Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.243
Filtrar
1.
World Neurosurg ; 133: e31-e61, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31415895

RESUMO

BACKGROUND: The association between matrix metalloproteinase 9 (MMP-9) gene -1562C/T (rs3918242) polymorphism and the susceptibility of ischemic stroke (IS) has been investigated. However, results were ambiguous and inconsistent. Therefore, we performed this study to better assess the potential relationship between rs3918242 polymorphism and susceptibility risk of IS. METHODS: We included case-control studies concerning the relationship between the rs3918242 polymorphism and IS, and odds ratios with corresponding 95% confidence intervals were used to describe the associations. Furthermore, meta-regression analyses, heterogeneity, cumulative analyses, sensitivity analyses, and publication bias were examined. RESULTS: A total of 19 studies were included for analysis. Significant associations with the risk of IS were detected for the rs3918242 polymorphism in overall population, Asians, and whites. When available data were stratified by gender, we found a significant correlation with the risk of IS in both males and females. Further subgroup analysis by the subtypes of IS showed that the rs3918242 polymorphism was significantly correlated with the risk of patients with large artery atherosclerosis. When stratified by age, we found that the rs3918242 polymorphism was significantly correlated with the risk of IS in patients both aged ≥65 years and >65 years. Both the diabetes and the nondiabetes subgroups reached significant results, and in an analysis stratified by smoking status, an increased risk of IS was associated with smoking. CONCLUSIONS: The rs3918242 polymorphism may be a susceptible predictor of susceptibility of IS. Further large-scale studies are needed to verify the results of our findings.


Assuntos
Isquemia Encefálica/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Adulto , Distribuição por Idade , Idoso , Aterosclerose/epidemiologia , Isquemia Encefálica/enzimologia , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Fumar Cigarros/epidemiologia , Comorbidade , Intervalos de Confiança , Diabetes Mellitus/epidemiologia , Grupos Étnicos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Embolia Intracraniana/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Distribuição por Sexo
2.
BMC Neurol ; 19(1): 291, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31735164

RESUMO

BACKGROUND: Mutations of cyclooxygenase gene (COX gene) may increase the susceptibility of ischemic stroke. We investigated five variants (rs5788, rs1330344, rs3842788, rs20417, and rs689466) of two COX genes in order to explaining the association between these polymorphisms and we also investigated the association between these variants and ischemic stroke risk to determine whether gene-gene interaction between these genes increases the susceptibility of ischemic stroke or its subtypes. METHODS: A total of 1981 study subjects (1078 cases and 903 control subjects) were recruited. The interaction of multiple factors was investigated using Multifactor Dimensionality Reduction. The additive effect of single nucleotide polymorphisms on ischemic stroke or its subtypes were analyzed by multiple factor logistic regression. RESULTS: At COX-1(rs1330344), AA genotype carriers had a lower susceptibility of ischemic stroke (OR = 0.657, 95%CI = 0.437-0.988, P = 0.044), and A allele carriers had a lower susceptibility of ischemic stroke (OR = 0.812, 95%CI = 0.657-0.978, P = 0.029). At COX-1(rs3842788), AA genotype carriers had a higher susceptibility of ischemic stroke (OR = 5.203, 95% CI = 1.519-5.159, P = 0.016). At COX-2 (rs689466), AA genotype carriers had a higher susceptibility of large-artery atherosclerosis (OR = 1.404, 95% CI = 1.019-1.934, P = 0.038). COX-1(rs1330344, rs3842788) and COX-2 rs689466 interacted in SVO, but had no additive effect with ischemic stroke and other subtypes. CONCLUSIONS: At rs1330344, AA genotype may reduce the susceptibility of ischemic stroke. At rs3842788, AA genotype may increase the susceptibility of ischemic stroke. At rs689466, AA genotype may increase the susceptibility of large-artery atherosclerosis (LAA). COX - 1(rs1330344, rs3842788) and COX-2 rs689466 interacted in small vessel occlusion (SVO), but had no additive effect with ischemic stroke and other subtypes.


Assuntos
Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Predisposição Genética para Doença/genética , Acidente Vascular Cerebral/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/enzimologia , Aterosclerose/genética , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/enzimologia
3.
Biol Pharm Bull ; 42(9): 1569-1574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474717

RESUMO

The pathophysiological mechanism of central post-stroke pain (CPSP) is complicated and not well understood. Recently, it has been reported that an increase in the levels of spinal nitric oxide synthetase (NOS) occurs in cerebral ischemia, and spinal NOS is involved in the development of neuropathic pain. The aim of this study was to elucidate the mechanism of spinal NOS signaling in the development of CPSP. Male ddY mice were subjected to 30-min long bilateral carotid artery occlusion (BCAO). The withdrawal responses to mechanical stimuli were significantly increased as determined with von Frey test on days 1 and 3 after BCAO. Protein expression of spinal N(G),N(G)-dimethylarginine dimethylaminohydralase 1 (DDAH1), a key enzyme involved in the metabolism of the endogenous NOS, increased on day 1 after BCAO, but not on day 3. Intrathecal (i.t.) injection of PD404182, a DDAH1 inhibitor, significantly suppressed mechanical allodynia on day 1, but not on day 3 after BCAO. In addition, i.t. administration of NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, significantly blocked mechanical allodynia on days 1 and 3 after BCAO. Furthermore, BCAO-induced increment of spinal NOS activity was inhibited by the pretreatment with PD404182. These results suggest that mechanical allodynia in the early stage of CPSP is caused by increment of NOS activity through upregulated DDAH1 in the spinal cord.


Assuntos
Amidoidrolases/metabolismo , Isquemia Encefálica/complicações , Hiperalgesia/etiologia , Neuralgia/etiologia , Óxido Nítrico Sintase/metabolismo , Medula Espinal/enzimologia , Animais , Isquemia Encefálica/enzimologia , Hiperalgesia/enzimologia , Masculino , Camundongos Endogâmicos , Neuralgia/enzimologia , Transdução de Sinais
4.
Mol Med Rep ; 20(2): 863-870, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173191

RESUMO

CaMKII is a calcium­activated kinase, proved to be modulated by oxidation. Currently, the oxidative activation of CaMKII exists in several models of asthma, chronic rhinosinusitis with nasal polyps, cardiovascular disease, diabetes mellitus, acute ischemic stroke and cancer. Oxidized CaMKII (ox­CaMKII) may be important in several of these diseases. The present review examines the mechanism underlying the oxidative activation of CaMKII and summarizes the current findings associated with the function of ox­CaMKII in inflammatory diseases. Taken together, the findings of this review aim to improve current understanding of the function of ox­CaMKII and provide novel insights for future research.


Assuntos
Asma/enzimologia , Isquemia Encefálica/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Doenças Cardiovasculares/enzimologia , Diabetes Mellitus/enzimologia , Pólipos Nasais/enzimologia , Neoplasias/enzimologia , Sinusite/enzimologia , Animais , Asma/tratamento farmacológico , Asma/genética , Asma/patologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Ativação Enzimática , Expressão Gênica , Humanos , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/genética , Pólipos Nasais/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Oxirredução , Estresse Oxidativo , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sinusite/tratamento farmacológico , Sinusite/genética , Sinusite/patologia
5.
J Vet Med Sci ; 81(7): 1047-1054, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31092742

RESUMO

Quercetin is a plant flavonoid that has anti-oxidant, anti-inflammatory, anti-cancer, and anti-ischemic properties. Moreover, quercetin exerts neuroprotective effects against focal cerebral ischemia. Protein phosphatase 2A (PP2A) is a form of serine/threonine phosphatase that modulates various biological functions. Among PP2A subunit types, subunit B exists abundantly in brain tissue and plays an essential function in nervous system. We previously reported the decrease of PP2A subunit B in focal cerebral animal model. This study explored the change of PP2A subunit B expression by quercetin treatment in cerebral ischemic animal model and glutamate-treated hippocampal-derived (HT22) cell culture. Quercetin (10 mg/kg) or vehicle was injected intraperitoneally into male rats before 30 min of middle cerebral artery occlusion (MCAO), and cerebral cortices were isolated 24 hr after MCAO. MCAO induced the neurological behavioral deficit and increased infarct volume. However, quercetin treatment attenuated the increase of neurological deficit and infarction. We detected the alleviation of MCAO-induced the decrease in PP2A subunit B by quercetin treatment using a proteomic approach. Reverse-transcription PCR and Western blot analyses confirmed lower PP2A subunit B expression levels in MCAO group with vehicle. However, quercetin treatment attenuated MCAO-induced this reduction. We also observed the neuroprotective effect of quercetin and the change of PP2A subunit B expression in glutamate-exposed HT22 cells. Glutamate exposure dramatically reduced cell viability and PP2A subunit B expression, and quercetin treatment significantly improved these decreases. We clearly showed that quercetin performs a neuroprotective function and modulates down-regulation of PP2A subunit B against MCAO injury and glutamate toxicity. Thus, our finding suggests that the regulation of PP2A subunit B by quercetin contributes to neuroprotective function in ischemic brain injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Ácido Glutâmico/toxicidade , Fármacos Neuroprotetores/farmacologia , Proteína Fosfatase 2/metabolismo , Quercetina/farmacologia , Animais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/etiologia , Linhagem Celular Transformada , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Proteína Fosfatase 2/genética , Ratos Sprague-Dawley
6.
J Stroke Cerebrovasc Dis ; 28(7): 1860-1865, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31064695

RESUMO

BACKGROUND AND PURPOSE: Previous studies have shown that common variants within CYP3A4 and CYP3A5 are associated with statin pharmacokinetics and the risk of cardiovascular disease. However, the association of variants in CYP3A4 and CYP3A5 with the prognosis of ischemic stroke remains undetermined. Therefore, we investigated this herein. METHODS: Four hundred thirty-three consecutive patients with acute ischemic stroke were recruited. The outcome at the 1-year follow-up was assessed using the modified Rankin Scale (mRS). Two variants, CYP3A4*1G and CYP3A5*3, were genotyped by the improved Multiple Ligase Detection Reaction platform. RESULTS: Binary logistic regression analysis showed that the CYP3A4*1G/*1G homozygote was associated with poor outcome at 1 year (mRS score ≥2) after adjustment for conventional factors in the additive model (odds ratio [OR] = 2.92; 95% confidence interval, 1.07-7.98; P = .037) and recessive model (OR = 3.37; 95% confidence interval, 1.26-9.04; P = .016). Subgroup analysis indicated that the CYP3A4*1G/*1G homozygote was associated with poor prognosis at 1 year among patients with stable high-intensity atorvastatin therapy (40-80 mg/d) after adjustment for conventional factors in the additive model (OR = 8.16; 95% confidence interval, 1.50-44.44; P = .015) and recessive model (OR = 9.06; 95% confidence interval, 1.72-47.64; P = .009). No significant association was identified between CYP3A5*3 and the 1-year outcome of patients with ischemic stroke. CONCLUSIONS: Our study findings suggest that the CYP3A4*1G/CYP3A4*1G genotype may be associated with poor prognosis at 1 year after acute ischemic stroke in the Han Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/genética , Citocromo P-450 CYP3A/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Atorvastatina/administração & dosagem , Atorvastatina/farmacocinética , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Isquemia Encefálica/etnologia , China/epidemiologia , Citocromo P-450 CYP3A/metabolismo , Avaliação da Deficiência , Feminino , Frequência do Gene , Homozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Prevenção Secundária/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/etnologia , Fatores de Tempo , Resultado do Tratamento
7.
Turk J Med Sci ; 49(2): 589-594, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30997974

RESUMO

Background/aim: We aimed to investigate the associations between endothelial nitric oxide synthase(eNOS) gene polymorphisms [G894T (rs1799983)], intron 4 (27-bpTR) variable number tandem repeat (VNTR) and T786C (rs2070744), and ischemic stroke in the Anatolian population. Materials and methods: This case-control study included 112 patients with "stroke of undetermined etiology" and 160 controls. Real-time polymerase chain reaction (RT-PCR) analysis was used to analyze these polymorphisms. Between-group frequencies of alleles and genotypes were compared using binary logistic regression analysis. Results: No significant difference was observed between the two groups in terms of the genotype and allele distributions of the eNOS G894T (rs1799983) polymorphism (P > 0.05). The a alleles and the 4b/a and 4a/a genotypes of the intron 4 (27-bpTR) VNTR polymorphism had significantly higher frequencies in the patient group than in the control group (OR: 2.715, P < 0.001; OR: 3.396, P < 0.001; OR: 10.631, P = 0.016, respectively). On the contrary, the TC genotype and C alleles of the T786C (rs2070744) polymorphism had a significantly lower frequency in the patient group than in the control group (OR: 0.244, P < 0.001, OR: 0.605, P = 0.006, respectively) Conclusion: Our findings indicate that the eNOS G894T and T786C [rs2070744] polymorphisms are not associated with the risk of ischemic stroke, whereas the intron 4 [27-bpTR] VNTR may be a risk factor in the Anatolian population.


Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença/genética , Íntrons/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/fisiopatologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Repetições Minissatélites/genética , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/fisiopatologia
8.
Restor Neurol Neurosci ; 37(2): 131-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988241

RESUMO

BACKGROUND: Cerebellar fastigial nucleus electrical stimulation (FNS) in rats has been shown to protect against brain ischemia/reperfusion (I/R) damage. Activation of telomerase has been reported to provide neuroprotection in animal models of stroke. OBJECTIVE: The aim of this study was to explore whether precondition FNS increases the expression of telomerase reverse transcriptase (TERT) and telomerase activity in rats after cerebral I/R injury. METHODS: One day after continuous stimulation of the fastigial cerebellar nucleus for 1 h, adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 24 h, 48 h and 72 h, while the I/R control groups received the same treatment without FNS. Ischemic lesion volumes were measured following TTC staining. The number of apoptotic cells was measured by using TUNEL assays. Subsequently, telomerase activity was examined by using TRAP-silver staining. Additionally, the expression level of TERT mRNA was assessed by using real-time fluorescence quantitative PCR. Finally, the expression of TERT protein was measured by using Western blotting. RESULTS: The results of our study demonstrated that FNS significantly decreased infarct volumes and improved neurological deficits when compared with the I/R control group. The telomerase activity in the I/R + FNS group was significantly increased compared with that in the I/R control group, particularly in the 24 h reperfusion subgroup (P < 0.05). FNS treatment significantly decreased the number of TUNEL-positive cells when compared with that in the I/R control group. Expression of TERT gradually increased, with the peak occurring after or before 48 h reperfusion and the 24 h and 72 h reperfusion subgroups demonstrating higher expression than each I/R control group (P < 0.05). CONCLUSIONS: Our results show that pre-FNS exerts neuroprotective effects that may be achieved by upregulating the expression of TERT and then by increasing telomerase activity.


Assuntos
Isquemia Encefálica/enzimologia , Isquemia Encefálica/terapia , Estimulação Encefálica Profunda , Telomerase/metabolismo , Animais , Isquemia Encefálica/patologia , Núcleos Cerebelares , Modelos Animais de Doenças , Masculino , Neuroproteção/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/terapia , Regulação para Cima
9.
J Stroke Cerebrovasc Dis ; 28(1): 21-25, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30268369

RESUMO

BACKGROUND: Stroke is one of the most common causes of disability and death. Higher alkaline phosphatase (ALP) levels have been associated with poor functional outcomes and mortality in previous studies. We investigated alterations in serum ALP concentrations and functional outcomes in patients with acute ischemic stroke (AIS). METHODS: Patients with first-ever AIS were recruited to participate in the study. Serum ALP levels were measured using a Cobas Integra 400 Plus automatic biochemical analyzer, and severity of stroke was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score on admission. Functional outcome was measured using the modified Rankin scale 1 year after admission. RESULTS: Serum ALP concentration was increased in patients with AIS (81.75 ± 20.49 versus 69.93 ± 16.12 U/L, P = .000) and the optimal ALP cutoff point for diagnosing patients with AIS was 81.50 U/L, with a sensitivity of 49.5% and specificity of 78.9%. However, there was no significant correlation between ALP and NIHSS scores (r = .170, P = .085) and ALP was not significantly different between favorable and unfavorable functional outcomes (81.76 ± .60 versus 81.70 ± 20.54 U/L, P = .802). CONCLUSIONS: Serum ALP concentration, which was increased in patients with AIS, might represent a low-potency biomarker for the diagnosis of AIS. However, this was not significantly correlated with NIHSS scores or the functional outcome after 1 year.


Assuntos
Fosfatase Alcalina/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/enzimologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/enzimologia , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença
10.
Neurol Res ; 41(2): 118-124, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30417762

RESUMO

OBJECTIVES: Oxidative stress is a known risk factor for the pathogenesis of atherosclerosis, the main cause of ischemic stroke. Glutathione S-transferase (GST) omega-1 and omega-2, members of phase II enzymes, play a role in the antioxidant system. The single nucleotide polymorphisms (SNPs), C419A and A424G in GST omega genes can cause a decrease in enzyme activity. The aim of this study was to investigate the possible association between these polymorphisms and ischemic stroke risk in a Turkish population. METHODS: The genotypes and allele frequencies for 239 patients and 130 controls were determined by the PCR/RFLP method. No significant differences were found between patients and controls in terms of genotype and allele frequencies. RESULTS: The frequency of the polymorphic 'A' allele was 0.358 in patients and 0.342 in controls for the C419A polymorphism in the GSTO1 gene. The frequency of the polymorphic 'G' allele for GSTO2 A424G SNP was 0.370 in patients and 0.404 in controls. The combined homozygous wild type genotype 'CCAG' was significantly higher in control group than in the patients. CONCLUSION: No significant difference was observed between the stroke patients and controls in terms of genotypes and allele distributions. Double combine haplotype CCAA was found to be protective against ischemic stroke when compare to other haplotypes. However, different genotypes of GSTO1 and GSTO2 were observed to have effects on stroke risk in subgroups of diabetics and smokers. In conclusion, the current study is the first to report this finding.


Assuntos
Isquemia Encefálica/genética , Glutationa Transferase/genética , Acidente Vascular Cerebral/genética , Idoso , Isquemia Encefálica/enzimologia , Isquemia Encefálica/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/epidemiologia , Turquia/epidemiologia
11.
Behav Brain Res ; 359: 528-535, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30412737

RESUMO

Heme oxygenase (HO-1), which may be induced by Cobaltic protoporphyrin IX chloride (CoPPIX) or Rosiglitazone (Ros), is a neuroprotective agent that effectively reduces ischemic stroke. Previous studies have shown that the neuroprotective mechanisms of HO-1 are related to JNK signaling. The expression of HO-1 protects cells from death through the JNK signaling pathway. This study aimed to ascertain whether the neuroprotective effect of HO-1 depends on the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and further influences the JNK signal transmission through HO-1. Prior to the ischemia-reperfusion experiment, CoPPIX was injected through the lateral ventricle for 5 consecutive days or Ros was administered via intraperitoneal administration in the week prior to transient ischemia. Our results demonstrated that HO-1 could inhibit the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and could ultimately diminish the phosphorylation of JNK3. Furthermore, the inhibition of JNK3 phosphorylation downregulated the level of p-c-Jun and elevated neuronal cell death in the CA1 of the hippocampus. Taken together, these findings suggested that HO-1 could ameliorate brain injury by regulating the MLK3-MKK7-JNK3 signaling module, which was scaffolded by JIP1 and JNK signaling during cerebral ischemia/reperfusion.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Isquemia Encefálica/enzimologia , Heme Oxigenase (Desciclizante)/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/enzimologia , Região CA1 Hipocampal/patologia , Morte Celular/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Rosiglitazona/farmacologia
12.
Int J Biol Sci ; 14(12): 1745-1754, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30416389

RESUMO

Sensorimotor recovery following ischemic stroke is highly related with structural modification and functional reorganization of residual brain tissues. Manipulations, such as treatment with small molecules, have been shown to enhance the synaptic plasticity and contribute to the recovery. Activation of the cAMP/CREB pathway is one of the pivotal approaches stimulating neuroplasticity. Phosphodiesterase 4 (PDE4) is a major enzyme controlling the hydrolysis of cAMP in the brain. Accumulating evidences have shown that inhibition of PDE4 is beneficial for the functional recovery after cerebral ischemia; i. subtype D of PDE4 (PDE4D) is viewed as a risk factor for ischemic stroke; ii. inhibition of PDE4 enhances neurological behaviors, such as learning and memory, after stroke in rodents; iii.PDE4 inhibition increases dendritic density, synaptic plasticity and neurogenesis; iv. activation of cAMP/CREB signaling by PDE4 inhibition causes an endogenous increase of BDNF, which is a potent modulator of neuroplasticity; v. PDE4 inhibition is believed to restrict neuroinflammation during ischemic stroke. Cumulatively, these findings provide a link between PDE4 inhibition and neuroplasticity after cerebral ischemia. Here, we summarized the possible roles of PDE4 inhibition in the recovery of cerebral stroke with an emphasis on neuroplasticity. We also made some recommendations for future research.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/fisiopatologia , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/fisiopatologia
13.
Int J Mol Sci ; 19(10)2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30274381

RESUMO

While arterial reflow after a stroke represents an important challenge for better outcomes, it is also very important that sudden recanalization does not produce local oxidative and nitrogen species, deleterious for the brain and more particularly the immature brain. Our objective was to determine whether a supply in prostaglandin (Pg) E1 (Alprostadil), via its action on arterial pressure, might progressively improve cerebral reperfusion in a neonatal stroke model. Arterial blood flow was measured using ultrasonography. Rate-limiting and Pg terminal synthesizing enzymes were evaluated using reverse-transcriptase polymerase chain reaction. Our data suggests that a supply in PgE1 might delay and improve the ipsilateral reperfusion by decreasing thromboxane A synthase-1 gene, the density of reactive astrocytes and lesion volume.


Assuntos
Alprostadil/uso terapêutico , Circulação Colateral/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Alprostadil/farmacologia , Animais , Animais Recém-Nascidos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Ratos Wistar , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/enzimologia , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismo
14.
J Stroke Cerebrovasc Dis ; 27(12): 3563-3569, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30201457

RESUMO

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in GLA, which encodes the enzyme α-galactosidase A (α-Gal A). Although the prevalence of Fabry disease in patients with stroke has been reported to range from 0% to 4%, few cohort studies have examined Japanese stroke patients. We aimed to clarify the prevalence of Fabry disease and the frequency of GLA mutations among patients with young-onset stroke in Japan. METHODS: From April 2015 to December 2016, we enrolled patients with young-onset (≤60 years old) ischemic stroke or intracerebral hemorrhage. We measured α-Gal A activity and the concentration of globotriaosylsphingosine in plasma. Genetic evaluations were performed in patients with low α-Gal A activity or high concentrations of globotriaosylsphingosine. RESULTS: Overall, 516 patients (median age of onset, 52 years old; 120 women) were consecutively enrolled in this study. Five patients (4 men and 1 woman) had low α-Gal A activity, and no patients were detected with the screen for plasma globotriaosylsphingosine levels. The genetic analysis did not identify a causative mutation responsible for classic Fabry disease in any of the patients, but 2 patients (.4%) carried the p.E66Q in GLA. CONCLUSIONS: No patient with Fabry disease was detected in our young-onset stroke cohort.


Assuntos
Isquemia Encefálica/sangue , Hemorragia Cerebral/sangue , Doença de Fabry/sangue , Glicolipídeos/sangue , Esfingolipídeos/sangue , Acidente Vascular Cerebral/sangue , alfa-Galactosidase/sangue , Adulto , Idade de Início , Isquemia Encefálica/enzimologia , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Hemorragia Cerebral/enzimologia , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/genética , Doença de Fabry/enzimologia , Doença de Fabry/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Adulto Jovem , alfa-Galactosidase/genética
15.
Curr Mol Med ; 18(3): 142-151, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30198433

RESUMO

BACKGROUND: LKB1/AMPK signaling pathway, as a metabolic checkpoint, is involved in the pathogenesis of cerebral ischemia injury. Minocycline, a tetracycline derivative, protects against cerebral ischemia via reducing inflammation, oxidative stress, and apoptosis. The aim of the study was to evaluate the influence of minocycline on oxidative biomarkers and LKB1/AMPK signaling pathway in Wistar rats with focal cerebral ischemia injury and to clarify the neuroprotective mechanism of minocycline against focal cerebral ischemia injury. METHODS: The focal cerebral ischemia injury of Wistar rats was established by inserting a thread into the left middle cerebral artery. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to label infarct volume. The levels of MDA and LPO were measured with a biochemical assay. All other items were determined by Western blotting. RESULTS: Minocycline decreased cerebral infarct volume, but had no effects on neurological scores. Minocycline improved the biological activity of GPx-1/2, GSS and GR, while limited the GGT1 activity in the hippocampus of cerebral ischemia-reperfusion rats. Minocycline also elevated the biological activity of SOD and counteracted lipid peroxidation. Minocycline enhanced the activity of both LKB1 and the levels of the three AMPK subunits in the hippocampus of cerebral ischemia-reperfusion rats. CONCLUSION: Minocycline effectively inhibits oxidative stress via modulating antioxidative enzymes and activating the LKB1/AMPK signaling pathway in the process of acute cerebral infarct.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Isquemia Encefálica/tratamento farmacológico , Minociclina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/patologia , Masculino , Ratos , Ratos Wistar
16.
Mol Med Rep ; 18(4): 3957-3964, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30106098

RESUMO

Focal ischemia/reperfusion (I/R) injury induced cerebral inflammation, aggravates brain damage. The aim of the present study was to investigate the protective mechanisms of dexmedetomidine (DEX) on I/R brain injury in rats. Sprague­Dawley rats were divided to seven experimental groups (18 rats/group): Sham surgery; middle cerebral artery occlusion (MCAO) surgery (90 min); DEX10 [10 µg/kg intraperitoneal (i.p.) injection 30 min prior to MCAO]; DEX50 (50 µg/kg i.p. 30 min prior to MCAO); DEX100 (100 µg/kg i.p. 30 min prior to MCAO); DEX50+Yohimbine [YOH; 5 mg/kg 10 min prior to DEX (50 µg/kg i.p.) administration and MCAO] and YOH (5 mg/kg 40 min prior to MCAO). At 24 h post­MCAO surgery, neurological deficit was examined by staining damaged brain tissues with 2,3,5­triphenyltetrazolium chloride. Neuronal apoptosis in the cerebral cortex was histologically assessed by terminal deoxynucleotidyl­transferase­mediated dUTP nick end labeling staining, and the expression levels of phosphorylated (p)­AMP­activated protein kinase (AMPK; Thr172) was detected by western blotting. In addition, the expression levels of tumor necrosis factor (TNF)­α and interleukin (IL)­1ß were assessed by ELISA. At days 1, 2 and 5 following I/R, motor functions were assessed by an observer blinded to the study. The brain infarct size, neurological deficit scores, number of apoptotic neurons, expression levels of pro­inflammatory cytokines TNF­α and IL­1ß were increased following MCAO, whereas the motor function scores were reduced. Pretreatment with DEX prior to MCAO can reverse the effects induced by I/R. Compared with rats in the Sham group, the expression levels of p­AMPK were mildly increased in the MCAO group and highly increased in the three DEX­treatment groups. Pretreatment with YOH reversed the above effects of DEX and produced a similar level of cerebral I/R injury. The results demonstrated that precondition with DEX exhibited anti­inflammatory effects on brain ischemic injury mediated by AMPK signal pathway.


Assuntos
Adenilato Quinase/metabolismo , Isquemia Encefálica/tratamento farmacológico , Dexmedetomidina/uso terapêutico , Inflamação/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/enzimologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Dexmedetomidina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Inflamação/enzimologia , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia
17.
Neurosci Lett ; 687: 37-42, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30125643

RESUMO

Strokes occur predominantly in the elderly and white matter (WM) is injured in most strokes, contributing to the disability associated with clinical deficits. Casein kinase 2 (CK2) is expressed in neuronal cells and was reported to be neuroprotective during cerebral ischemia. Recently, we reported that CK2 is abundantly expressed by glial cells and myelin. However, in contrast to its role in cerebral (gray matter) ischemia, CK2 activation during ischemia mediated WM injury via the CDK5 and AKT/GSK3ß signaling pathways (Bastian et al., 2018). Subsequently, CK2 inhibition using the small molecule inhibitor CX-4945 correlated with preservation of oligodendrocytes as well as conservation of axon structure and axonal mitochondria, leading to improved functional recovery. Notably, CK2 inhibition promoted WM function when applied before or after ischemic injury by differentially regulating the CDK5 and AKT/GSK3ß pathways. Specifically, blockade of the active conformation of AKT conferred post-ischemic protection to young, aging, and old WM, suggesting a common therapeutic target across age groups. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, it is important to consider the potential benefits of CK2 inhibitors during an ischemic attack.


Assuntos
Isquemia Encefálica/enzimologia , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Naftiridinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Substância Branca/enzimologia , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Humanos , Naftiridinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
18.
Curr Pharm Des ; 24(20): 2229-2235, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30014798

RESUMO

Stroke is the second-leading cause of death and a leading cause of serious long-term disability worldwide, with an increasing global burden due to the growing and aging population. However, strict eligibility criteria for current treatment opportunities make novel therapeutic approaches desirable. Oxidative stress plays a pivotal role during cerebral ischemia, eventually leading to neuronal injury and cell death. The significant correlation between redox imbalance and ischemic stroke has led to various treatment strategies targeting the endogenous antioxidant system in order to ameliorate the adverse prognosis in patients with cerebral infarction. One of the most extensively investigated cellular defense pathway in this regard is the Nrf2-heme oxygenase-1 (HO-1) axis. In this review, our aim is to focus on the potential clinical relevance of targeting the HO-1 pathway in ischemic stroke.


Assuntos
Isquemia Encefálica/etiologia , Heme Oxigenase-1/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/enzimologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/antagonistas & inibidores , Humanos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Acidente Vascular Cerebral/etiologia
19.
Brain Res Bull ; 142: 156-162, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30016727

RESUMO

Conventional protein kinase C (cPKC)γ and synapsin Ia/b have been implicated in the development of ischemic stroke, but their relationships and functions are unclear. In the present study, the oxygen-glucose deprivation (OGD)-induced ischemic insult in primary cultured cortical neurons in vitro and middle cerebral artery occlusion (MCAO)-induced ischemic stroke model in vivo were used to elucidate the function of cPKCγ and its modulation on synapsin Ia/b phosphorylation in ischemic stroke. We found that cPKCγ knockout significantly increased the infarct volume of mice after 1 h MCAO/72 h reperfusion by using triphenyltetrazolium chloride (TTC) staining. In the primarily cultured cortical neurons, cPKCγ knockout also aggravated the OGD-induced cell death and morphological damage of neurites, while cPKCγ restoration could alleviate the ischemic injury. Among the five phosphorylation sites of synapsin Ia/b, only the phosphorylation levels of Ser549 and 553 could be modulated by cPKCγ in neurons following 0.5 h OGD/24 h reoxygenation. In addition, we found that cPKCγ and synapsin Ia/b could be reciprocally co-immunoprecipitated in the cerebral cortex of MCAO mice. Taken together, we proposed that cPKCγ alleviates ischemic injury through modulating Ser549/553- synapsin Ia/b phosphorylation in neurons of mice.


Assuntos
Isquemia Encefálica/enzimologia , Hipóxia Celular/fisiologia , Neurônios/enzimologia , Proteína Quinase C/deficiência , Traumatismo por Reperfusão/enzimologia , Sinapsinas/metabolismo , Aciltransferases/fisiologia , Animais , Isquemia Encefálica/patologia , Células Cultivadas , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Proteínas de Escherichia coli/fisiologia , Glucose/deficiência , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuritos/enzimologia , Neuritos/patologia , Neurônios/patologia , Neuroproteção/fisiologia , Cultura Primária de Células , Proteína Quinase C/genética , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/patologia
20.
eNeuro ; 5(3)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963617

RESUMO

Acute ischemic stroke (AIS) is caused by clotting in the cerebral arteries, leading to brain oxygen deprivation and cerebral infarction. Recombinant human tissue plasminogen activator (tPA) is currently the only Food and Drug Administration-approved drug for ischemic stroke. However, tPA has to be administered within 4.5 h from the disease onset and delayed treatment of tPA can increase the risk of neurovascular impairment, including neuronal cell death, blood-brain barrier (BBB) disruption, and hemorrhagic transformation. A key contributing factor for tPA-induced neurovascular impairment is activation of matrix metalloproteinase-9 (MMP-9). We used a clinically-relevant mouse embolic model of focal-cerebral ischemia by insertion of a single embolus of blood clot to block the right middle cerebral artery. We showed that administration of the potent and highly selective gelatinase inhibitor SB-3CT extends the time window for administration of tPA, attenuating infarct volume, mitigating BBB disruption, and antagonizing the increase in cerebral hemorrhage induced by tPA treatment. We demonstrated that SB-3CT attenuates tPA-induced expression of vascular MMP-9, prevents gelatinase-mediated cleavage of extracellular laminin, rescues endothelial cells, and reduces caveolae-mediated transcytosis of endothelial cells. These results suggest that abrogation of MMP-9 activity mitigates the detrimental effects of tPA treatment, thus the combination treatment holds great promise for extending the therapeutic window for tPA thrombolysis, which opens the opportunity for clinical recourse to a greater number of patients.


Assuntos
Isquemia Encefálica/enzimologia , Gelatinases/metabolismo , Ativador de Plasminogênio Tecidual/administração & dosagem , Animais , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/prevenção & controle , Caveolina 1/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Gelatinases/antagonistas & inibidores , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Laminina/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Camundongos Endogâmicos C57BL , Sulfonas/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA