Engeletin protects against cerebral ischemia/reperfusion injury by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways

Engeletin is a natural derivative of Smilax glabra rhizomilax that exhibits anti-inflammatory activity and suppresses lipid peroxidation. In the present study, we sought to elucidate the mechanistic basis for the neuroprotective and pro-angiogenic activity of engeltin in a human umbilical vein endothelial cells (HUVECs) oxygen-glucose deprivation and reoxygenation (OGD/R) model system and a middle cerebral artery occlusion (MCAO) rat model of cerebral ischemia and reperfusion injury. These analyses revealed that engeletin (10, 20, or 40 mg/kg) was able to reduce the infarct volume, increase cerebral blood flow, improve neurological function, and bolster the expression of vascular endothelial growth factor (VEGF), vasohibin-2 (Vash-2), angiopoietin-1 (Ang-1), phosphorylated human angiopoietin receptor tyrosine kinase 2 (p-Tie2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in MCAO rats. Similarly, engeletin (100, 200, or 400 nM) markedly enhanced the migration, tube formation, and VEGF expression of HUVECs in an OGD/R model system, while the VEGF receptor (R) inhibitor axitinib reversed the observed changes in HUVEC tube formation activity and Vash-2, VEGF, and CD31 expression. These data suggested that engeletin exhibited significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improved cerebrovascular angiogenesis by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways.

Effects of statin therapy on outcomes of ischemic stroke: a real-world experience in Brazil / Efeitos da terapia com estatinas nos desfechos do acidente vascular cerebral isquêmico: uma experiência de mundo real no Brasil

ABSTRACT Background: Statin therapy has become one of the most important advances in stroke secondary prevention. Objective: To provide evidence from real-world data for evaluating detailed associations between secondary prevention of stroke and statin use in Brazil. Methods: We conducted a prospective cohort study including consecutive patients diagnosed with an ischemic stroke. Subjects were classified into non-statin, simvastatin 20 mg, simvastatin 40 mg, and high-potency statin groups. We also registered the onset of statin therapy, previous use of statins, the adherence to medication, and if there was discontinuation of the therapy. After two years, the functional outcome, stroke recurrence, major cardiovascular events, and mortality were assessed. Results: Among the 513 patients included in our cohort, there were 96 (18.7%) patients without statins, 169 (32.9%) with simvastatin 20 mg, 202 (39.3%) with simvastatin 40 mg, and 46 (9.0%) with high-potency statins. Patients without statins were at increased risk of stroke recurrence and worse functional outcomes. Concerning etiology, evidence of beneficial use of statins was observed in cases of large-artery atherosclerosis, small-vessel occlusion, and stroke of undetermined cause. Those who presented poor adherence to statins or discontinuation of the treatment had worse prognosis after stroke whereas the early onset of statins use was associated with better outcomes. Patients with simvastatin 40 mg and high-potency statins presented the best functional recovery throughout the follow-up. Conclusions: Statins play an important role in the treatment of ischemic stroke, preventing stroke recurrence and cardiovascular events, and improving functional performance.

RESUMO Introdução: A terapia com estatinas tornou-se um dos avanços mais importantes na prevenção secundária do acidente vascular cerebral (AVC). Objetivo: Fornecer evidências de dados do mundo real para avaliar associações detalhadas entre a prevenção secundária do AVC e o uso de estatinas no Brasil. Métodos: Realizamos um estudo de coorte prospectivo, incluindo pacientes consecutivos com diagnóstico de AVC isquêmico. Os indivíduos foram classificados em grupos sem estatinas, sinvastatina 20 mg, sinvastatina 40 mg e estatina de alta potência. Também registramos o início da terapêutica com estatinas, o uso prévio de estatinas, a adesão à medicação e se houve descontinuação da terapia. Após dois anos, foram avaliados o resultado funcional, a recorrência do AVC, os principais eventos cardiovasculares e a mortalidade. Resultados: Entre os 513 pacientes incluídos em nossa coorte, havia 96 (18,7%) pacientes sem estatinas, 169 (32,9%) com sinvastatina 20 mg, 202 (39,3%) com sinvastatina 40 mg e 46 (9,0%) com estatinas de alta potência. Pacientes sem estatinas apresentaram maior risco de recorrência de AVC e piores resultados funcionais. Em relação à etiologia, foram observadas evidências do benefício das estatinas nos casos de aterosclerose de grandes artérias, oclusão de pequenos vasos e AVC de causa indeterminada. Aqueles com baixa adesão às estatinas ou que interromperam o uso tiveram pior prognóstico após o AVC, enquanto o início precoce do uso de estatinas foi associado a melhores resultados. Pacientes com sinvastatina 40 mg e estatinas de alta potência apresentaram melhor recuperação funcional ao longo do período de acompanhamento. Conclusões: As estatinas desempenham um importante papel no tratamento do AVC isquêmico, prevenindo sua recorrência e eventos cardiovasculares e melhorando o desempenho funcional.

Protective effect of extract of the Camellia japonica L. on cerebral ischemia-reperfusion injury in rats / Efeito protetor do extrato da Camellia japonica L. na lesão de reperfusão isquêmica cerebral em ratos

ABSTRACT Objective: We investigated the protective effect of the extract of the Camellia japonica L. flower on cerebral ischemia-reperfusion injury in rats. Methods: The rat ischemia-reperfusion injury was induced by middle cerebral artery occlusion for 90 minutes and reperfusion for 48 hours. The animals received an intravenous injection once a day of 20, 40, 80 mg/kg extract of C. japonica for three consecutive days before the ischemia reperfusion. The learning and memory function, the infarct volume, serum malondialdehyde (MDA) level and lactate dehydrogenase activity, and extravasation of immunoglobulin G (IgG) into cerebral parenchyma were assessed as the cell damage index. Results: Pretreatment with extract of C. japonica markedly reduced the infarct volume, serum malondialdehyde level and lactate dehydrogenase activity, and markedly inhibited the extravasation of IgG. Moreover, pretreatment with extract of C. japonica may also inhibit the learning and memory deficits induced by an ischemia-reperfusion injury. Conclusion: It was concluded that pretreatment with extract of C. japonica has a protective effect on cerebral ischemia-reperfusion injury in rats.

RESUMO Objetivo: Investigamos o efeito protetor do extrato da flor de Camellia japonica L. (ECJ) na lesão de reperfusão isquêmica cerebral (I/R) em ratos. Métodos: A lesão de I/R de rato foi induzida por uma oclusão da artéria cerebral média por 90 minutos e reperfusão por 48 horas. Os animais receberam uma injeção intravenosa uma vez ao dia de 20, 40, 80 mg/kg de ECJ por três dias consecutivos antes da I/R. A função de aprendizagem e memória, o volume do infarto, o nível sérico de malondialdeído (MDA), a atividade da desidrogenase láctica e o extravasamento de imunoglobulina (IgG) no parênquima cerebral foram avaliados como índices de dano celular. Resultados: O pré-tratamento com ECJ reduziu acentuadamente o volume do infarto, o nível sérico de MDA e a atividade da desidrogenase láctica, e inibiu marcadamente o extravasamento de IgG. Além disso, o pré-tratamento com ECJ também poderia inibir os déficits de aprendizado e memória induzidos pela lesão de I/R. Conclusão: O pré-tratamento com ECJ tem um efeito protetor contra lesão cerebral de I/R em ratos.

Efficacy of phosphocreatine pre-administration on XIAP and Smac in ischemic penumbra of rats with focal cerebral ischemia reperfusion injury

Abstract Purpose: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). Methods: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B <intraperitoneally injected with 20 mg/kg (10 mg/ml) of saline before preparing the ischemia-reperfusion (IR) model>, and group C <intraperitoneally injected with 20 mg/kg (10 mg/ml) of PCr immediately before preparing the IR model>. After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. Results: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. Conclusions: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.

Anticoagulation in patients with cardiac manifestations of Chagas disease and cardioembolic ischemic stroke / Anticoagulação nas manifestações cardíacas da doença de Chagas e acidente vascular cerebral isquêmico cardioembólico

ABSTRACT Objectives To describe anticoagulation characteristics in patients with cardiac complications from Chagas disease and compare participants with and without cardioembolic ischemic stroke (CIS). Methods A retrospective cohort of patients with Chagas disease, using anticoagulation, conducted from January 2011 to December 2014. Results Forty-two patients with Chagas disease who were using anticoagulation were studied (age 62.9±12.4 years), 59.5% female and 47.6% with previous CIS, 78.6% with non-valvular atrial fibrillation and 69.7% with dilated cardiomyopathy. Warfarin was used in 78.6% of patients and dabigatran (at different times) in 38%. In the warfarin group, those with CIS had more medical appointments per person-years of follow-up (11.7 vs 7.9), a higher proportion of international normalized ratios within the therapeutic range (57% vs 42% medical appointments, p = 0.025) and an eight times higher frequency of minor bleeding (0.64 vs 0.07 medical appointments). Conclusion Patients with Chagas disease and previous CIS had better control of INR with a higher frequency of minor bleeding.

RESUMO Objetivos descrever as características da anticoagulação em pacientes com manifestações cardíacas da doença de Chagas (MCDC) e comparar os participantes com sem acidente vascular cerebral isquêmico cardioembólico (AVCIC). Resultados 42 pacientes com MCDC em anticoagulação foram estudados (62,9 ± 12,4 anos), 59,5% do sexo feminino e 47,6% com AVCIC prévio, 78,6% portadores de fibrilação atrial não valvar e 69,7% com cardiomiopatia dilatada. Varfarina foi utilizada em 78,6% dos pacientes e dabigatrana em 38% (em momentos diferentes). No grupo da varfarina, aqueles com AVCIC tiveram mais consultas médicas por pessoas-ano de seguimento (11,7 vs 7,9), maior taxa de RNI na faixa terapêutica (57% vs 42% consultas médicas, p = 0,025) e uma frequência oito vezes maior de sangramento menor (0,64 vs. 0,07 consultas médicas). Conclusão pacientes com MCDC e AVCIC prévio têm melhor controle de RNI com maior frequência de sangramento menor.

Protective effect and mechanism of Lactobacillus on cerebral ischemia reperfusion injury in rats

The present study was designed to investigate the protective effects and mechanism of inactivated lactobacillus (ILA) on cerebral ischemia reperfusion injury (CIRI) in rats. In this experiment, 30 male Sprague Dawley rats were randomly divided into control group, IRI groups, and ILA group. A middle cerebral artery occlusion and reperfusion model was prepared. The rats were killed after 24 hours of recovery of blood flow of cerebral ischemia resulting from 60-min occlusion. The cerebral infarction volume and neurological scores were assayed by staining and behavioral observation. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assayed by biochemical kits. Cell apoptosis was assayed by Tunnel and the Toll-like receptor (TLR)-4, IkB, and A20 were assayed by western blot. The neurobehavioral scores in IRI rats were significantly lower compared to the control group while ILA improved the neurobehavioral scores of the ILA groups. The cerebral infarction volume and neural cell apoptosis of rats in the ILA groups decreased significantly compared with those in the IRI group. In addition, MDA level in the ILA groups decreased whereas SOD activity increased compared to the IRI group. Moreover, ILA also inhibited the expression of TLR-4 and promoted the expression of IkB and A20. ILA inhibited the apoptosis of neural cells, decreased cerebral infarction volume, and reduced oxidative stress through inhibition of TLR-4/NF-kappa B signaling, improving neurobehavioral scores. Thus from the present study it was concluded that ILA has protective effect on CIRI.

Retinoic acid protects from experimental cerebral infarction by upregulating GAP-43 expression

The aim of this study was to investigate whether exogenous retinoic acid (RA) can upregulate the mRNA and protein expression of growth-associated protein 43 (GAP-43), thereby promoting brain functional recovery in a rat distal middle cerebral artery occlusion (MCAO) model of ischemia. A total of 216 male Sprague Dawley rats weighing 300–320 g were divided into 3 groups: sham-operated group, MCAO+vehicle group and MCAO+RA group. Focal cortical infarction was induced with a distal MCAO model. The expression of GAP-43 mRNA and protein in the ipsilateral perifocal region was assessed using qPCR and immunocytochemistry at 1, 3, 7, 14, 21, and 28 days after distal MCAO. In addition, an intraperitoneal injection of RA was given 12 h before MCAO and continued every day until the animal was sacrificed. Following ischemia, the expression of GAP-43 first increased considerably and then decreased. Administration of RA reduced infarction volume, promoted neurological functional recovery and upregulated expression of GAP-43. Administration of RA can ameliorate neuronal damage and promote nerve regeneration by upregulating the expression of GAP-43 in the perifocal region after distal MCAO.

Histopathologic comparison of dexmedetomidine's and thiopental's cerebral protective effects on focal cerebral ischemia in rats / Comparação histopatológica dos efeitos protetores cerebrais de dexmedetomidina e tiopental sobre isquemia cerebral focal em ratos

Abstract This study was designed to investigate whether dexmedetomidine and thiopental have cerebral protective effects after focal cerebral ischemia in rats. Thirty male Sprague Dawley rats were randomly assigned to three groups: control group (Group C, n = 10), dexmedetomidine group (Group D, n = 10), thiopental group (Group T, n = 10). After all rats were anesthetized, they were intubated, then mechanically ventilated. A catheter was inserted into the right femoral artery for continuous mean arterial pressure, physiological parameters and blood sampling at baseline, 5 min after occlusion and 20 min after reperfusion. A catheter was inserted into the left femoral vein for intravenous (IV) medication administration. Right common carotid artery of each rat was isolated and clamped for 45 min. At the end of the duration common carotid artery were unclamped and the brain reperfusion was achieved for 90 min. Dexmedetomidine was administered for Group D IV infusion, and Group T received thiopental IV. According to histopathologic scores cerebral ischemia was documented in all rats in Group C, but no ischemia was found in three rats in Group T and in four rats in Group D. Grade 3 cerebral ischemia was documented in three rats in Group C, and in only one rat in both groups T and D. For histopathologic grades the difference between Group T and Group D was not significant (p > 0.05). But the differences between Group C and Group T (p < 0.05) and Group C and Group D (p < 0.01) were statically significant. In conclusion, we demonstrated that dexmedetomidine and thiopental have experimental histopathologic cerebral protective effects on experimental focal cerebral ischemia in rats.

Resumo Este estudo foi desenhado para investigar se dexmedetomidina e tiopental têm efeitos protetores cerebrais após isquemia cerebral focal em ratos. Trinta ratos da linhagem Sprague Dawley foram randomicamente alocados em três grupos: controle (Grupo C, n = 10), dexmedetomidina (Grupo D, n = 10) e tiopental (Grupo T, n = 10). Após a anestesia, foram intubados e ventilados mecanicamente. Um cateter foi inserido na artéria femoral direita para monitoração contínua da pressão arterial média (PAM) e dos parâmetros fisiológicos e para coleta de amostras de sangue na fase basal, 5 minutos após a oclusão e 20 minutos após a reperfusão. Um cateter foi inserido na veia femoral esquerda para administração intravenosa (IV) de medicamentos. A artéria carótida comum direita de cada rato foi isolada e pinçada durante 45 minutos. No fim dos 45 minutos, o pinçamento foi removido e a reperfusão do cérebro foi obtida por 90 minutos. Dexmedetomidina foi administrada por infusão IV no Grupo D e tiopental no Grupo T. De acordo com as pontuações histopatológicas, isquemia cerebral foi observada em todos os ratos do Grupo C, mas não foi encontrada em três ratos do Grupo T e em quatro ratos do Grupo D. O grau 3 de isquemia cerebral foi encontrada em três ratos do grupo C e em apenas um rato de ambos os grupos T e D. Para os graus histopatológicos, a diferença entre o Grupo T e o Grupo D não foi significativa (p > 0,05). Porém, as diferenças entre o Grupo C e o Grupo T (p < 0,05) e entre o Grupo C e o Grupo D (p < 0,01) foram estatisticamente significativas. Em conclusão, demonstramos que dexmedetomidina e tiopental têm efeitos histopatológicos protetores cerebrais sobre isquemia cerebral focal experimental em ratos.

Por qué es importante lograr metas de hipertensión arterial sistémica... A propósito un caso clínico que inició como evento vascular cerebral isquémico / Why is it important to achieve the goals of treatment of hypertension.... About a case that began as ischemic stroke

Resumen La hipertensión arterial sistémica (HAS) es una de las condiciones más frecuentes que se ve en atención primaria de las enfermedades cardiovasculares y que tiene como consecuencias; dependiendo del "órgano blanco" que afecte, producir la cardiopatía isquémica, la vasculopatía cerebral o la nefropatía crónica. Dentro de la patogénesis de la HAS se encuentran implicados varios mecanismos fisiopatológicos; de los cuales actualmente, por señalar los más importantes y frecuentes, juegan un papel el incremento en los niveles de adrenalina, el sistema renina-angiotensina-aldosterona y en fecha reciente, mucho se menciona la participación de la resistencia a la insulina y la hiperinsulinemia. Dichos procesos conllevan un desequilibrio entre el tono simpático y el parasimpático, aunado a la hipersensibilidad por el sodio desencadenan uno de los mecanismos fisiopatogénicos de la HAS. Actualmente se define la HAS como el hallazgo de cifras de tensión arterial mayores a 140/90 mm Hg. Este es uno de los padecimientos que más afecta a la población mundial encontrando prevalencias en grupos etarios y de género de 45 al 55% en varones entre los 45 y 70 años y del 45 al 65% en mujeres de ese mismo grupo etario. En el 2013 se publicaron las guías clínicas más recientes para su tratamiento y las metas recomendadas, con lo que se ha logrado disminuir sus complicaciones y mortalidad; dentro de las que destacan enfermedades vasculares como la cardiopatía isquémica y la cerebral y renal. En el presente trabajo se comenta un caso clínico que ejemplifica las complicaciones secundarias en un diagnóstico tardío, el daño a "órgano blanco" por exposición a largo plazo y el inadecuado cumplimiento de las metas terapéuticas.

Abstract Systemic arterial hypertension (SAH) is one of the most common conditions seen in primary care of cardiovascular disease and whose consequences; depending on the "target organ" affecting produce ischemic heart disease, cerebral vascular disease or chronic kidney disease. In the pathogenesis of HAS are several physiopathological mechanisms involved; of which currently, to name the most important and frequent play a role in increasing adrenaline levels, the renin-angiotensin-aldosterone system and recently, much the participation of insulin resistance and hyperinsulinemia mentioned. These processes lead to an imbalance between the sympathetic and parasympathetic tone, coupled with hypersensitivity sodium trigger one of the pathophysiologic mechanisms of hypertension. SAH is currently defined as finding numbers of older blood pressure 140/90 mm Hg. This is one of the diseases that most affect the world population prevalences found in age and gender groups 45 to 55% in men between 45 and 70 years and 45 to 65% in women of the same age group. In 2013 most recent clinical guidelines for treatment and the recommended goals, which has managed to reduce its complications and mortality were published; among which include vascular diseases such as ischemic heart and brain and kidney. In this paper a case that exemplifies the secondary complications in late diagnosis, damage to "target organ" by long-term exposure and inadequate compliance with therapeutic goals discussed.

Cirugía de hombro en posición en silla de playa: prevención de complicaciones isquémicas / Shoulder arthroscopy in a beach chair position: prevention of ischaemic complications

La cirugía artroscópica de hombro en posición de silla de playa es una cirugía frecuente y se asocia a buenos resultados. Causa preocupación el reporte de casos de isquemia cerebral asociados a morbimortalidad. Este artículo hace una revisión de la literatura referente a estos casos, realizando un análisis de los factores involucrados y de los cambios que ocurren al sentar a un paciente bajo el efecto de la anestesia general y/o regional. Es muy importante que el equipo quirúrgico comprenda las limitaciones de la técnica y concilie una buena exposición quirúrgica junto con el menor impacto hemodinámico. Actualmente se sugiere sentar a los pacientes con ángulos no mayores a 45°, evitar errores en la lectura de la presión arterial, que traduzcan un adecuado flujo sanguíneo cerebral. Cuando se mide oxigenación cerebral mediante NIRS (ScO2) las mayores caídas de los valores se asocian a anestesia general en ventilación mecánica con hiperventilación y en ángulos de posición de 80-90°. La anestesia regional se asocia a menores caídas de ScO2, pero requiere de un equipo con experiencia...

Shoulder arthroscopic surgery performed in the beach chair position is common and is associated with good results. The report of cases of cerebral ischaemia associated with morbidity and mortality is a cause for concern. This article presents a review of the literature concerning these cases, as well as an analysis of the factors involved and the changes that occur in patients when the beach chair position is used under general or regional anaesthesia. It is very important that the surgical team understands the limitations of the technique, and combines a good surgical exposure along with the least haemodynamic impact. Beach chair positions with angles not greater than 45°, are now suggested in order avoid errors in the blood pressure reading, which may lead to an adequate cerebral blood flow. When measuring cerebral oxygenation using NIRS (ScO2), the biggest drops in the values are associated with general anaesthesia and mechanical ventilation with hyperventilation and position angles of 80-90 degrees. Regional anaesthesia is associated with lower falls of ScO2, but requires an experienced team...

Neuroprotección por ácido valproico y cambios en la expresión de Bcl-2 y caspasa-3 activada en ratas sometidas a isquemia/reperfusión / Neuroprotective action of valproic acid accompanied of the modification on the expression of Bcl-2 and activated caspase-3 in the brain of rats submitted to ischemia/reperfusion

El ácido valproico, que además de ser un conocido antiepiléptico, una serie de trabajos en los últimos años lo proponen como un agente neuroprotector. En éste trabajo se investigó primeramente, si el ácido valproico protege a las neuronas del daño producido por el estrés oxidativo inducido por la isquemia-reperfusión en el cerebro de ratas sanas sometidas a la oclusión transitoria de la arteria cerebral media derecha; en segundo lugar, se indagó si este fármaco induce cambios en la expresión de Bcl-2 y caspasa 3-activada como un posible mecanismo de acción sobre la muerte celular del tipo apoptótico. La evaluación neurológica de los animales que fueron sometidos a isquemia/reperfusión y recibieron ácido valproico fue mejor que los que no lo recibieron. Por otro lado, los niveles de malondialdehído en el hemisferio cerebral derecho en las ratas tratadas con ácido valproico fueron inferiores a los del mismo hemisferio del grupo control, mientras la cantidad de proteínas carboniladas se redujeron un 67% en comparación al grupo control. Además, se encontró por western blot, que en homogeneizados de tejido cerebral de los animales sometidos a isquemia/reperfusión y que recibieron ácido valproico, hubo un aumento significativo de la densidad de las bandas correspondientes a Bcl-2 y una disminución de caspasa 3-activada en comparación a los que no fueron tratados con este fármaco. Se concluye que el tratamiento con ácido valproico previno el déficit neurológico en ratas sanas sometidas a isquemia-reperfusión, bloqueando el efecto de los radicales libres sobre lípidos y proteínas de la corteza cerebral afectada y se sugiere que posiblemente este fármaco interviene en la muerte por apoptosis inducida durante este tipo de lesión, pudiendo ser una alternativa terapéutica en el tratamiento de la isquemia cerebral.

Valproic acid, apart from being known as an anti-epileptic drug, has been proposed in the past few years, as a neuroprotective agent. The purpose of this study was to investigate firstly, if valproic acid protects the neurons from the damage produced by oxidative stress induced by ischemia-reperfusion in the brain of healthy rats, under the transitory occlusion of the right middle cerebral artery. Secondly it was studied if this antiepileptic drug induces changes on the expression of Bcl-2 and activated caspase-3 as a possible mechanism of action on apoptosis. The neurological evaluation of the animals that were subject to ischemia-reperfusion and received valproic acid was better than the ones who didn’t receive it. On another subject, the levels of malondialdehyde on the right cerebral hemisphere in the rats treated with valproic acid were below the levels of the control group in the same hemisphere, whereas the amount of carbonylated proteins was reduced by 67% compared to the control group. Besides, it was found by western blot, that in homogenized brain tissue of the animals under ischemia-reperfusion which received valproic acid, there was a rise on the density of the bands corresponding to Bcl-2, and a reduction of activated 3-capase in comparison to the ones who were not treated with the antiepileptic drug. It’s concluded that the treatment with valproic acid prevented the neurological deficit in healthy rats under Ischemia-reperfusion, blocking the effect of free radicals on lipids and proteins of the affected brain cortex, and it is suggested that the same drug intervenes on apoptosis induced during this type of damage, being able to be a therapeutic alternative in the treatment of cerebral ischemia.

Limb remote ischemic post-conditioning reduces brain reperfusion injury by reversing eNOS uncoupling.

Limb remote ischemic postconditioning (LRIP) can reduce ischemia-reperfusion injury (IRI), but its mechanisms are still unclear. We hypothesize that LRIP reduces IRI by reversing eNOS uncoupling. Focal ischemia was induced in Sprague-Dawley rats by middle cerebral artery occlusion for 2 h followed by a 24 h reperfusion. Before this surgery, folic acid (FA) was administered to the drug treatment group by gavage for 11 days. After a 24 h reperfusion, behavioural testing, vascular function, NO concentration and superoxide dismutase activity in the serum were determined. In addition, the infarct size of the brain was also detected. The mRNA of eNOS, nNOS, GTP cyclohydrolase I (GTPCH), P22phox and xanthine oxidase (XO) in the ischemic region were detected by RT-PCR, and nitrotyrosine (Tyr-NO2) was detected using Western blot analysis. The results showed that LRIP, FA and FA+LRIP all could improve behavioural score, and increase NO–mediated endothelium-dependent vasomotor responses, reduce infarction of rats subjected to IRI. Western blot and RT-PCR analyses showed that the Tyr-NO2 levels and the mRNA expression of NADPH oxidase catalytic subunit P22phox and XO were up-regulated in the ischemic brain, which was significantly inhibited by LRIP, FA and FA+LRIP. The mRNA expression of the rate-limiting enzyme in BH4 synthesis, GTPCH, was down-regulated in the ischemic brain, which could be significantly augmented by LRIP and FA+LRIP. It can be concluded that IRI induces eNOS uncoupling in the cerebral ischemic region and LRIP partially reverses the eNOS uncoupling induced by IRI.

Interleukin-10 may protect against progressing injury during the acute phase of ischemic stroke / Interleucinas 1B, 2 e 10 e prognostico neurologico durante a fase aguda do AVC isquemico

Atherosclerosis is an inflammatory disease, and ischemic stroke is one of its most common and devastating manifestations. Proinflammatory cytokines play a key role in the progression of the irreversible ischemic lesions. The presence of anti-inflammatory mediators may prevent secondary ischemic injury. Objectives 1) To assess the relationship between stroke severity and the serum levels of IL-1β, IL-2, and IL-10; and 2) To analyze the neurological outcome after 72 h of ischemic stroke onset and expression of interleukins. Method We measured the serum levels of IL-1β, IL-2, and IL-10 in 26 patients with acute stroke. Neurological impairment was scored using the National Institute of Health Stroke Scale within the first 72 h after stroke onset. Thirty healthy subjects were analyzed as controls. Results Patients with IL-10 <925.0 pg/mL presented with neurological deterioration within the first 72 h. Conclusion IL-10 may protect against ischemic injury during the acute phase of stroke. .

Aterosclerose é considerada um doença inflamatória e o acidente vascular cerebral (AVC) isquêmico uma de suas principais manifestações. Citocinas pró-inflamatórias exercem importante função na progressão para uma lesão isquêmica irreversível. A presença de mediadores anti-inflamatórios age prevenindo a lesão isquêmica secundária. Objetivos 1) Avaliar a relação entre gravidade do AVC e níveis de IL-1β, IL-2 e IL-10; 2) Avaliar a relação entre prognóstico neurológico nas primeiras 72 horas do AVC e o nível destas citocinas. Método Mensuramos os níveis de IL-1β, IL-2 e IL-10 de 26 pacientes com AVC isquêmico. O comprometimento neurológico foi avaliado através da escala do National Institute of Health nas primeiras 72 horas do AVC. Trinta indivíduos saudáveis foram usados como controles. Resultados Pacientes com IL-10 <925,0 pg/mL apresentaram deterioração neurológica nas primeiras 72 horas após o início do AVC. Conclusão IL-10 pode apresentar um efeito protetor contra a progresso da lesão isquêmica durante a fase aguda do AVC. .

Tratamiento trombolítico del ictus isquémico agudo / Thrombolytic therapy of the ischemic stroke

El tratamiento trombolítico ha producido un cambio positivo en la actitud de los clínicos ante los pacientes con ictus isquémico agudo. Un modesto beneficio de un 13% contrasta con un aumento del 10% en la ocurrencia de hemorragia intracerebral sintomática. Sin embargo, la mortalidad no es diferente entre los pacientes que reciben el agente trombolítico rt-PA y los que reciben placebo. Se continua estudiando la ventana terapéutica extendida actualmente hasta 4,5 horas de iniciado el evento y la organización de la atención que permita beneficiar a un mayor número de pacientes, pues por varias razones solo son elegibles en promedio 3%. Se revisan los estudios más relevantes sobre la trombólisis especialmente intravenosa: el NINDS, el ECAS III, el IST-3 y el DIDAS y DEDAS. Se describen las principales complicaciones de este tipo de terapia: la hemorragia intracerebral sintomática, otros tipos de hemorragias, angioedema y ruptura miocárdica

Thrombolytic therapy has positively changed the attitude of clinicians to treat patients with acute ischemic stroke. Treated patients were 13% more likely to achieve a recover with no significant disability after 3 month. This benefit was achieved at the cost of a 10% increase in the rate of symptomatic intracranial hemorrhage. However, this increase did not result in a higher rate of death or severe disability in the treated group. Intravenous rt-PA can be given with significant but decreasing benefit and an acceptable risk to benefit ratio up to 4,5 hours as therapeutic window. Thrombolytic therapy remains substantially underused. Most relevant trials which deal with thrombolytic therapy: NINDS, ECAS III, IST-3, DIDAS andDEDAS, are analyzed. The most frequent complications of this therapy are described

Impact of aspirin use in the incidence of thromboembolic events after bioprosthesis replacement in patients with rheumatic disease / Impacto da aspirina na incidência de eventos tromboembólicos após implante de bioprótese valvar cardíaca na doença reumática crônica

INTRODUCTION: There is still much debate regarding the kind of antithrombotic therapy in the immediate postoperative period of bioprosthesis replacement (first three months). Thus, the authors consider relevant to determine the contemporary incidence of thromboembolic events in rheumatic patients early after implantation of aortic and mitral bioprosthesis replacement (first 90 days in the post-operative period) and perform a comparison between isolated Aspirin uses versus no-antiplatelet therapy, in this same context. METHODS: Between the period of January 2010 to July 2012, all consecutive rheumatic patients, with basal sinus rhythm, who performed mitral and aortic valve replacement with bioprosthesis (pericardial bovine), were included in this prospective cohort study, 184 patients in total. The primary endpoint evaluated were the rate of embolic events. RESULTS: In the first 30 days, there were three cerebral ischemic events among patients treated in Aspirin group (5.2%) compared with two events in patients without Aspirin therapy (1.7%), HR = 3.18; 95% CI 0.5 to 19.6; P=0.33. Between 31 and 90 days postoperatively, no patient had a primary outcome. The embolism-free survival, bleeding events and the overall survival were not statistically significant between the aspirin and no-antiplatelet groups. CONCLUSION: In conclusion, in this prospective cohort of rheumatic patients, we found a low and very rare incidence rate of embolic events during the first 90 days postoperative period in mitral and isolated aortic position, respectively. The use of aspirin did not significantly reduce the rate of thromboembolism.

INTRODUÇÃO: Ainda existem controvérsias em relação à melhor estratégia de terapia antitrombótica nos três meses iniciais de pós-operatório de implante de bioprótese valvar cardíaca. Assim, os autores consideram relevante determinar a incidência contemporânea de episódios de isquemia cerebral nos meses iniciais (primeiros 90 dias de pós-operatório), e realizar uma comparação entre a aspirina isolada versus a não terapia antiplaquetária no mesmo contexto. MÉTODOS: Entre o período de janeiro de 2010 a julho de 2012, consecutivamente todos pacientes reumáticos com ritmo sinusal basal, que realizaram a substituição da valva mitral, e ou aórtica, por bioprótese (pericárdio bovino), foram incluídos neste estudo de coorte prospectivo, totalizando 184 pacientes. O desfecho primário avaliado foi a ocorrência de eventos embólicos. RESULTADOS: Nos primeiros 30 dias, três (5,2%) eventos isquêmicos cerebrais foram observados em pacientes do grupo aspirina, em comparação com dois (1,7%) eventos em pacientes sem terapia aspirina, RR = 3,18, 95% IC 0,5-19,6; P=0,33. Entre 31 e 90 dias do pós-operatório, nenhum paciente apresentou episódios de embolia cerebral ou periférica. A sobrevida livre de eventos embólicos, sangramentos e a sobrevida geral não foram estatisticamente significativas entre os grupos aspirina e não-aspirina. CONCLUSÃO: Constatou-se baixa incidência de eventos embólicos durante os primeiros 90 dias de pós-operatório de troca valvar por bioprótese envolvendo a posição mitral, e uma ainda menor para mesma situação para troca aórtica isolada. O uso da aspirina não influenciou de maneira significativa na redução de episódios tromboembólicos.

Ischemia preconditioning is neuroprotective in a rat cerebral ischemic injury model through autophagy activation and apoptosis inhibition

Sublethal ischemic preconditioning (IPC) is a powerful inducer of ischemic brain tolerance. However, its underlying mechanisms are still not well understood. In this study, we chose four different IPC paradigms, namely 5 min (5 min duration), 5×5 min (5 min duration, 2 episodes, 15-min interval), 5×5×5 min (5 min duration, 3 episodes, 15-min intervals), and 15 min (15 min duration), and demonstrated that three episodes of 5 min IPC activated autophagy to the greatest extent 24 h after IPC, as evidenced by Beclin expression and LC3-I/II conversion. Autophagic activation was mediated by the tuberous sclerosis type 1 (TSC1)-mTor signal pathway as IPC increased TSC1 but decreased mTor phosphorylation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and hematoxylin and eosin staining confirmed that IPC protected against cerebral ischemic/reperfusion (I/R) injury. Critically, 3-methyladenine, an inhibitor of autophagy, abolished the neuroprotection of IPC and, by contrast, rapamycin, an autophagy inducer, potentiated it. Cleaved caspase-3 expression, neurological scores, and infarct volume in different groups further confirmed the protection of IPC against I/R injury. Taken together, our data indicate that autophagy activation might underlie the protection of IPC against ischemic injury by inhibiting apoptosis.

Preconditioning with oil mixes of high ratio Omega-9: Omega-6 and a low ratio Omega-6:Omega-3 in rats subjected to brain ischemia/reperfusion / Pré-condicionamento com misturas de óleos com Ômega-9: Ômega-6 (alta relação) e Ômega-6:Ômega-3 (baixa relação) em ratos submetidos à isquemia/reperfusão cerebral

PURPOSE: This study aimed to assess the effects of preconditioning with mixtures of oils containing high/low ratio of ω-6/ω-3 and ω-9/ω-6, respectively, in an experimental model of cerebral ischemia-reperfusion (I/R). METHODS: Forty-two Wistar rats were randomly distributed into two groups: control (n=24) and test (n=18). Control group was subdivided in 4 subgroups (n=6): G1: Sham-Water; G2: I/R-Water; G3: Sham-Isolipidic and G4: I/R-Isolipid. The animals received water or a isolipid mixture containing ω-3 oils (8:1 ratio) and ω-9/ω-6 (0.4:1 ratio) by gavage for seven days. Test group included 3 subgroups (n=6) G5: I/R-Mix1, G: 6 I/R-Mix2 and G7: I/R-Mix3. Test group animals received oily mixtures of ω-3 (1.4:1 ratio) and ω-6 (3.4:1 ratio), differing only in source of ω-3: G5 (alpha-linolenic acid); G6 (alpha-linolenic, docosahexaenoic and eicosapentaenoic acids), and G7 (alpha-linolenic and docosahexaenoic acids). On day 7 I/R rats underwent cerebral ischemia with bilateral occlusion of common carotid arteries for 1 hour followed by reperfusion for 3 hours. G1 and G3 animals underwent sham operation. Concluded the experiment, animals were decapitated and their brains sliced for red neurons (RN) count in CA3 area of the hippocampus. Variables were compared using ANOVA-Tukey test. RESULTS: The use of different mix preparations promoted a decrease in red cell count in all three groups (G5/G6/G7), compared with G2/G4, confirming the protective effect of different oil blends, regardless of ω-3 source. CONCLUSION: Pre-conditioning with mixtures of oils containing high ratio ω-6/ω-3 and low ω-9/ω-6 relationship protects brain neurons against I/R injury in an experimental model.

OBJETIVO: Avaliar os efeitos do pré-condicionamento com misturas de óleos contendo relação alta/baixa de ω-6/ω-3 e ω-9/ω-6, respectivamente, em um modelo experimental de isquemia/reperfusão (I/R) cerebral. MÉTODOS: Quarenta e dois ratos foram distribuídos aleatoriamente em dois grupos: controle (n=24) e teste (n=18). Grupo controle foi subdividido em quatro subgrupos (n=6): G1: Sham-Água; G2: I/R-Água; G3: Sham-Isolipídico e G4: I/R-Isolipídico. Os animais receberam água ou uma mistura isolipidica contendo ω-6/ω-3 óleos (8:1) e ω-9/ω-6 (0,4:1) por gavagem, durante sete dias. O grupo teste incluiu três subgrupos (n=6) G5: I/R-Mix1, G: 6 I/R-Mix2 e G7: I/R-Mix3. Animais do grupo teste receberam de misturas de óleos ω-6/ω-3 (1,4:1) e ω-9/ω-6 (3,4:1), diferindo apenas na fonte de -3: G5:alpha-linolênico; G6: ácidos alpha-linolênico, eicosapentaenóico e docosahexaenóico e G7:ácidos alpha-linolênico e docosahexaenóico. No 7º dia os grupos I/R foram submetidos à isquemia cerebral (1h) por oclusão bilateral das artérias carótidas comuns seguida de reperfusão (3h). Ratos G1 e G3 foram submetidos à operação simulada. Concluído o experimento, os animais foram decapitados e seus cérebros fatiados para contagem dos neurônios vermelhos na área CA3 do hipocampo. As variáveis foram comparadas pelo teste de ANOVA-Tukey. RESULTADOS: A utilização de diferentes misturas de óleos promoveu uma diminuição na contagem de células vermelhas nos grupos G5/G6/G7, em comparação com G2/G4, confirmando o efeito protetor das misturas de óleos, independentemente da origem de ω-3. CONCLUSÃO: O pré-condicionamento com misturas de óleos contendo alta proporção de ω-6/ω-3 e baixa proporção de ω-9/ω-6 protege os neurônios cerebrais da lesão de I/R em um modelo experimental.

Uso de simvastatina en la prevención de la isquemia cerebral en la hemorragia subaracnoídea aneurismática / Use of simvastatin in brain ischemia prevention in aneurysmal subarachnoid hemorrhage

Introducción: El vasoespasmo cerebral es una complicación temida y aun no resuelta en los pacientes que cursan con hemorragia subaracnoídea neurismática (HSA), y que significa una importante morbi-mortalidad en dichos pacientes. Material y métodos: Se revisaron los registros de 161 pacientes ingresados en el Hospital Carlos Van Buren de Valparaíso por HSA entre entre Mayo de 2007 y Agosto de 2009, comparando la aparición de complicaciones isquémicas y resultados funcionales, según fuesen o no tratados con Simvastatina (40 mg/día). Resultados: El grupo de pacientes tratados con Simvastatina presentó significativamente menos infartos cerebrales (9,30 por ciento vs. 24,58 por ciento, p=0,02) y menos mortalidad intrahospitalaria (1,24 por ciento vs. 11,80 por ciento, p=0,04). Conclusiones: Si bien el diseño del estudio impide atribuir las diferencias encontradas al uso de Simvastatina, dado el contexto del mismo, es muy probable que así sea. El uso de estatinas en la hemorragia subaracnoídea aneurismática, como profilaxis del vasoespasmo es aún un tema controversial y promisorio, que se encuentra en plena etapa de estudio y desarrollo.

Background: Vasospasm is a feared complication in patients who present with aneurysmal subarachnoid hemorrhage (SAH) and that means significant morbidity and mortality in these patients. Material and methods: We reviewed the records of 161 patients admitted to the Hospital Carlos Van Buren with SAH between May 2007 and August 2009, comparing the occurrence of ischemic complications and functional results as they were or not treated with simvastatin (40mg/day). Results: The patient group treated with simvastatin had significantly fewer strokes (p = 0.02) and fewer hospital mortality (p = 0.04). Conclusions: Although the study design precludes attributing the differences found when using simvastatin, given the context, it is likely to be so. The use of statins in aneurismal subarachnoid hemorrhage for vasospasm prophylaxis is still a controversial and promising topic, wich is under full development and study.

Protective effect of Yulangsan polysaccharide on focal cerebral ischemia/reperfusion injury in rats and its underlying mechanism

To study the focal cerebral ischemia/reperfusion [I/R] injury induced by a middle cerebral artery occlusion [MCAO], and the effects of Yulangsan [YLS] polysaccharide on this injury. This study took place in the Pharmacology Research Laboratory at Guangxi Medical University, China, between March and May 2007. Two hundred and forty rats were randomly divided into I/R group, sham-operated group, high-, medium-, and low-dose of YLS polysaccharide groups, and nimodipine [Nim] group. The animals were intragastrically administered with drugs for 7 days. An operation was performed to induce an MCAO model in the rats. Reperfusion was started after 2 hours of MCAO. The influences of YLS polysaccharide on the neurological score, the brain water content, the infarct volume, the activities of super oxide dismutase [SOD] and nitric oxide synthase [NOS], the contents of malondialdehyde [MDA] and nitric oxide [NO], the expressions of B-cell lymphoma/leukemia-2 [Bcl-2] and Bcl-2-associated X protein [Bax] in brain tissue were investigated; the morphological changes of rat cerebral cortical neurons were observed. Compared with the I/R group, YLS polysaccharide reduced the neurological score, the brain water content, the infract volume, MDA and NO contents, the NOS activity, and the expression of Bax, and increased SOD activity, and the expression of Bcl-2 in the brain tissue, and neuronal edema was reduced. The YLS polysaccharide has a protective effect on cerebral ischemia/reperfusion injury; the mechanism may be related to attenuating free radicals, and increasing the Bcl-2/Bax ratio