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1.
CNS Neurosci Ther ; 25(9): 1030-1041, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31218845

RESUMO

INTRODUCTION: L-glutamine is an antioxidant that plays a role in a variety of biochemical processes. Given that oxidative stress is a key component of stroke pathology, the potential of L-glutamine in the treatment of ischemic stroke is worth exploring. AIMS: In this study, we investigated the effect and mechanisms of action of L-glutamine after cerebral ischemic injury. RESULTS: L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in mice. L-glutamine administration increased the expression of heat-shock protein 70 (HSP70) in astrocytes and endothelial cells. Such effects were abolished by the coadministration of Apoptozole, an inhibitor of the ATPase activity of HSP70. L-glutamine also reduced oxidative stress and neuronal apoptosis, and increased the level of superoxide dismutase, glutathione, and brain-derived neurotrophic factor. Cotreatment with Apoptozole abolished these effects. Cell culture study further revealed that the conditioned medium from astrocytes cultured with L-glutamine reduced the apoptosis of neurons after oxygen-glucose deprivation. CONCLUSION: L-glutamine attenuated ischemic brain injury and promoted functional recovery via HSP70, suggesting its potential in ischemic stroke therapy.

2.
CNS Neurosci Ther ; 25(6): 748-758, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30784219

RESUMO

INTRODUCTION: Dl-3-N-butylphthalide (NBP), a small molecule drug used clinically in the acute phase of ischemic stroke, has been shown to improve functional recovery and promote angiogenesis and collateral vessel circulation after experimental cerebral ischemia. However, the underlying molecular mechanism is unknown. AIMS: To explore the potential molecular mechanism of angiogenesis induced by NBP after cerebral ischemia. RESULTS: NBP treatment attenuated body weight loss, reduced brain infarct volume, and improved neurobehavioral outcomes during focal ischemia compared to the control rats (P < 0.05). NBP increased the number of CD31+ microvessels, the number of CD31+ /BrdU+ proliferating endothelial cells, and the functional vascular density (P < 0.05). Further study demonstrated that NBP also promoted the expression of vascular endothelial growth factor and angiopoietin-1 (P < 0.05), which was accompanied by upregulated sonic hedgehog expression in astrocytes in vivo and in vitro. CONCLUSION: NBP treatment promoted the expression of vascular endothelial growth factor and angiopoietin-1, induced angiogenesis, and improved neurobehavioral recovery. These effects were associated with increased sonic hedgehog expression after NBP treatment. Our results broadened the clinical application of NBP to include the later phase of ischemia.

3.
CNS Neurosci Ther ; 22(12): 961-969, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27390218

RESUMO

AIMS: MicroRNAs play an important role in the pathogenesis of ischemic brain injury and in the repair process during postischemic condition. However, the key miRNAs and their function in these processes remain unclear. METHODS: Circulating blood MicroRNAs profiles were examined in the ischemic stroke patients. The predicted network of difference was analyzed by ingenuity pathway analysis. The key MicroRNAs were selected, and the function was further studied in a mouse ischemia model. The predicted downstream target was confirmed. RESULTS: We found that 24 MicroRNAs were differently expressed in stroke patients compared to the control (P < 0.05). Bioinformatic analysis showed a MicroRNAs regulated network with the highest score in the stroke cascade, which was consisted of 10 MicroRNAs including key hypoxia-related miR-210 and its predicted downstream target brain derived neurotrophic factor (BDNF). Lentivirus-mediated miR-210 overexpression enhanced the microvessel density and the number of neural progenitor cells in the ischemic mouse brain (P < 0.05) and improved neurobehavioral outcomes in the ischemic mouse (P < 0.05). MiR-210 upregulation increased mBDNF/proBDNF protein expression in the normal and ischemic mouse brain. The dual-luciferase reporter assay identified that BDNF was the direct target of miR-210. CONCLUSION: MiR-210 is a crucial ischemic stroke-associated MicroRNAs and a potential target for the stroke therapy.


Assuntos
Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/terapia , Lentivirus , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Idoso , Animais , Infarto Encefálico/etiologia , Mapeamento Cromossômico , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Humanos , Infarto da Artéria Cerebral Média/complicações , Lentivirus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Neovascularização Patológica/etiologia , Neovascularização Patológica/terapia , Neurogênese/fisiologia , Neuropeptídeos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo
4.
CNS Neurosci Ther ; 22(4): 316-24, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26842484

RESUMO

OBJECTIVES: Dynamically observe cerebral vascular changes in hyperglycemic rats in vivo and explore the effect of diabetes on endothelial function after ischemic stroke. BACKGROUND: Diabetes affects both large and small vessels in the brain, but the dynamic process and mechanism are unclear. METHODS: We investigated the structural and functional changes of brain vasculature in living hyperglycemic rats and their impact on stroke outcomes via a novel technique: synchrotron radiation angiography. We also examined the effect of prolonged fasudil treatment on arterial reactivity and hemorrhagic transformation. Adult Sprague Dawley rats were treated by streptozotocin to induce type 1 diabetes. These hyperglycemic rats received fasudil pretreatment and then underwent transient middle cerebral artery occlusion. RESULTS: We found that diabetes caused arteries narrowing in the circus Willis as early as 2 weeks after streptozotocin injection (P < 0.05). These vessels were further constricted after middle cerebral artery occlusion. L-NAME could induce regional constrictions and impaired relaxation in hyperglycemic animals. Furthermore, hemorrhagic transformation was also increased in the hyperglycemic rats compared to the control (P < 0.05). In fasudil-treated rats, the internal carotid artery narrowing was ameliorated and L-NAME-induced regional constriction was abolished. Importantly, stroke prognosis was improved in fasudil-treated rats compared to the control (P < 0.05). CONCLUSIONS: Our dynamic angiographic data demonstrated that diabetes could impair the cerebral arterial reactivity. Prolonged fasudil treatment could attenuate arterial dysfunction and improve the prognosis of ischemic stroke by affecting both the large and small vasculature.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Artérias Cerebrais/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Hiperglicemia/fisiopatologia , Infarto da Artéria Cerebral Média/fisiopatologia , Vasodilatadores/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Angiografia Cerebral , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/patologia , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Diabetes Mellitus Experimental/patologia , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , Hiperglicemia/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , NG-Nitroarginina Metil Éster , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão , Ratos Sprague-Dawley
5.
CNS Neurosci Ther ; 21(4): 337-47, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25676164

RESUMO

Stem cell-based therapy for ischemic stroke has been widely explored in animal models and provides strong evidence of benefits. In this review, we summarize the types of stem cells, various delivery routes, and tracking tools for stem cell therapy of ischemic stroke. MSCs, EPCs, and NSCs are the most explored cell types for ischemic stroke treatment. Although the mechanisms of stem cell-based therapies are not fully understood, the most possible functions of the transplanted cells are releasing growth factors and regulating microenvironment through paracrine mechanism. Clinical application of stem cell-based therapy is still in its infancy. The next decade of stem cell research in stroke field needs to focus on combining different stem cells and different imaging modalities to fully explore the potential of this therapeutic avenue: from bench to bedside and vice versa.


Assuntos
Isquemia Encefálica/terapia , Transplante de Células-Tronco/métodos , Acidente Vascular Cerebral/terapia , Animais , Encéfalo/fisiopatologia , Isquemia Encefálica/fisiopatologia , Ensaios Clínicos como Assunto , Humanos , Acidente Vascular Cerebral/fisiopatologia
6.
CNS Neurosci Ther ; 19(12): 969-77, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24164711

RESUMO

AIMS: To study whether adiponectin (APN) could improve neurological outcomes in aged mice after ischemic stroke. METHODS: Adeno-associated virus carrying APN gene was injected into aged and young adult mice 7 days before transient middle cerebral artery occlusion (tMCAO). Atrophic volumes and neurobehavioral deficiencies were determined up to 28 days after tMCAO. Focal angiogenesis was determined based on blood vessel number in the ischemic regions. RESULTS: Increased atrophic volume and more sever neurobehavioral deficits were found in the aged mice compared with young adult mice (P < 0.05). AAV-APN gene transfer attenuated atrophic volume and improved neurobehavioral outcomes, along with increased focal angiogenesis in both aged and young adult mice, compared with control animals (P < 0.05). In addition, the attenuation of atrophic volume and the improvement in neurobehavioral outcomes were much more significant in aged mice than in young adult mice after AAV-APN administration (P < 0.05). The number of microvessels in aged AAV-APN mouse ischemic brain was higher than in young adult AAV-APN treated mouse brain (P < 0.05). CONCLUSIONS: Our results demonstrate that APN overexpression reduces ischemic brain injury and improves neurobehavioral function recovery in aged mice than in young mice, suggesting APN is more beneficial in aged animals after ischemic stroke.


Assuntos
Adiponectina/metabolismo , Envelhecimento , Isquemia Encefálica/complicações , Regulação da Expressão Gênica/fisiologia , Transtornos Mentais/etiologia , Transtornos Mentais/terapia , Adenoviridae/genética , Adiponectina/genética , Fatores Etários , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Microvasos/metabolismo , Microvasos/patologia , Fosfopiruvato Hidratase/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo
7.
Neurosci Lett ; 536: 41-6, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23328441

RESUMO

Necroptosis was reported as one backup way of programmed cell death when apoptosis was blocked, and the receptor interacting protein 1 was considered as the key necroptosis regulator protein. Here, we report the neuroprotective effects of curcumin which attenuates necroptosis. Primary cortical neurons were cultured and were injured by ferrous chloride, z.vad.fmk was applied to block apoptosis, curcumin was administrated to protect neurons, necrostatin-1 was applied to inhibit necroptosis if needed. Cell viability was measured by detecting lactate dehydrogenase activity in lysates of surviving cells, and assessed by cell counting kit-8. The expression of receptor interacting protein 1 was detected by immunoblot and immunofluorescence. Results showed that necroptosis mainly occurred in the concentrations of ferrous chloride ranging from 100 to 200µM, curcumin attenuated necroptosis in a dose-dependent manner. Furthermore, curcumin decreased expression of receptor interacting protein 1 in a dose- and time-dependent manner. Taken together, these findings suggest that curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Curcumina/farmacologia , Sobrecarga de Ferro/patologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose , Células Cultivadas , Córtex Cerebral/patologia , Relação Dose-Resposta a Droga , Embrião de Mamíferos/citologia , Compostos Ferrosos/toxicidade , Sobrecarga de Ferro/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Neurônios/patologia
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