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1.
J Stroke Cerebrovasc Dis ; 29(2): 104541, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31810719

RESUMO

BACKGROUND AND AIMS: The characteristics of clot causing acute ischemic stroke, such as size, content, and location, are among the main determinants of response to intravenous tissue plasminogen activator [IV tPA]. Clot heterogeneity and permeability are under-recognized features that might provide additional information in predicting the efficacy of IV tPA. METHODS AND PATIENTS: Patients with proximal middle cerebral artery occlusion treated with "IV tPA alone" were included. The mean Hounsfield's unit (HU) value, as objective measure of clot attenuation, and its standard deviation (SD), as proposed measure of clot heterogeneity, were obtained. The difference in HU values between CT Angiography and CT was defined as "clot permeability", or "perviousness'. The size (length and volume-mm3) of pre-clot pouch and occluding clot along with ASPECT score and Maas' silvian and leptomeningeal collateral score were measured. RESULTS: The study included 84 cases (44 women, age: 68 ± 14 years, pretPA NIHSS: 16 ± 5). Patients with excellent response to tPA (31%) had lower thrombus volume (37.54 ± 32.37 versus 63.49 ± 37.36, P = .009) and heterogeneity (4.05 ± 1.49 versus 5.35 ± 2.34, P = .011), along with higher clot permeability (48 ± 35.48 to 31.32 ± 18.62, P = .006). However, significance of permeability did not survived in the regression analysis with adjustment for NIHSS (ß:-.296, P = .003); clot volume (ß:-.240, P = .014) and collateral status (ß:.346, P < .001). In patients with good prognosis, clot volume was significantly lower (37.76 ± 30.08 versus 67.57 ± 37.83, P < .001), whereas permeability was significantly higher (43.97 ± 32.33 versus 31.13 ± 19.01, P = .026). However, this effect did not persist in the regression analysis after adjustment for NIHSS (ß:-.399, P < .001), collateral status (ß: .343, P < .001) and clot volume (ß:-.297, P = .001). Clot permeability was significantly higher (45.78 ± 36.34 versus 33 ± 20.2, P = .045) and heterogeneity was lower (4.1 ± 1.55 to 5.27 ± 2.32, P = .028) in patients with dramatic response to tPA (27%). In patients responding positively to IV tPA (48%), clot permeability was numerically higher (39.85 ± 31.79 to 33.47 ± 19.28, P = .268), while clot volume (48.15 ± 34.5 to 62.07 ± 39.62, P = .093) was lower. Clot volume, permeability and heterogeneity did not show a significant difference in any (38.1%) or symptomatic (8.3%) bleeders after IV tPA. The chance of IV tPA to be beneficial increased in patients with clot volume lower than 45 mm3, with an increased likelihood of this benefit to be observed within the first day after IV tPA. Our detailed explorative ROC analysis was not able to detect a volume threshold above which the positive effect of IV tPA disappeared. CONCLUSION: Clot volume is critical for the effectiveness of IV tPA in acute ischemic stroke. Clot permeability and heterogeneity may modify its effect. CT technologies, which are readily available when evaluating a stroke patient in an emergency setting, provide us with useful parameters regarding the size, permeability and heterogeneity of the clot.


Assuntos
Coagulação Sanguínea , Fibrinolíticos/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/diagnóstico , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Permeabilidade , Recuperação de Função Fisiológica , Sistema de Registros , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
2.
J Ethnopharmacol ; 246: 112212, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31494200

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: ANNAO tablets derive from Chinese classical prescriptions of Angong Niuhuang Pills with modified compositions, which have been singly or combined used for stoke associated neurological disorders. However the underlying mechanism is not yet well-defined, the present study investigated its anti-ischemic effects in rat middle cerebral artery occlusion (MCAO) model and focused on mitochondrial quality control. MATERIALS AND METHODS: Rats were subjected to 2 h of brain ischemia followed by 1 day or up to 7 days of reperfusion. Vehicle, ANNAO tablets or Edaravone were given at 1h after the start of reperfusion for 1 day or successive 7 days in MCAO rats. For the behavior assessment, Longa test and modified Neurological Severity Scores (m NSS) test were performed. Following the behavioral assessment, we assessed the protein expressions related to mitochondrial function. Moreover, we also assessed the neuroprotective effects of ANNAO tablets by immunohistochemical analysis. RESULTS: Compared with sham rats, ANNAO tablets improved the behavioral performance and decreased the infarction volume in the MCAO rats. Western blotting results showed that ANNAO tablets altered the expression level of multiple proteins related to mitochondrial function, elevated the ratio of Bcl-2/Bax and inhibited the apoptosis. Additionally, ANNAO tablets increased the number of NeuN positive neurons. CONCLUSIONS: The obtained data demonstrated that ANNAO tablets exhibited an obvious anti-cerebral ischemia-reperfusion effect, which could be attributed to the improvement of mitochondrial quality control.


Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Masculino , Mitocôndrias/fisiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Ratos Sprague-Dawley , Comprimidos
3.
Rev Med Chil ; 147(7): 932-934, 2019 Jul.
Artigo em Espanhol | MEDLINE | ID: mdl-31859993

RESUMO

We report an 89-year-old male under oral anticoagulant therapy with a therapeutic international normalized ratio, presenting at the emergency room with right side hemiparesis and aphasia. Neuroimaging was compatible with an acute middle cerebral artery ischemic stroke. Anticoagulation was reverted with the use of four factor prothrombin complex, followed by thrombolysis with alteplase, with a favorable evolution, returning to his basal functional status.


Assuntos
Acenocumarol/efeitos adversos , Anlodipino/efeitos adversos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Metformina/efeitos adversos , Protrombina/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/métodos , Acenocumarol/administração & dosagem , Administração Intravenosa , Idoso de 80 Anos ou mais , Anlodipino/administração & dosagem , Humanos , Infarto da Artéria Cerebral Média/etiologia , Masculino , Metformina/administração & dosagem , Acidente Vascular Cerebral/etiologia , Tomografia Computadorizada por Raios X
4.
J Stroke Cerebrovasc Dis ; 28(12): 104470, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31680031

RESUMO

BACKGROUND: The nitric oxide (NO)-producing activity of endothelial nitric oxide synthase (eNOS) plays a significant role in maintaining endothelial function and protecting against the stroke injury. However, the activity of the eNOS enzyme and the metabolism of major NO metabolite S-nitrosoglutathione (GSNO) are dysregulated after stroke, causing endothelial dysfunction. We investigated whether an administration of exogenous of GSNO or enhancing the level of endogenous GSNO protects against neurovascular injury in wild-type (WT) and eNOS-null (endothelial dysfunction) mouse models of cerebral ischemia-reperfusion (IR). METHODS: Transient cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO) for 60 minutes in male adult WT and eNOS null mice. GSNO (0.1 mg/kg body weight, intravenously) or N6022 (GSNO reductase inhibitor, 5.0 mg/kg body weight, intravenously) was administered 30 minutes before MCAO in preinjury and at the reperfusion in postinjury studies. Brain infarctions, edema, and neurobehavioral functions were evaluated at 24 hours after the reperfusion. RESULTS: eNOS-null mice had a higher degree (P< .05) of injury than WT. Pre- or postinjury treatment with either GSNO or N6022 significantly reduced infarct volume, improved neurological and sensorimotor function in both WT and eNOS-null mice. CONCLUSION: Reduced brain infarctions and edema, and improved neurobehavioral functions by pre- or postinjury GSNO treatment of eNOS knock out mice indicate that GSNO can attenuate IR injury, likely by mimicking the eNOS-derived NO-dependent anti-ischemic and anti-inflammatory functions. Neurovascular protection by GSNO/N6022 in both pre- and postischemic injury groups support GSNO as a promising drug candidate for the prevention and treatment of stroke injury.


Assuntos
Álcool Desidrogenase/antagonistas & inibidores , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Pirróis/farmacologia , S-Nitrosoglutationa/farmacologia , Álcool Desidrogenase/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/patologia , Edema Encefálico/enzimologia , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/deficiência , Óxido Nítrico Sintase Tipo III/genética
5.
Life Sci ; 239: 117036, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697951

RESUMO

AIMS: Previous literature has shown that melatonin plays a critical role in protecting against cerebral ischemia/reperfusion (I/R) injury. Sirtuin3(SIRT3), as one member of the sirtuin family, protects against oxidative stress-related diseases. However, the association between melatonin and SIRT3 in cerebral I/R injury is not well understood. Our experiment was planned to investigate whether melatonin protects against cerebral I/R injury through SIRT3 activation. MAIN METHODS: We selected transient middle cerebral artery occlusion (tMCAO) mice as the model of cerebral I/R injury. Male C57/BL6 mice were pre-treated with or without a selective SIRT3 inhibitor and then subjected to tMCAO surgery. Melatonin (20 mg/kg) was given to mice by intraperitoneal injection after ischemia and before reperfusion. Then, we observed the changes in the SIRT3 and downstream relative proteins, infarction volume, neurological score, Nissl, H&E and TUNEL staining, and the expression of apoptosis proteins after tMCAO. KEY FINDINGS: Melatonin upregulated the expression of SIRT3 after tMCAO, and alleviated the neurological dysfunction and cell apoptosis through SIRT3 activation. SIGNIFICANCE: Our research proved that melatonin promoted SIRT3 expression after tMCAO and alleviated cerebral I/R injury by activating the SIRT3 signaling pathway. This study provides novel therapeutic targets and mechanisms for the treatment of ischemic stroke in the clinic, especially during cerebrovascular reperfusion.


Assuntos
Melatonina/farmacologia , Traumatismo por Reperfusão/metabolismo , Sirtuína 3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Melatonina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/fisiologia , Acidente Vascular Cerebral/tratamento farmacológico
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 300-303, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701710

RESUMO

OBJECTIVE: To investigate the effects of 1,25-dihydroxyvitamin D3 (1,25-VitD3) supplementation on cerebral injury after ischemia/reperfusion (I/R) in mice with middle cerebral artery occlusion (MCAO). METHODS: Male C57BL6 mice were randomly divided into Sham group, Vehicle group and 1,25-VitD3 group, with 10 mice in each group. Vehicle group and 1,25-VitD3 group were given MCAO for 1 hour, and then killed after reperfusion for 24 hours. Mice in 1,25-VitD3 group were treated with 1,25-VitD3 at the dose of 100 ng/(kg·d) by injected intraperitoneally for 5 days before MCAO operation. Cerebral ischemic penumbra areas of each group were collected for TTC staining, RT-PCR, TTC staining and immunohistochemistry assay. The function defect of mice was evaluated by using neurological function score. RESULTS: Compared with the sham group, the volume of cerebral infarction in Vehicle group was increased significantly, and the expressions of IL-6, IL-1beta and Gp91phox in brain tissues were increased significantly (P<0.05); compared with Vehicle group, supplementation of 1,25-VitD3 reduced the volume of cerebral infarction by about 50% in I/R mice (P<0.05), and the expressions of IL-6, IL-1beta and Gp91phox in brain tissues of 1,25-VitD3 group were decreased significantly (P<0.05). The expression of Foxp3, a T-regulatory cell marker, was significantly increased in the brain of mice (P<0.05), while the expression of Rorc, a transcription factor, was significantly decreased (P<0.05), suggesting that Th17/gamma Delta T-cell response was reduced and the number of neutrophils in the brain injury site of mice was significantly reduced (P<0.05). CONCLUSION: Vitamin D could alleviate the development of cerebral infarction after arterial occlusion (MCAO) reperfusion, and its mechanism may be through regulating the inflammatory response in mouse brain I/R.


Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Vitamina D/farmacologia , Animais , Encéfalo , Citocinas/metabolismo , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Linfócitos T , Células Th17
7.
Neurol Res ; 41(11): 1034-1042, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584350

RESUMO

Objectives: To investigate the thrombolysis with recombinant human prourokinase (rhPro-UK) on thromboembolic stroke in rats at different therapeutic time windows (TTW). Methods: Rats were subjected to embolic middle cerebral artery occlusion. RhPro-UK and positive control drugs rt-PA,UK were administered 3 h, 4.5 h, 6 h after inducing thromboem-bolic stroke. Neurological deficit scoring (NDS) was evaluated at 6 h and 24 h after the treatment. The lesion volume in cerebral hemispheres was measured by MRI scanning machine after 6 h of thrombolysis, and the infarct volume was measured by TTC stain, together with hemorrhagic volume quantified by a spectrophotometric assay after 24 h of thrombolysis. Results: RhPro-UK 10, 20 × 104 U/kg significantly improved the NDS after cerebral thromboembolism in rats at 3 h, 4.5 h TTW, and at the 6 h TTW, the NDS was improved by 28.0% (P = 0.0690) and 29.2% (P = 0.0927) at 6 h and 24 h after rhPro-UK 20 ×104 U/kg administration, respectively. RhPro-UK 10, 20 × 104 U/kg significantly reduced the brain lesions measured by MRI at 3 h and 4.5 h TTW. RhPro-UK 10, 20 × 104 U/kg significantly reduced the cerebral infarction measured by TTC at 3 h, 4.5 h TTW. There was no increase in cerebral hemorrhage compared with untreated group after rhPro-UK administration. Conclusions: RhPro-UK had an obvious therapeutic effect on ischemic stroke caused by thrombosis, and could be started within 4.5 h TTW with less side effects of cerebral hemorrhage than that of UK.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Embolia Intracraniana/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Embolia Intracraniana/complicações , Masculino , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Tromboembolia/complicações , Tromboembolia/tratamento farmacológico , Terapia Trombolítica/métodos , Fatores de Tempo
8.
Gen Physiol Biophys ; 38(5): 389-397, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31595881

RESUMO

Stroke is a leading cause of disability and death in the worldwide. Therefore, prevention of stroke is critically important. Genistein, a natural phytoestrogen extracted from soybeans, has been found to be a potential neuroprotective agent for stroke prevention. However, the role of genistein and its underlying mechanism in ovariectomized rats has been rarely evaluated. In this study, ovariectomized rats were treated with genistein (10 mg/kg) or vehicle daily for two weeks before they received middle cerebral artery occlusion (MCAO) and reperfusion. Seventy-two hours after reperfusion, the neurological function was evaluated by Garcia test, infarct volumes were detected by 2,3,5-triphenyltetrazolium chloride staining; and neuronal damage and cell apoptosis were detected by Nissl and Tunel staining in the ischemic penumbra, respectively. In addition, Western blotting was used to detect the activity of PI3K-Akt-mTOR signal pathway in the ischemic penumbra in different groups. And we found that genistein treatment in ovariectomized rats significantly improved neurological outcomes, reduced infarct volumes, decreased neuronal damage and cell apoptosis, and increased the activity of PI3K-Akt-mTOR signal pathway. Our findings indicated that treatment genistein could alleviate neuronal apoptosis induced by cerebral ischemia in ovariectomized rats via promoting the activity of PI3K-Akt-mTOR signal pathway, which provides a new molecular mechanism for the neuroprotective effects of genistein against stroke.


Assuntos
Genisteína/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Infarto da Artéria Cerebral Média/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Ovariectomia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 20(19)2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31569558

RESUMO

Diabetes causes various macrovascular and microvascular alterations, often culminating in major clinical complications (first of all, stroke) that lack an effective therapeutic intervention. N-palmitoylethanolamide-oxazoline (PEA-OXA) possesses anti-inflammatory and potent neuroprotective effects. Although recent studies have explained the neuroprotective properties of PEA-OXA, nothing is known about its effects in treating cerebral ischemia. METHODS: Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAo) in the right hemisphere. Middle cerebral artery (MCA) occlusion was provided by introducing a 4-0 nylon monofilament (Ethilon; Johnson & Johnson, Somerville, NJ, USA) precoated with silicone via the external carotid artery into the internal carotid artery to occlude the MCA. RESULTS: A neurological severity score and infarct volumes were carried out to assess the neuroprotective effects of PEA-OXA. Moreover, we observed PEA-OXA-mediated improvements in tissue histology shown by a reduction in lesion size and an improvement in apoptosis level (assessed by caspases, Bax, and Bcl-2 modulation and a TUNEL assay), which further supported the efficacy of PEA-OXA therapy. We also found that PEA-OXA treatment was able to reduce mast cell degranulation and reduce the MCAo-induced expression of NF-κB pathways, cytokines, and neurotrophic factors. CONCLUSIONS: based on these findings, we propose that PEA-OXA could be useful in decreasing the risk of impairment or improving function in ischemia/reperfusion brain injury-related disorders.


Assuntos
Complicações do Diabetes , Etanolaminas/farmacologia , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/metabolismo , Ácidos Palmíticos/farmacologia , Substâncias Protetoras/farmacologia , Sirtuína 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Degranulação Celular , Citocinas/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , NF-kappa B/metabolismo , Ratos , Sirtuína 1/genética , Proteína Desacopladora 2
10.
J Stroke Cerebrovasc Dis ; 28(11): 104365, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530482

RESUMO

A 64-year-old woman was admitted to our hospital 48 minutes after sudden onset of dysphasia and right hemiplegia. Head computed tomography revealed small infarcts in the left putamen and 4-dimensional computed tomography angiography depicted high-degree stenosis in the left middle cerebral artery and delayed filling of the contrast media in the left middle cerebral artery territory. The patient underwent intravenous tissue plasminogen activator treatment. On day 5 of hospitalization, the patient underwent conventional cerebral angiography, revealing internal carotid artery to middle cerebral artery dissection. Fortunately, subarachnoid hemorrhage as an adverse effect did not occur, although iv-tPA was administered without detecting middle cerebral artery dissection.


Assuntos
Angiografia Digital , Dissecação da Artéria Carótida Interna/diagnóstico por imagem , Angiografia Cerebral/métodos , Angiografia por Tomografia Computadorizada , Fibrinolíticos/administração & dosagem , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
11.
J Pharm Pharmacol ; 71(11): 1725-1733, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31523814

RESUMO

OBJECTIVES: Oxidative stress and inflammation have a critical role in the pathogenesis of ischaemic stroke. Alpha-pinene is a monoterpenoid molecule with anti-inflammatory and antioxidant properties. The nobility of the present study was to evaluate the neuroprotective effect of α-pinene in ischaemic stroke. METHODS: Ischaemic stroke was induced by transient middle cerebral artery occlusion followed by 24 h reperfusion in male Wistar rats. Alpha-pinene (25, 50 and 100 mg/kg, i.p.) was administered in the beginning of reperfusion. Then, the neurobehavioural function, infarct volume, brain oedema, antioxidant enzyme activity and the concentration of malondialdehyde (MDA), nitric oxide (NO) and interleukin-6 (IL-6) were evaluated by different methods in the brain. KEY FINDINGS: Alpha-pinene (50 and 100 mg/kg) elicited a significant decrease in the brain oedema and infarct size as well as an improvement in the neurobehavioural function. Besides, α-pinene (100 mg/kg) restored the function of superoxide dismutase, catalase and glutathione peroxidase and reduced the concentration of MDA, NO and IL-6 in the hippocampus, cortex and striatum. CONCLUSIONS: It was ultimately attainted that α-pinene exerts neuroprotective effect in ischaemic stroke in rat through the restoration of antioxidant enzymes activity, attenuation of lipid peroxidation and reduction of inflammation in the ischaemic brains.


Assuntos
/farmacologia , Isquemia Encefálica/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Isquemia Encefálica/metabolismo , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Acidente Vascular Cerebral/metabolismo , Superóxido Dismutase/metabolismo
12.
Mol Med Rep ; 20(4): 3942-3950, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485662

RESUMO

Intracarotid cold saline infusion (ICSI) brings about neuroprotective effects in ischemic stroke. However, the involvement of serum and glucocorticoid­regulated kinase 1 (SGK1) in the underlying mechanism of ICSI is not fully understood; therefore, we used the rat middle cerebral artery occlusion (MCAO) model to investigate the neuroprotective effects of ICSI on ischemic stroke in rats, as well as the involvement of SGK1 in these effects. ICSI decreased infarct size and brain swelling, as determined by 2,3,5­triphenyltetrazolium chloride staining and the dry­wet weight method, respectively. The results of terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) and Nissl staining showed that ICSI also suppressed apoptosis and increased the relative integral optical density (IOD) values of Nissl bodies in the rat MCAO model. Regarding the mechanism, the results of immunohistochemistry and western blotting revealed that ICSI upregulated SGK1 expression and downregulated beclin­1 and LC­3 expression in the rat MCAO model. In addition, SGK1 knockdown increased ICSI­mediated infarct size and brain swelling, promoted apoptosis, and reduced the IOD values of Nissl bodies in the rat MCAO model. In addition, we found that SGK1 knockdown upregulated beclin­1 and LC­3 expression mediated by ICSI. Overall, ICSI had a neuroprotective effect on ischemic stroke after reperfusion by upregulating SGK1 and inhibiting autophagy.


Assuntos
Proteínas Imediatamente Precoces/genética , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Solução Salina/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/genética , Edema Encefálico/patologia , Temperatura Baixa , Proteínas Imediatamente Precoces/análise , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infusões Intra-Arteriais , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Proteínas Serina-Treonina Quinases/análise , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Solução Salina/administração & dosagem
13.
Biomed Pharmacother ; 118: 109260, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31548176

RESUMO

OBJECTIVE: Cerebral ischemia reperfusion injury (CIRI) is a major cause of ischemic stroke (IS) deterioration. Considering the intricate mechanism of the pathological process of CIRI, most drugs only work on one target. The neurovascular unit (NVU) puts forward the concept of neuroprotection from nerve protection to global stabilization. The NVU plays an important role in maintaining the brain microenvironment. This would promote neuronal survival and overall neurological recovery, which would likely lead to the reduction of mortality rate. Previous studies have shown that 4-methoxy benzyl alcohol (4-MA) ameliorated neurological score and cerebral infarct volume and reduced the concentration of Evans blue (EB) in brain tissue. In this research, we investigated the effects of 4-MA on NVU microenvironment improvement in rats impaired by middle cerebral artery occlusion/reperfusion (MCAO/R). METHODS: First, we established a rat model of middle cerebral artery occlusion (MCAO) so as to use Western blot analysis, immunofluorescence and transmission electron microscopy (TEM) evaluating the NVU's protection of 4-MA. Then we established a primary cortical neuron model of oxygen glucose deprivation and re-oxygenation (OGD/R) with the objective of identifying whether 4-MA exhibited anti-oxidant and anti-apoptotic effects on neurons. RESULTS: NVU ultra structural changes were improved by 4-MA. Immunofluorescence and western blot showed that 4-MA protected NVUs through enhancement of the expression of the symbolic neuronal proteins Microtubule Associated Protein-2(MAP-2), and attenuation of protein expression of Asy symbolic protein Glial Fibrillary Acidic Protein(GFAP). Furthermore, in the OGD/R model of I/R injury in vitro, 4-MA significantly increased Superoxide dismutase(SOD), Nitric Oxide(NO), B-cell lymphoma-2(Bcl-2), decreased Bcl-2-Associated X(Bax) and increased Bcl-2/Bax. CONCLUSION: 4-MA can play the role of anti-ischemic stroke drug by ameliorating the microenvironment of NVUs while its neuroprotective effects will contribute towards the inhibition of the antioxidant and anti-apoptotic activities.


Assuntos
Álcool Benzílico/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo
14.
J Stroke Cerebrovasc Dis ; 28(11): 104288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31395423

RESUMO

PURPOSE: The present study was to observe the therapeutic efficiency of Clematichinenoside (AR) on cerebral ischemic injury in rats, especially on neurological and motor function recovery and to explore the underlying mechanism. METHODS: Following middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, rats were treated orally with 32, 16, and 8 mg/kg AR respectively for 14 days during which cerebral injury was evaluated and proinflammatory factors tumor necrosis factor-α and interleukin-6 as well as neurotrophic factors brain-derived neurotrophic factor and Neurotrophin-3 levels were determined with ELISA kits. Immunohistochemical analysis on number of neurons and reactive astrocytes in the hippocampus was to demonstrate the effect of AR on neuronal survival. Motor, learning, and memory recovery were assessed by Morris water maze, passive avoidance experiment, and rotatory rod test. Neuroprotection and anti-inflammation-related Notch and nuclear factor-κB (NF-κB) signaling pathways were analyzed by PCR and Western blot techniques on mammalian achaete-scute homologs1, Notch-1, intracellular Notch receptor domain, Jagged-1, transcription factor hairy, enhancer of split1 (Hes1), as well as the nuclear import of NF-κB in hippocampus. RESULTS: AR administration reduced cerebral injury in rats exposed to MCAO/R and after treatment of AR for 14 days, proinflammatory reaction was inhibited, with neuronal survival rate raised and motor function recovery facilitated. PCR and WB analysis of Notch/NF-κB signaling pathway revealed the inhibitory effect of AR on pathway related components. CONCLUSIONS: AR is beneficial to recovery of neurological and motor function in rats after cerebral ischemic injury via inhibiting Notch/NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptor Notch1/metabolismo , Saponinas/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/psicologia , Masculino , Memória/efeitos dos fármacos , Neurotrofina 3/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais
15.
Int Immunopharmacol ; 75: 105760, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323530

RESUMO

Neuroinflammation crucially influences functional recovery after ischemic stroke. Wnt-3a, a novel Wnt protein that specifically promotes Wnt/ß-catenin signaling pathway, has been shown to regulate apoptosis and cell proliferation, but how it affects ischemic stroke-induced toxic brain inflammation remains unknown. Using a transient middle cerebral artery occlusion (tMCAO) mouse model in this study, we found that intranasal Wnt-3a-treated tMCAO mice had apparently reduced infarct volume and decreased brain water content after being allowed to recover for 72 h, as well as better neurologic outcomes on days 3, 7, and 14. Mice received Wnt-3a had significantly fewer tMCAO-induced peri-infarct TUNEL-positive cells compared with those received vehicle. Further, Wnt-3a-delivered tMCAO mice had notably fewer peri-infarct CD68-positive cells and lower ionized calcium-binding adapter molecule (Iba)-1 protein level. Wnt-3a significantly downregulated the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α, and upregulated the expression of arginase 1 (Arg1) and CD206. Finally, Wnt-3a obviously decreased the number of tMCAO-induced peri-infarct glial fibrillary acidic protein (GFAP)/C3-positive cells, increased the number of GFAP/S100A10-positive cells, attenuated the protein levels of GFAP and interleukin 15 (IL15), and elevated IL33 protein level. Our findings suggest that intranasal Wnt-3a could ameliorate toxic responses of microglia/macrophages and astrocytes in ischemic brain injury, supporting that Wnt-3a might be potentially appropriate for ischemic stroke treatment functioning as an immunomodulatory agent.


Assuntos
Fatores Imunológicos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Proteína Wnt3A/uso terapêutico , Administração Intranasal , Animais , Astrócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos
16.
Cells ; 8(7)2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323885

RESUMO

Neuroinflammation is a major cause of central nervous system (CNS) damage and can result in long-term disability and mortality. Therefore, the development of effective anti-neuroinflammatory agents for neuroprotection is vital. To our surprise, the naturally occurring molecule alantolactone (Ala) was reported to significantly inhibit tumor growth and metastasis as a result of its excellent anti-inflammatory effects. Thus, we proposed that it could also act as an anti-neuroinflammatory agent. Thus, in this study, a coculture system of BV2 cells and PC12 cells were used as an in vitro neuroinflammatory model to investigate the anti-neuroinflammatory mechanism of Ala. The results indicated that Ala downregulated the expression of proinflammatory factors by suppressing the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Further evaluation using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model supported the conclusion that Ala could (1) alleviate cerebral ischemia-reperfusion injury; (2) reduce neurological deficits, cerebral infarct volume, and brain edema; and (3) attenuate the apoptosis and necrosis of neurons. In sum, Ala demonstrates anti-neuroinflammatory properties that contribute to the amelioration of CNS damage, and it could be a promising candidate for future applications in CNS injury treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lactonas/uso terapêutico , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Ratos , Ratos Sprague-Dawley , Sesquiterpenos de Eudesmano/uso terapêutico
17.
Mol Med Rep ; 20(3): 2365-2372, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322214

RESUMO

The current study used a rat middle cerebral artery occlusion (MCAO) model with the aim to explore the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain ischemia/reperfusion injury in rats. Improvement in the infarct­side microcirculation and the overall recovery of neurological function were detected by triphenyltetrazolium chloride staining, laser speckle blood flow monitoring, latex perfusion, immunofluorescence and immunoblotting. The results revealed that administration of CPCGI for 7 consecutive days following ischemic stroke contributed to the recovery of neurological function and the reduction of cerebral infarct volume in rats. Blood flow monitoring results demonstrated that the administration of CPCGI effectively promoted cerebral blood flow following stroke, and contributed to the protection of the ischemic side blood vessels. In addition, CPCGI treatment increased the numbers of new blood vessels in the peripheral ischemic region, and upregulated the expression levels of vascular endothelial growth factor, angiopoietin 1 and its receptor TEK receptor tyrosine kinase, fibroblast growth factor and Wnt signaling pathway­associated proteins. Taken together, the present results indicated that CPCGI improved the blood circulation and neurological function following cerebral ischemia/reperfusion in rats.


Assuntos
Cerebrosídeos/uso terapêutico , Gangliosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cerebrosídeos/administração & dosagem , Gangliosídeos/administração & dosagem , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia
18.
J Ethnopharmacol ; 242: 112051, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279072

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHWD) is used in classical traditional Chinese medicine to prevent and treat cerebral ischemia. Glycosides, which are effective components extracted from BYHWD, mainly include astragaloside IV, paeoniflorin, and amygdalin. These glycosides are the primary pharmacologically effective constituents of BYHWD that act against cerebral ischemic nerve injury; however, the mechanism of action of BYHWD is still unclear. AIM OF THE STUDY: The present study aimed to determine the effect of BYHWD glycosides on pyroptosis after cerebral ischemia reperfusion injury and explore whether its mechanism involves the classical pyroptosis pathway mediated by NLRP3. MATERIAL AND METHODS: Adult male Sprague-Dawley rats (n = 140) were randomly divided into seven groups: sham, cerebral ischemia and reperfusion (I/R), glycosides (0.064 g/kg, 0.128 g/kg, and 0.256 g/kg), BYHWD, and AC-YVAD-CMK (caspase-1 inhibitor). A rat model of cerebral I/R was established via classic middle cerebral artery occlusion (MCAO) for 2 h, followed by 24-h reperfusion. Neurological function was estimated using neurological defect scores. Brain infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and nerve cell damage was evaluated by Nissl staining. Pyroptosis was detected using TUNEL and caspase-1 immunofluorescence double staining. Protein expression of NLRP3, ASC, caspase-1, pro-caspase-1, and IL-1ß was analyzed using Western blot analysis. RESULTS: Glycosides improved neurological dysfunction, alleviated neuronal damage, and inhibited neuronal pyroptosis. The 0.128 g/kg glycosides group showed the most significant effects. Furthermore, we observed that this group showed significant inhibition of the expression of NLRP3, ASC, pro-caspase-1, caspase-1, and IL-1ß proteins of the NLRP3-mediated classical pathway of pyroptosis. CONCLUSIONS: Glycosides exert neuroprotective effects by inhibiting pyroptosis of neurons after cerebral I/R injury. The underlying mechanism of action is closely related to the regulation of the classical pyroptosis pathway by NLRP3.


Assuntos
Medicamentos de Ervas Chinesas , Glicosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Caspase 1/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Interleucina-1beta/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piroptose/efeitos dos fármacos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo
19.
J Stroke Cerebrovasc Dis ; 28(10): 104276, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31350168

RESUMO

BACKGROUND: We tested the hypothesis that inhibition of p70 ribosomal S6 kinase (S6K1) would decrease infarct size and improve microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. METHODS: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 hour and reperfusion for 2 hours with or without PF-4708671 (S6K1 inhibitor, 75 mg/kg, 15 minutes after blockade). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small vessel (20-60 µm diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. RESULTS: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O2 saturation (23 of 80 veins with O2 saturation below 45%). PF-4708671 did not significantly alter cerebral blood flow or O2 consumption. However, it significantly reduced the number of small veins with low O2 saturations in the reperfused region (6 of 80 veins with O2 saturation below 45%). This was associated with a significantly reduced cortical infarct size after S6K1 inhibition (12.9 ± .8% control versus 6.6 ± .3% PF-4708671). CONCLUSION: This suggests that S6K1 inhibition is important for cell survival and that it reduces the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Piperazinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo
20.
J Mol Neurosci ; 69(2): 333-342, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31290093

RESUMO

Identifying novel neuroprotectants that can halt or reverse the neurological effects of stroke is of interest to both clinicians and scientists. We and others previously showed the pre-clinical neuroprotective efficacy of neuregulin-1 (NRG-1) in rats following focal brain ischemia. In this study, we examined neuroprotection by exogenous and endogenous NRG-1 using a mouse model of ischemic stroke. C57BL6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by reperfusion. NRG-1 or vehicle was infused intra-arterially (i.a.) or intravenously (i.v.) after MCAO and before the onset of reperfusion. NRG-1 treatment (16 µg/kg; i.a.) reduced cerebral cortical infarct volume by 72% in mice when delivered post-ischemia. NRG-1 also inhibited neuronal injury as measured by Fluoro Jade B labeling and rescued NeuN immunoreactivity in neurons. Neuroprotection by NRG-1 was also observed in mice when administered i.v. (100 µg/kg) in both male and female mice. We investigated whether endogenous NRG-1 was neuroprotective using male and female heterozygous NRG-1 knockout mice (NRG-1+/-) compared with wild-type mice (WT) littermates. NRG-1+/- and WT mice were subjected to MCAO for 45 min, and infarct size was measured 24 h following MCAO. NRG-1+/- mice displayed a sixfold increase in cortical infarct size compared with WT mice. These results demonstrate that NRG-1 treatment mitigates neuronal damage following cerebral ischemia. We further showed that reduced endogenous NRG-1 results in exacerbated neuronal injury in vivo. These findings suggest that NRG-1 represents a promising therapy to treat stroke in human patients.


Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Neuregulina-1/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Feminino , Heterozigoto , Infarto da Artéria Cerebral Média/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuregulina-1/genética
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