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1.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668340

RESUMO

Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Oxazóis/farmacologia , Receptores sigma/agonistas , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Braz J Med Biol Res ; 54(4): e10498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33656055

RESUMO

It is known that neuronal apoptosis contributes to pathology of cerebral ischemia injury. Zonisamide (ZNS) has shown anti-apoptosis effects in recent studies. The present study investigated whether the anti-apoptotic effect can account for the neuroprotective action of ZNS on cerebral ischemia. Neuronal cells were maintained under oxygen-glucose deprivation conditions to simulate cerebral ischemia and treated with ZNS simultaneously. The apoptosis of the cells and expression of apoptosis-related proteins were investigated by flow cytometry and western blot analysis, respectively. A cerebral ischemia mouse model was created via middle cerebral artery occlusion, and the mice were treated with ZNS. Neurological deficit scores and infarct volumes of the cerebral ischemia mice were measured. The apoptosis status of the neuronal cells was evaluated by TUNEL staining. In vitro, the ZNS treatment inhibited both the apoptosis of the neuronal cells and apoptosis-related protein expression (caspase-3, caspase-8, and calpain-1) induced by the oxygen-glucose deprivation. The anti-apoptosis effect of ZNS could occur through the blocking of reactive oxygen species. Moreover, ZNS treatment significantly ameliorated neurological deficits and reduced infarct volumes in the cerebral ischemia mice model. In this study, ZNS exerted neuroprotective effects by inhibition of apoptosis in neuronal cells in cerebral ischemia. Therefore, ZNS might be a promising therapy for cerebral ischemia.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Apoptose , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Camundongos , Fármacos Neuroprotetores/farmacologia , Zonisamida/farmacologia
3.
Neurosci Lett ; 750: 135766, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33639221

RESUMO

Ischemic stroke is one of the major diseases that cause mortality and morbidity of human beings, but there is still lack of effective treatment and prevention. We found that 2-(2-Benzofuranyl)-2-Imidazoline (2-BFI) is potently protective against stroke and acute inflammatory immune disease. Moreover, the mammalian target of rapamycin (mTOR) signaling contributes effectively to the modulation of post-stroke neuroinflammatory response. However, whether the protection of 2-BFI against ischemic injury is through mTOR-mediated neuroinflammatory response remains unestablished. Here, we used 2-BFI to treat ischemic rats induced by distal middle cerebral artery occlusion (dMCAO). We found that 2-BFI administration after dMCAO improved the neurological deficits and decreased the infarct volume. 2-BFI reduced phosphorylation of mTOR and p70S6, increased IL-10 and TGF-ß, and decreased IFN-γ levels in ischemic rats. Our results demonstrated that 2-BFI attenuates ischemic injury by inhibiting the activation of mTOR signaling and modulating neuroinflammation after stroke in rats.


Assuntos
Marcadores de Afinidade/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzofuranos/uso terapêutico , Imidazóis/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Marcadores de Afinidade/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Imidazóis/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
4.
J Stroke Cerebrovasc Dis ; 30(3): 105595, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33450605

RESUMO

BACKGROUND: Endovascular thrombectomy (EVT) is highly effective but may also lead to hemorrhagic transformation (HT) and edema, which may be more pronounced in severe ischemia. We sought to determine whether glibenclamide can attenuate HT and edema in a severe ischemia-reperfusion model that reflects EVT. METHODS: Using a transient middle cerebral artery occlusion (tMCAo) rodent model of stroke, we studied two rat cohorts, one without rt-PA and a second cohort treated with rt-PA. Glibenclamide or vehicle control was administered as an intravenous bolus at reperfusion, followed by continuous subcutaneous administration with an osmotic pump. RESULTS: Compared to vehicle control, glibenclamide improved neurological outcome (median 7, interquartile range [IQR 6-8] vs. control median 6 [IQR 0-6], p = 0.025), reduced stroke volume (323 ± 42 vs. 484 ± 60 mm3, p < 0.01), swelling volume (10 ± 4 vs. 28 ± 7%, p < 0.01) and water content (84 ± 1 vs. 85 ± 1%, p < 0.05). Glibenclamide administration also reduced HT based on ECASS criteria, densitometry (0.94 ± 0.1 vs. 1.15 ± 0.2, p < 0.01), and quantitative hemoglobin concentration (2.7 ± 1.5 vs. 6.2 ± 4.6 uL, p = 0.011). In the second cohort with rt-PA coadministration, concordant effects on HT were observed with glibenclamide. CONCLUSIONS: Taken together, these studies demonstrated that glibenclamide reduced the amount of edema and HT after severe ischemia. This study suggests that co-administration of glibenclamide may be worth further study in severe stroke patients treated with EVT with or without IV rt-PA.


Assuntos
Edema Encefálico/prevenção & controle , Glibureto/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Hemorragias Intracranianas/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/patologia , Modelos Animais de Doenças , Fibrinolíticos/farmacologia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/patologia , Infusões Subcutâneas , Injeções Intravenosas , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/patologia , Masculino , Ratos Wistar , Traumatismo por Reperfusão/diagnóstico por imagem , Traumatismo por Reperfusão/patologia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/farmacologia
5.
Life Sci ; 271: 119111, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33513398

RESUMO

BACKGROUND: Sevoflurane (Sevo) is neuroprotective in brain damage, thus our objective was to further investigate the impact of Sevo treatment on nerve regeneration and repair of neurological deficit in brain damage rats by regulating miR-490-5p and cyclin-dependent kinases 1 (CDK1). METHODS: The rat middle cerebral artery occlusion model was established. miR-490-5p and CDK1 levels in brain tissues were tested. The behavioral changes, the number of glial fibrillary acidic protein (GFAP) positive cells, ionized calcium-binding adapter molecule-1 (Iba-1) and Nestin mRNA expression, the survival and apoptosis of neurons in peripheral tissues of infarct areas were detected by a series of assays. Furthermore, the target relationship between miR-490-5p and CDK1 was verified. RESULTS: miR-490-5p was reduced and CDK1 was raised in brain tissues of brain damage rats. Sevo raised miR-490-5p and decreased CDK1 to improve neurological deficits, reduce apoptotic neurons, suppress expression levels of GFAP and Iba-1, and increase Nestin expression and the number of surviving neurons in peripheral tissue in infarct area, and alleviate the pathological changes of brain tissues of brain damage rats. CDK1 was negatively regulated by miR-490-5p. CONCLUSION: Our study presents that Sevo treatment is involved in neurogenesis and repair of neurological deficit of brain damage rats via up-regulating miR-490-5p and inhibiting CDK1.


Assuntos
Proteína Quinase CDC2/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , MicroRNAs/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Doenças do Sistema Nervoso/metabolismo , Sevoflurano/uso terapêutico , Animais , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , MicroRNAs/antagonistas & inibidores , Regeneração Nervosa/fisiologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sevoflurano/farmacologia
6.
J Stroke Cerebrovasc Dis ; 30(4): 105630, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33497934

RESUMO

BACKGROUND: The therapeutic effects of dimethyl fumarate (DMF) in patients with multiple sclerosis and animal models of neurologic disease were reported. The density and the distribution pattern of motor neurons are important in transmitting the signal and controlling the movement-related functions. The present study evaluated the effects of DMF treatment on the neurological functions, infarct volume, and spatial distribution of the neurons in the primary motor cortex after cerebral ischemia. METHODS: Thirty-three Sprague-Dawley rats were randomly divided into three groups: The sham group underwent surgery without middle cerebral artery occlusion (MCAO) and drug. The vehicle and treatment groups after MCAO received a vehicle or DMF for three consecutive days. Post-stroke neurological and motor functions were assessed. At the end of the third day, the brains were removed, and the cerebral infarct volume was evaluated. We used cresyl violet staining to analyze the density and the spatial arrangement of motor cortical neurons using Voronoi tessellation. RESULTS: Treatment of the brain ischemia for three days with DMF could not significantly reduce the neurological and motor function deficits and infarct volume. However, it reduced the neuronal area and death and preserved their spatial distribution in the normal regular pattern. CONCLUSION: Cerebral ischemia decreased the neuronal density of the primary motor cortex and changed their distributions to a random pattern. DMF treatment during sub-acute ischemic stroke did not significantly improve the neurological deficit scores. However, it could prevent neuronal swelling and death and preserved the spatial distribution of the cortical neurons in their normal pattern.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , /fisiopatologia , Masculino , Córtex Motor/patologia , Córtex Motor/fisiopatologia , Neurônios Motores/patologia , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Fatores de Tempo
7.
J Stroke Cerebrovasc Dis ; 30(4): 105629, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33497937

RESUMO

BACKGROUND: Limb Shaking Syndrome (LSS) is usually associated with internal carotid occlusion. There are few reported-cases in context of middle cerebral artery stenosis. METHODS: We presented LSS in a patient with middle cerebral artery stenosis disease. RESULTS: The patient was a 62-year-old man, smoker, with high blood pressure who suffered left hemifacial and limbs myoclonus. He was initially diagnosed with focal seizures and he started antiepileptic treatment. However, he repeated the episodes. The electroencephalogram showed no abnormalities, and a vascular study with ultrasounds and angio-MRI evidenced severe middle cerebral stenosis. Finally, a diagnosis of Limb Shaking Syndrome was established and he started antiplatelet and high dose lipid-lowering treatment. CONCLUSION: Not all abnormal movements are due to epileptic seizures. When we evaluate a patient with vascular risk factors it is important to perform a complete vascular study to discard not only critical carotid stenosis but also intracranial disease.


Assuntos
Infarto da Artéria Cerebral Média/complicações , Ataque Isquêmico Transitório/complicações , Tremor/etiologia , Erros de Diagnóstico , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Humanos , Hipolipemiantes/uso terapêutico , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/fisiopatologia , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Recidiva , Síndrome , Resultado do Tratamento , Tremor/diagnóstico , Tremor/fisiopatologia
8.
Nutr Metab Cardiovasc Dis ; 31(1): 333-343, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500109

RESUMO

BACKGROUND AND AIMS: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury. METHODS AND RESULTS: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly. CONCLUSIONS: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.


Assuntos
Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Liraglutida/farmacologia , Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Estreptozocina
9.
Eur J Med Chem ; 212: 113119, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383258

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) plays important role in ethanol metabolism, and also serves as an important shield from the damage occurring under oxidative stress. A special inactive variant was found carried by 35-45% of East Asians. The variant carriers have recently been found at the higher risk for the diseases related to the damage occurring under oxidative stress, such as cardiovascular and cerebrovascular diseases. As a result, ALDH2 activators may potentially serve as a new class of therapeutics. Herein, N-benzylanilines were found as novel allosteric activators of ALDH2 by computational virtual screening using ligand-based and structure-based screening parallel screening strategy. Then a structural optimization was performed and has led to the discovery of the compound C6. It has good activity in vitro and in vivo, which could reduce infarct size by ∼70% in ischemic stroke rat models. This study provided good lead compounds for the further development of ALDH2 activators.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Descoberta de Drogas , Infarto da Artéria Cerebral Média/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Infarto da Artéria Cerebral Média/patologia , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
10.
Stroke ; 52(1): 203-212, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33317416

RESUMO

BACKGROUND AND PURPOSE: There is interest in what happens over time to the thrombus after intravenous alteplase. We study the effect of alteplase on thrombus structure and its impact on clinical outcome in patients with acute stroke. METHODS: Intravenous alteplase treated stroke patients with intracranial internal carotid artery or middle cerebral artery occlusion identified on baseline computed tomography angiography and with follow-up vascular imaging (computed tomography angiography or first run of angiography before endovascular therapy) were enrolled from INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography). Thrombus movement after intravenous alteplase was classified into complete recanalization, thrombus migration, thrombus fragmentation, and no change. Thrombus migration was diagnosed when occlusion site moved distally and graded according to degrees of thrombus movement (grade 0-3). Thrombus fragmentation was diagnosed when a new distal occlusion in addition to the primary occlusion was identified on follow-up imaging. The association between thrombus movement and clinical outcome was also evaluated. RESULTS: Among 427 patients in this study, thrombus movement was seen in 54% with a median time of 123 minutes from alteplase administration to follow-up imaging, and sub-classified as marked (thrombus migration grade 2-3 + complete recanalization; 27%) and mild to moderate thrombus movement (thrombus fragmentation + thrombus migration grade 0-1; 27%). In patients with proximal M1/internal carotid artery occlusion, marked thrombus movement was associated with a higher rate of good outcome (90-day modified Rankin Scale, 0-2) compared with mild to moderate movement (52% versus 27%; adjusted odds ratio, 5.64 [95% CI, 1.72-20.10]). No difference was seen in outcomes between mild to moderate thrombus movement and no change. In M1 distal/M2 occlusion, marked thrombus movement was associated with improved 90-day good outcome compared with no change (70% versus 56%; adjusted odds ratio, 2.54 [95% CI, 1.21-5.51]). CONCLUSIONS: Early thrombus movement is common after intravenous alteplase. Marked thrombus migration leads to good clinical outcomes. Thrombus dynamics over time should be further evaluated in clinical trials of acute reperfusion therapy.


Assuntos
Fibrinolíticos/uso terapêutico , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/tratamento farmacológico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Artéria Carótida Interna , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/tratamento farmacológico , Angiografia por Tomografia Computadorizada , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Reperfusão , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
11.
J Stroke Cerebrovasc Dis ; 29(9): 105071, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807473

RESUMO

BACKGROUND: Chinese medicine Tongxinluo capsule (TXL) has been extensively used to treat ischemic stroke in China, and one of its mechanisms is to protect against blood brain barrier (BBB) disruption after stroke. However, the underlying protective mechanisms are not fully illuminated. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP-1) is involved in BBB disruption after brain ischemia. In this study, we explored whether TXL could downregulate LRP-1 expression and subsequently protect against BBB disruption after stroke using permanent middle cerebral artery occlusion (pMCAO) in mice. METHODS: The animal model of ischemic stroke was induced by pMCAO in male adult C57BL/6J mice. The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 h after pMCAO. Meanwhile, the LRP-1 antagonist receptor associated protein (RAP) was intracerebroventricularly injected at 1 and 21 h after stroke. We measured the following parameters at 6 and 24 h: LRP-1 protein level, BBB leakage, and the expression of tight junction (TJ) proteins including occludin, claudin-5 and zonula occludens-1 (ZO-1). RESULTS: Our results showed that TXL downregulated LRP-1 level, upregulated these TJ proteins level, and reduced BBB leakage in peri-infarct regions after pMCAO. Further study found that the inhibitor RAP played the same role as did TXL in upregulating these TJ proteins level and reducing BBB leakage after stroke. CONCLUSION: Our study demonstrates that TXL protects against BBB disruption after stroke via inhibiting the LRP-1 pathway.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Administração Oral , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Cápsulas , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
12.
Cerebrovasc Dis ; 49(4): 346-354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756048

RESUMO

BACKGROUND: Inflammatory response exerts an important role in ischemia/reperfusion (I/R) injury. TLR4 and myeloid differentiation factor 88 (MyD88) are key components in inflammation and are involved in the cerebral I/R injury. Irisin is a skeletal muscle-derived myokine produced after exercise, which was found to suppress inflammation. In this study, we investigated whether irisin could protect the brain from I/R injury through the TLR4/MyD88 pathway. METHODS: Male Sprague Dawley rats (20 months, 190 ∼ 240 g) were pretreated with irisin at 10, 50, or 100 mg/kg for consecutive 3 days and then subjected to surgery of middle cerebral artery occlusion or sham operation. Infarct size and neuron loss were measured to evaluate brain damage. The mRNA and protein levels of TLR4 and MyD88 were measured by in situ hybridization and immunohistochemistry, respectively. NF-κB activation was assessed by electrophoretic mobility shift assay. Neurological function was evaluated by neurobehavior score test and passive avoidance test. RESULTS: Irisin could reduce neuronal damage and neurofunctional impairment after I/R injury. This effect was mediated by downregulating the TLR4/MyD88 and inhibiting NF-κB activation. CONCLUSION: Irisin plays a beneficial effect in I/R injury through regulating the TLR4/MyD88 pathway.


Assuntos
Encéfalo/efeitos dos fármacos , Fibronectinas/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Receptor 4 Toll-Like/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , 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 , NF-kappa B/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
13.
J Stroke Cerebrovasc Dis ; 29(8): 104977, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689608

RESUMO

BACKGROUND: Ischemic stroke is a severe neurological disorder that affected millions of people worldwide. Neuro-inflammation and apoptosis play an essential role in the pathogenesis of neuronal death during ischemic stroke. Alpha-pinene is a bicyclic terpenoid with anti-inflammatory and anti-apoptotic activities. Accordingly, the main purpose of this study was to assess the protective effect of α-pinene in ischemic stroke. MATERIALS AND METHODS: To induce ischemic stroke in male Wistar rats, the middle cerebral artery was occluded for 60 min followed by 24 h reperfusion. Alpha-pinene was injected intraperitoneally at the beginning of reperfusion. A day after reperfusion, the neurological deficits, volume of infarct area, and blood-brain barrier (BBB) permeability were evaluated. The mRNA expression of inflammatory cytokines as well as pro- and anti-apoptotic genes was assessed by using reverse transcription-polymerase chain reaction. The protein levels of inflammatory cytokines were also measured by ELISA method. RESULTS: The results showed that α-pinene (50 and 100 mg/kg) significantly improved sensorimotor function and decreased the volume of infarct area in the brain. The high permeability of BBB was also alleviated by α-pinene (50 and 100 mg/kg) in ischemic areas. Besides, α-pinene (100 mg/kg) attenuated neuro-inflammation through decreasing both the gene and protein expression of TNF-α and IL-1ß in the hippocampus, cortex, and striatum. Besides, α-pinene (100 mg/kg) suppressed apoptosis via downregulation of the pro-apoptotic Bax mRNA expression with a concomitant upregulation of anti-apoptotic Bcl-2 gene expression. CONCLUSIONS: Overall, it was concluded that α-pinene exerts neuroprotective effect during ischemic stroke through attenuating neuroinflammation and inhibition of apoptosis.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Monoterpenos Bicíclicos/farmacologia , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
J Stroke Cerebrovasc Dis ; 29(8): 104818, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32439352

RESUMO

BACKGROUND: During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear. METHODS: Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO. RESULTS: Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice. CONCLUSION: The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Cinamatos/farmacologia , Depsídeos/farmacologia , Suplementos Nutricionais , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Aldeídos/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL
15.
Ann Vasc Surg ; 68: 476-486, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32422289

RESUMO

BACKGROUND: This study aims to evaluate the potential effect and the underlying mechanism of C-C motif chemokine ligand 2 (CCL2) in ischemic stroke. METHODS: An integrated bioinformatics analysis was performed to identify the differentially expressed (DE) genes and their related pathways in ischemic stroke. In vivo study of a rat model of middle cerebral artery occlusion (MCAO) was further established to assess the effect of CCL2 on severity of neurologic impairments. The expression levels of proinflammatory cytokines were also evaluated using the ELISA assay, and Western blot was also used to determine the expression of CCL2 and other DE proteins in the related pathways. RESULTS: A total of 88 DE genes were identified from the microarray dataset of ischemic stroke. The bioinformatics analysis revealed that CCL2 was highly expressed in ischemic stroke tissue and promoted the ischemic stroke progression via activation of the chemokine signaling pathway and cytokine-cytokine receptor interaction pathway. The in vivo study of the ischemic stroke rat model also showed that the CCL2 expression was elevated in the MCAO/R rats, with significant neurological impairments and ischemic infarct area in the brain tissue being observed. The administration of CCL2 inhibitors significantly inhibited the inflammatory response, attenuated the neurological impairments, and decreased the ischemic infarct area in the MCAO/R rats. Furthermore, the downregulation of CCL2 also inhibited the expression of the pathway-related proteins including CCL7, CCR2, CXCL16, and TNF-α. CONCLUSIONS: These results indicate that the CCL2/chemokine signaling pathway is responsible for ischemic stroke progression and might represent a potential therapeutic target for ischemic stroke treatment.


Assuntos
Encéfalo/metabolismo , Quimiocina CCL2/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/genética , Modelos Animais de Doenças , Humanos , Indazóis/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Locomoção , Masculino , Fármacos Neuroprotetores/farmacologia , Propionatos/farmacologia , Mapas de Interação de Proteínas , Ratos Sprague-Dawley , Transdução de Sinais , Transcriptoma , Regulação para Cima
17.
J Steroid Biochem Mol Biol ; 202: 105667, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32407868

RESUMO

Ischemic stroke is the leading cause of human disability and mortality in the world. Neuroinflammation is the main pathological event following ischemia which contributes to secondary brain tissue damage and is driven by infiltration of circulating immune cells such as macrophages. Because of neuroprotective properties against ischemic brain damage, estrogens have the potential to become of therapeutic interest. However, the exact mechanisms of neuroprotection and signaling pathways is not completely understood. In the current study, 12-week-old male Wistar rats underwent an experimental ischemia by occluding the middle cerebral artery transiently (tMCAO) for 1 h. Male rats subjected to tMCAO were randomly assigned to receive 17ß-estradiol or vehicle treatment. The animals were sacrificed 72 h post tMCAO, transcardially perfused and the brains were proceeded either for TTC staining and gene analysis or for flow cytometry (CD45, CD11b, CD11c, CD40). We found that 17ß-estradiol substitution significantly reduced the cortical infarct which was paralleled by an improved Garcia test scoring. Flow cytometry revealed that CD45+ cells as well as CD45+CD11b+CD11c+ cells were massively increased in tMCAO animals and numbers were nearly restored to sham levels after 17ß-estradiol treatment. Gene expression analysis showed a reperfusion time-dependent upregulation of the markers CD45, CD11b and the activation marker CD40. The reduction in gene expression after 72 h of reperfusion and simultaneous 17ß-estradiol substitution did not reach statistical significance. These data indicate that 17ß-estradiol alleviated the cerebral ischemia-reperfusion injury and selectively suppressed the activation of the neuroinflammatory cascade via reduction of the number of activated microglia or infiltrated monocyte-derived macrophages in brain.


Assuntos
Estradiol/farmacologia , Infarto da Artéria Cerebral Média/imunologia , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/imunologia , Animais , Citocinas/imunologia , Estradiol/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Fármacos Neuroprotetores/uso terapêutico , Ratos Wistar , Acidente Vascular Cerebral/tratamento farmacológico
18.
J Thromb Haemost ; 18(8): 2031-2033, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464707

RESUMO

Coronavirus disease 2019 (COVID-19) is a pandemic disease currently affecting millions of people worldwide. Its neurological implications are poorly understood, and further study is urgently required. A hypercoagulable state has been reported in patients with severe COVID-19, but nothing is known about coagulopathy in patients with milder disease. We describe cases of patients in New York City presenting with stroke secondary to large vessel thrombosis without occlusion, incidentally found to have COVID-19 with only mild respiratory symptoms. This is in contrast to the venous thrombosis and microangiopathy that has been reported in patients with severe COVID-19. Our cases suggest that even in the absence of severe disease, patients with COVID-19 may be at increased risk of thrombus formation leading to stroke, perhaps resulting from viral involvement of the endothelium. Further systematic study is needed because this may have implications for primary and secondary stroke prevention in patients with COVID-19.


Assuntos
Betacoronavirus , Trombose das Artérias Carótidas/etiologia , Infecções por Coronavirus/complicações , Infarto da Artéria Cerebral Média/etiologia , Pandemias , Pneumonia Viral/complicações , Adulto , Idoso , Anticoagulantes/uso terapêutico , Betacoronavirus/isolamento & purificação , Biomarcadores , Proteína C-Reativa/análise , Trombose das Artérias Carótidas/sangue , Trombose das Artérias Carótidas/diagnóstico por imagem , Trombose das Artérias Carótidas/tratamento farmacológico , Angiografia Cerebral , Angiografia por Tomografia Computadorizada , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Emergências , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hemiplegia/etiologia , Humanos , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Tromboflebite/complicações
19.
J Stroke Cerebrovasc Dis ; 29(6): 104796, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32220555

RESUMO

We administered intravenous thrombolytic therapy to a 51-year-old female patient with a 101-min stroke onset. The patient was unconscious during the manifestation of symptoms. Computed tomography angiography examination of the intracranial artery at the time of admission suggested that the left middle cerebral artery was occluded. The patient regained consciousness after the intravenous thrombolytic treatment was administered. On an urgent cerebral angiography, it was revealed that the recanalization of the left middle cerebral artery was successful. Although blood perfusion was restored, occlusion of the distal blood flow remained. The symptoms of the patient gradually improved after the treatment. However, 6 months after the onset of the condition, intracranial aneurysms formed distal to the recanalized arteries that were previously embolized. The full process underlying the development of cerebral embolism caused by atrial myxomas and subsequent formation of aneurysms is illustrated in this patient. Although the underlying mechanism remains unclear, intravenous thrombolysis can successfully restore cerebral blood flow in and may improve the prognosis of patients with cerebral embolism caused by cardiac myxoma. Despite the positive revascularization therapy, the occurrence of the complication of intracranial aneurysms is possible. Long-term follow-up to evaluate the progression of myxomatous aneurysms after cerebral embolism with conservative treatment may be a suitable strategy for managing such patients.


Assuntos
Fibrinolíticos/administração & dosagem , Neoplasias Cardíacas/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Aneurisma Intracraniano/etiologia , Embolia Intracraniana/etiologia , Mixoma/complicações , Células Neoplásicas Circulantes/patologia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Feminino , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/cirurgia , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/etiologia , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/patologia , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/patologia , Pessoa de Meia-Idade , Mixoma/patologia , Mixoma/cirurgia , Fatores de Risco , Resultado do Tratamento
20.
J Clin Neurosci ; 73: 252-258, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32037062

RESUMO

Cerebral collaterals is crucially important in the pathophysiology of acute ischemic stroke and associated with outcome after reperfusion therapy. We explored the effectiveness of collateral augmentation treatment with a combination of acetazolamide (ACZ) and head-down tilt (HDT) in the transient middle cerebral artery occlusion (MCAO) rat model. Transient MCAO was induced in all animals for 1.5 h, followed by reperfusion for 22.5 h. Seventy-two male Wistar rats were divided into four treatment groups: control, ACZ, HDT, and combination. Twenty sham rats, which underwent surgery, were randomly allocated to these groups. Twenty-four hours after MCAO or sham surgery, we measured the infarction volume, brain edema (aquaporin-4 [AQP4], and brain water content), and neurological deficits (Garcia and Longa tests). Collateral augmentation treatments were associated with reduced infarction volume, less brain edema, and better neurological outcomes compared with untreated animals. More specifically, ACZ and HDT treatments resulted in small infarction volumes, and HDT was associated with a low AQP4 expression and improved neurological score, while the combination of ACZ and HDT improved neurological scores and reduced brain water content. This study shows that collateral augmentation treatments are associated with a better stroke prognosis compared with untreated animals after transient MCAO. The combination of ACZ and HDT seems to have some synergistic effect, but was not proven to be superior to HDT treatment alone.


Assuntos
Acetazolamida/uso terapêutico , Anticonvulsivantes/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Decúbito Inclinado com Rebaixamento da Cabeça , Infarto da Artéria Cerebral Média/terapia , Acetazolamida/administração & dosagem , Animais , Anticonvulsivantes/administração & dosagem , Inibidores da Anidrase Carbônica/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Ratos , Ratos Wistar
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