.5 and 3.2 kg were randomly divided into three groups: the SAH group (n=24), sham-operated group (n=24) and the SAH + atorvastatin group (n=24). A double SAH model was employed. The sham-operated group were injected with the same dose of saline solution, the SAH + atorvastatin group received atorvastatin 20 mg/kg/day after SAH. All rabbit brain samples were taken at 72 h after the SAH model was established successfully. Brain edema was detected using the dry-wet method after experimental SAH was induced; AQP4 and caspase-3 expression was measured by western blot analysis, and neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining at 72 h after SAH. The results indicated that brain edema and injury appeared soon after SAH, while brain edema and EBI were ameliorated and increased behavior scores were noted after prophylactic use of atorvastatin. Compared with the SAH group, the level of AQP4 and the cerebral content of water was significantly decreased (P<0.01) by atorvastatin, and TUNEL staining and studying the expression of caspase-3 showed that the apoptosis of neurons was reduced markedly both in the hippocampus and brain cortex by atorvastatin. The results suggest that atorvastatin ameliorated brain edema and EBI after SAH, which was related to its inhibition of AQP4 expression. Our findings provide evidence that atorvastatin is an effective and well-tolerated approach for treating SAH in various clinical settings.