Protective effects of histone deacetylase 6 specific inhibitor tubastatin A on subarachnoid hemorrhage in rats and the underlying mechanisms / 中南大学学报(医学版)

OBJECTIVES@#Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms.@*METHODS@#Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubAL group (giving 25 mg/kg TubA), and a SAH+TubAH group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery.@*RESULTS@#The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubAH group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubAL group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) .@*CONCLUSIONS@#HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.

Schisandrin B Inhibits NLRP3 Inflammasome Pathway and Attenuates Early Brain Injury in Rats of Subarachnoid Hemorrhage / 中国结合医学杂志

OBJECTIVE@#To determine whether Schisandrin B (Sch B) attenuates early brain injury (EBI) in rats with subarachnoid hemorrhage (SAH).@*METHODS@#Sprague-Dawley rats were divided into sham (sham operation), SAH, SAH+vehicle, and SAH+Sch B groups using a random number table. Rats underwent SAH by endovascular perforation and received Sch B (100 mg/kg) or normal saline after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evan's blue extravasation, and terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining were carried out 24 h after SAH. Immunofluorescent staining was performed to detect the expressions of ionized calcium binding adapter molecule 1 (Iba-1) and myeloperoxidase (MPO) in the rat brain, while the expressions of B-cell lymphoma 2 (Bcl-2), Bax, Caspase-3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated specklike protein containing the caspase-1 activator domain (ASC), Caspase-1, interleukin (IL)-1β, and IL-18 in the rat brains were detected by Western blot.@*RESULTS@#Compared with the SAH group, Sch B significantly improved the neurological function, reduced brain water content, Evan's blue content, and apoptotic cells number in the brain of rats (P<0.05 or P<0.01). Moreover, Sch B decreased SAH-induced expressions of Iba-1 and MPO (P<0.01). SAH caused the elevated expressions of Bax, Caspase-3, NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in the rat brain (P<0.01), all of which were inhibited by Sch B (P<0.01). In addition, Sch B increased the Bcl-2 expression (P<0.01).@*CONCLUSION@#Sch B attenuated SAH-induced EBI, which might be associated with the inhibition of neuroinflammation, neuronal apoptosis, and the NLRP3 inflammatory signaling pathway.

Hydrogen-rich saline alleviates early brain injury through regulating of ER stress and autophagy after experimental subarachnoid hemorrhage

ABSTRACT Purpose: Subarachnoid hemorrhage (SAH) is a common complication of cerebral vascular disease. Hydrogen has been reported to alleviate early brain injury (EBI) through oxidative stress injury, reactive oxygen species (ROS), and autophagy. Autophagy is a programmed cell death mechanism that plays a vital role in neuronal cell death after SAH. However, the precise role of autophagy in hydrogen-mediated neuroprotection following SAH has not been confirmed. Methods: In the present study, the objective was to investigate the neuroprotective effects and potential molecular mechanisms of hydrogen-rich saline in SAH-induced EBI by regulating neural autophagy in the C57BL/6 mice model. Mortality, neurological score, brain water content, ROS, malondialdehyde (MDA), and neuronal death were evaluated. Results: The results show that hydrogen-rich saline treatment markedly increased the survival rate and neurological score, increased neuron survival, downregulated the autophagy protein expression of Beclin-1 and LC3, and endoplasmic reticulum (ER) stress. That indicates that hydrogen-rich saline-mediated inhibition of autophagy and ER stress ameliorate neuronal death after SAH. The neuroprotective capacity of hydrogen-rich saline is partly dependent on the ROS/Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Conclusions: The results of this study demonstrate that hydrogen-rich saline improves neurological outcomes in mice and reduces neuronal death by protecting against neural autophagy and ER stress.

Eficácia e segurança da milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea: uma revisão sistemática / Efficacy and safety of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage: a systematic review

RESUMO Objetivo: Revisar sistematicamente a evidência atual da eficácia de milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea. Métodos: Triaram-se as bases de dados Pubmed®, Cochrane e Embase quanto a artigos publicados entre abril de 2001 e fevereiro de 2019. Dois revisores independentes realizaram uma triagem metodológica da qualidade e a extração dos dados dos estudos. Resultados: Encontraram-se 22 estudos considerados relevantes, sendo que apenas um deles era um ensaio randomizado controlado. Os estudos demonstraram acentuada heterogeneidade e debilidade de seus critérios metodológicos. A maioria dos pacientes apresentava vasoespasmo moderado a grave. O principal método para diagnóstico do vasoespasmo foi a angiografia. Em três estudos, realizou-se administração de milrinona por via intra-arterial; em nove estudos, a administração foi endovenosa, e, em seis estudos, utilizaram-se ambas as vias de administração. A via intratecal foi utilizada em dois estudos, em um estudo, a administração foi realizada via cisterna e, em um estudo, a via de administração foi a endovascular. Os efeitos colaterais de milrinona foram descritos em seis estudos. Vinte e um estudos indicaram a resolução do vasoespasmo. Conclusão: A evidência atual indica que o uso de milrinona teve um papel no tratamento do vasoespasmo após hemorragia subaracnóidea aneurismática. Contudo, só foi realizado um ensaio randomizado controlado, com baixo nível de qualidade. Nossos achados indicam a necessidade de futuros estudos randomizados controlados com desfechos centrados no paciente, com o fim de proporcionar recomendações definitivas.

ABSTRACT Objective: To systematically review the current evidence on the efficacy of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage. Methods: The Pubmed®, Cochrane and Embase databases were screened for articles published from April 2001 to February 2019. Two independent reviewers performed the methodological quality screening and data extraction of the studies. Results: Twenty-two studies were found to be relevant, and only one of these was a randomized control trial. Studies showed marked heterogeneity and weaknesses in key methodological criteria. Most patients presented with moderate to severe vasospasm. Angiography was the main method of diagnosing vasospasm. Intra-arterial administration of milrinone was performed in three studies, intravenous administration was performed in nine studies, and both routes of administration in six studies; the intrathecal route was used in two studies, the cisternal route in one study and endovascular administration in one study. The side effects of milrinone were described in six studies. Twenty-one studies indicated resolution of vasospasm. Conclusion: The current evidence indicates that milrinone may have a role in treatment of vasospasm after aneurysmal subarachnoid hemorrhage. However, only one randomized control trial was performed, with a low quality level. Our findings indicate the need for future randomized control trials with patient-centered outcomes to provide definitive recommendations.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

BACKGROUND: Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. METHODS: Sprague-Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. RESULTS: TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. CONCLUSIONS: Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.

Vasoespasmo cerebral y déficit isquémico tardío en la hemorragia subaracnoídea aneurismática: guías para su manejo clínico / Cerebral vasospasm and delayed ischemic deficit in the aneurysmal subarachnoid hemorrhage: guidelines to its clinical management

La presente revisión del tema Vasoespasmo y Déficit Isquémico Cerebral tardío (DIT) en la Hemorragia subaracnoidea aneurismática tiene como objetivo actualizar su manejo, basado en las hipótesis mas aceptadas que se han logrado para explicar su patogénesis. Se efectúa una introducción con conceptos generales, se revisan las bases patogénicas del Vasoespasmo y se plantea su manejo, tomando en cuenta su diagnóstico, monitorización, profilaxis y manejo avanzado de acuerdo a las últimas Guías de Manejo Clínico y según medicina basada en las evidencias.

The objective of the present review on cerebral vasospasm and cerebral delayed isquemic deficit due to subarachnoid haemorrhage secondary to ruptured cerebral aneurysm, is to update their management, based on the most accepted pathophysiological hypotesis explaining their pathogenetic mechanisms. An introduction is performed presenting general concepts, review of the most recent research works explaining their pathogenesis, and the management is stated touching diagnosis, monitoring, prophylaxis, and advanced management according with the last clinical guidelines for his management using medicine based on evidences.

Profilaxis con drogas antiepilépticas en enfermedades neurológicas / Prophylactic treatment with antiepileptic drugs in neurological conditions

El uso profiláctico de drogas antiepilépticas en enfermedades neurológicas como el accidente cerebrovascular isquémico y hemorrágico, la hemorragia subaracnoidea, el traumatismo de cráneo y los tumores cerebrales ha sido motivo de controversia durante muchos años. Estas drogas son indicadas con el fin de disminuir el daño neurológico secundario a las crisis epilépticas. Sin embargo, la escasa evidencia científica disponible para avalar esta hipótesis, las potenciales interacciones farmacológicas, los efectos adversos y algunos informes sobre neurotoxicidad generan dudas en cuanto a esta conducta terapéutica. En esta revisión, analizamos la evidencia acerca del uso profiláctico de drogas epilépticas en las enfermedades neurológicas arriba mencionadas.

Prophylactic use of antiepileptic drugs in neurological conditions such as ischemic and hemorrhagic stroke, subarachnoid hemorrhage, head injury, and brain tumors has been matter of debate for many years. These drugs are used for reducing secondary neurological damage caused by epileptic seizures. However, the evidence supporting this indication is scarce. Potential drug interactions, side effects, and even neurotoxicity related to these drugs have raised concern about this therapeutic approach. In this review, we examine the evidence on the prophylactic use of antiepileptic drugs in the neurological disorders above mentioned.

Progressive cervicocranial arteriopathy with dilatations and stenoses: case report

Relatamos o caso de uma doente de 36 anos que apresentou oclusão de um aneurisma fusiforme de artéria basilar associado a infarto pontino e dois episódios de hemorragia subaracnóide provavelmente devido a dissecção arterial. Ela também apresentava aneurismas fusiformes assintomáticos na artéria cerebral média direita e na artéria carótida interna esquerda. Ao longo de 5 anos, lesões compatíveis com displasia fibromuscular foram observadas na artéria vertebral direita, assim como oclusão da artéria vertebral esquerda. Esta combinação de lesões sugere que um mecanismo etiopatogênico comum tenha causado diferentes graus de comprometimento da camada média de artérias cervicocranianas.

Hemorragia subaracnoidea de causa aneurismática / Subarachnoid hemorrhage by aneurysmatic cause

La hemorragia subaracnoidea (HSA) por rotura aneurismática es responsable del 6 por ciento de los accidentes cerebrovasculares. Los aneurismas cerebrales se encuentran presentes en el 0.2 - 9.9 por ciento de la población y la tasa de sangrado es de 10 por 100.000 habitantes. La conferencia de consenso analizó los distintos esquemas de tratamiento y efectuó recomendaciones terapeúticas de acuerdo a los criterios de la medicina basada en la evidencia. Se determinaron los niveles de evidencia, de I a V. Los grados de recomendación fueron clasificados en: A, determinado por evidencias de nivel I, B por evidencia de nivel II, y C sugerido por evidencias de niveles III, IV y V. Las recomendaciones deben adaptarse a cada paciente. Sin embargo las de grado A constituyen estándares para el tratamiento. La gravedad de los pacientes al ingreso fue evaluada sobre la base de la escala de Hunt y Hess. Se analizaron sucesivamente: las medidas de tratamiento general, la prevención y tratamiento del vasoespasmo cerebral, el diagnóstico y tratamiento de la hiponatremia y la prevención de las convulsiones

Hemorragia Subaracnoidea Producida por la Ruptura de los Aneurismas Cerebrales / Subarachnoid Hemorrhage from Rupture of Cerebrals Aneurysms

La hemorragia subaracnoidea producida por la ruptura de un aneurisma cerebral es una entidad relativamente frecuente que afecta a una población activa y es capaz de generar altos grados de incapacidad y mortalidad. Se debe resaltar la importancia que el diagnóstico precoz tiene sobre el pronóstico. Los dos principales problemas que generan las mayores complicaciones son el resangrado y el vasoespasmo arterial. Un adecuado entendimiento de la fisiología es vital para obtener los mejores resultados terapéuticos, evitando aumentar la morbi-mortalidad que ya posee por si sola esta entidad

Uso da minodipina em hemorragia meníngea espontânea por rotura de aneurisma / Use of nimodipine in spontaneous meningeal haemorrhage through aneurysm rupture

Os autores apresentam os resultados do uso do antagonista de cálcio "Nimodipina" na profilaxia do vasoespasmo cerebral pós-hemorragia meníngea espontânea por rotura de aneurisma. O trabalho é baseado no estudo duplo-cego de 30 pacientes dos quais 15 receberam minodipina e 15 placebo. É ressaltada a gravidade desta complicaçäo nos sangramentos subaracnóideos. Os resultados säo semelhantes aos da literatura a respeito, aparentemente indicando um efeito benéfico da droga nestes pacientes

Uso de antifibrinolíticos em hemorragia subaracnóidea por ruptura de aneurisma cerebral: nota preliminar / Use of antifibrinolytics in subarachnoid hemorrhage due to cerebral aneurysm rupture

A utilizaçäo de drogas antifibrinolíticas (AFL), com o intuito de evitar o ressangramento de aneurisma cerebral, permanece como uma questäo controversa. embora eles sejam reconhecidos como capazes de reduzir os riscos de uma nova hemorrágia, os AFL aumentam os índices de outras complicaçöes que acompanham as hemorragias subaracnóides (HSA) por ruptura aneurismática. Nesta nota preliminar, os autores dividem os aneurismas cerebrais, baseados no stress hemodinâmico a que estäo submetidos, em 2 grupos: os de <>. A partir destes conceitos, propöem um protocolo de utilizaçäo dos AFL nas HSA por anurismas da artéria cerebral média (considerados de <>), contraindicando-os nos aneurismas do complexo artéria cerebral - artéria comunicante anterior (aneurismas de <> fluxo>>)

Acción de la nimodipina en el déficit isquémico retardado de la hemorragia subaracnoidea / Effect of nimodipine in the delayed ischemic deficit of subarachnoid hemorrhage

Se incluyen 35 pacientes de ambos sexos, ingresados al Servicio de neurocirugía del Hospital C. Van Buren entre noviembre 1986 a julio 1988. Los criterios de inclusión al estudio fueron edad entre los 15 y 70 años, diagnóstico de hemorragia subaracnoidea (H.S.A.) secundaria a aneurisma cerebral roto, ingresados dentro de las 96 horas posteriores a la H.S.A. inicial y con grado neurológico según la escala de Hunt y Hess de I a V. El tratamiento consistió en nimodipina (Nimotop-Bayer) EV 2 mg/hr, durante 14 días, y luego 60 mg c/ 6 hrs. oral durante 7 días. En esta comunicación interesa comentar 4 aspectos: 1) presencia de complicaciones neurológicas más frecuentes durante las primeras 2 semanas de evolución de la H.S.A.: resangriamiento, 0 casos, déficit isquémico retardado (DIR) 9 casos (25,7%) ya sea DIR temporal, 5 casos o DIR permanente, 4 casos. Se comenta que de los 5 casos con DIR temporal a 4 se efectuó clipaje temporal de arterias aferentes durante el acto operatorio, y que de los 4 con DIR permanente a 2 se le efectuó clipaje temporal por ruptura prematura del aneurisma (5,7%), en 1 caso el clip definitivo incluyó una arteria perforante, y 1 caso demostró en la T.A.C. de control un pequeño infarto frontal probablemente debido a presión de la espátula. 2) Clínicamente la nimodipina EV demostró ser efectiva al mejorar tanto el grado de compromiso neurológico (según Hunt y Hess), como el grado de compromiso de conciencia (según escala de Glasgow), pudiendo optar así con mejores posibilidades a la cirugía. 3) En esta serie 11 casos presentaron vasoespasmo angiográfico (31,4%), 5 casos durante el tratamiento (14,2%) y 6 antes de iniciar el tratamiento con nimodipina (17,2%)...

Cerebral vasospasm

Vasoespasmo cerebral ocorre em patologias como enxaqueca, hemorragia subaracnóidea, trauma de crânio, após isquemia e/ou hipoxia. A fisiopatologia do vasoespasmo cerebral nestas patologias näo está completamente desvendada. Neste artigo säo analisados os fatores neuroquímicos e morfológicos responsáveis pelo controle circulatório cerebral. As alteraçöes circulatórios que seguem a hemorragia subaracnóidea säo utilizadas como exemplo. Conclui-se que fatores bioquímicos, fisiológicos e morfológicos säo responsáveis pelas manifestaçöes vasculares que ocorrem após a hemorragia subaracnóidea. Alternativas de tratamento do vasoespasmo cerebral säo discutidas