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.

Ameliorative effect of scutellarin on acute alcohol brain injury in mice / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Drinking culture has high significance in both China and the world, whether in the entertainment sector or in social occasions; according to the World Health Organization's 2018 Global Alcohol and Health Report, about 3 million people died from excessive drinking in 2016, accounting for 5.3% of the total global deaths that year. Oxidative stress and inflammation are the most common pathological phenomena caused by alcohol abuse (Snyder et al., 2017). Scutellarin, a kind of flavonoid, is one of the main active ingredients extracted from breviscapine. It exerts anti-inflammatory, antioxidant, and vasodilation effects, and has been used to treat cardiovascular diseases and alcoholic liver injury. Although scutellarin can effectively alleviate multi-target organ injury induced by different forms of stimulation, its protective effect on alcoholic brain injury has not been well-defined. Therefore, the present study established an acute alcohol mice brain injury model to explore the effect of scutellarin on acute alcoholic brain injury. The study was carried out based on the targets of oxidative stress and inflammation, which is of great significance for the targeted therapy of clinical alcohol diseases.

The effect of Hippophae rhamnoides L. extract on acrylamideinduced brain injury in rats

ABSTRACT Purpose: Reactive oxygen species (ROS), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) have been shown in the pathogenesis of acrylamide neurotoxicity. Hippophae rhamnoides L. extract (HRE) has a cytoprotective effect by stabilizing the production of ROS, IL-1β and TNF-α. The objective of the article was to investigate the effect of HRE on acrylamide-induced brain damage in rats biochemically and histopathologically. Methods: To the HRE+acrylamide only (ACR) group (n=6) of the animals, HRE was administered orally at a dose of 50 mg / kg into the stomach by gavage. The same volume of solvent (olive oil) was administered orally to the ACR (n=6) and healthy (HG) (n=6) groups. One hour after HRE administration, acrylamide was given orally at a dose of 20 mg/kg to HRE+ACR and ACR groups in the same way. This procedure was repeated once a day for 30 days. At the end of this period, brain tissues extracted from animals killed with 50 mg/kg thiopental anesthesia were examined biochemically and histopathologically. Results: It has been shown that HRE prevents the increase of malondialdehyde (MDA), myeloperoxidase (MPO), IL-1β and TNF-α with acrylamide and the decrease of total glutathione (tGSH) and glutathione reductase (GSHRd) levels in brain tissue. Conclusions: HRE may be useful in the treatment of acrylamide-induced neurotoxicity.

Effect of volume replacement during combined experimental hemorrhagic shock and traumatic brain injury in prostanoids, brain pathology and pupil status / Efeito da reposição volêmica durante o choque hemorrágico combinado com traumatismo craniencefálico sobre prostanóides, patologia cerebral e status pupilar

Traumatic brain injury (TBI) is the main cause of trauma-related deaths. Systemic hypotension and intracranial hypertension causes cerebral ischemia by altering metabolism of prostanoids. We describe prostanoid, pupilar and pathological response during resuscitation with hypertonic saline solution (HSS) in TBI. Method Fifteen dogs were randomized in three groups according to resuscitation after TBI (control group; lactated Ringer’s (LR) group and HSS group), with measurement of thromboxane, prostaglandin, macroscopic and microscopic pathological evaluation and pupil evaluation.Result Concentration of prostaglandin is greater in the cerebral venous blood than in plasma and the opposite happens with concentration of thromboxane. Pathology revealed edema in groups with the exception of group treated with HSS.Discussion and conclusion There is a balance between the concentrations of prostaglandin and thromboxane. HSS prevented the formation of cerebral edema macroscopically detectable. Pupillary reversal occurred earlier in HSS group than in LR group.

O traumatismo cranioencefálico (TCE) é a principal causa de morte relacionada ao trauma. O choque hemorrágico e hipertensão intracraniana causam isquemia cerebral alterando o metabolismo de prostanóides. Neste estudo, relatamos o comportamento dos prostanóides, resposta pupilar e patologia durante a reposição volêmica com solução salina hipertônica (SSH) no TCE. Método Quinze cachorros foram randomizados em três grupos (controle, grupo de Ringer lactato e grupo de SSH) e foram avaliados tromboxane, prostaglandina, avaliação patológica macroscópica e microscópica e status pupilar.Resultado A concentração de prostaglandina é maior no sangue cerebral em comparação ao plasma, e o inverso ocorre com o tromboxane. A patologia revelou edema em todos os grupos, com exceção do grupo tratado com SSH.Discussão e conclusão Existe um equilíbrio entre concentrações cerebrais e plasmáticas de prostaglandina e tromboxane. A SSH protegeu o cérebro da formação de edema pós traumático.

Minimally traumatic alveolar ridge augmentation with a tunnel injectable thermo-sensitive alginate scaffold

Injectable bone substitutes and techniques have been developed for use in minimally invasive procedures for bone augmentation. Objective : To develop a novel injectable thermo-sensitive alginate hydrogel (TSAH) as a scaffold to induce bone regeneration, using a minimally invasive tunnelling technique. Material and Methods : An injectable TSAH was prepared from a copolymer solution of 8.0 wt% Poly(N-isopropylacrylamide) (PNIPAAm) and 8.0 wt% AAlg-g-PNIPAAm. In vitro properties of the material, such as its microstructure and the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2), were investigated. Then, with the subperiosteal tunnelling technique, this material, carrying rhBMP-2, was injected under the labial periosteum of the maxillary anterior alveolar ridge in a rabbit model. New bone formation was evaluated by means of X-ray, micro-computed tomography (micro-CT), fluorescence labelling, histological study, and immunohistochemistry study. Results : The material exhibited good injectability and thermo-irreversible properties. SEM showed an interconnected porous microstructure of the TSAH. The result of ALP activity indicated sustained delivery of BMP-2 from the TSAH from days 3 to 15. In a rabbit model, both TSAH and TSAH/rhBMP-2 induced alveolar ridge augmentation. The percentage of mineralised tissue in the TSAH/rhBMP-2 group (41.6±3.79%) was significantly higher than in the TSAH group (31.3±7.21%; p<0.05). The density of the regenerating tissue was higher in the TSAH/rhBMP-2 group than in the other groups (TSAH group, positive control, blank control; p<0.05). Conclusions : The TSAH provided convenient handling properties for clinical application. To some extent, TSAH could induce ridge augmentation and mineral deposition, which can be enhanced when combined with rhBMP-2 for a minimally invasive tunnelling injection. .

Blockade of CXCR1/2 chemokine receptors protects against brain damage in ischemic stroke in mice

OBJECTIVE: Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice. METHODS: C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/lmperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-iβ was measured by ELISA. RESULTS: Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-iβ were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre-treatment. CONCLUSIONS: Our results suggest that the blockade of the CXCR1/2 receptors by reparixin promotes neuroprotective effects by reducing the levels of polymorphonuclear infiltration in the brain and the tissue damage associated with middle cerebral artery occlusion and reperfusion.

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.

Intensive insulin therapy versus conventional glycemic control in patients with acute neurological injury: a prospective controlled trial

OBJECTIVE: To compare intensive insulin therapy to conventional glycemic control in patients with acute neurological injury evaluating neurological outcome and morbimortality. METHOD: Patients with two glycemias above 150 mg/dL 12 hours after admission were randomized to receive intensive insulin therapy (G1) or conventional treatment (G2). We evaluated a subgroup of patients with acute brain injury from July, 2004 to June, 2006. RESULTS: G1 patients (n=31) received 70.5 (45.1-87.5) units of insulin/day while G2 patients (n=19) received 2 (0.6-14.1) units/day (p<0.0001). The median glycemia was comparable in both groups (p=0.16). Hypoglycemia occurred in 2 patients (6.4 percent) in G1 and in 1 patient (5.8 percent) in G2 (p=1.0). Mortality in G1 was of 25.8 percent and of 35.2 percent in G2 (relative reduction of 27 percent). Neurological outcome was similar in both groups. CONCLUSION: A less strict intensive insulin therapy can reduce hypoglycemia and still maintain its benefits.

OBJETIVO: Comparar insulinoterapia intensiva com controle convencional da glicemia em pacientes com injuria cerebral aguda avaliando evolução neurológica e morbimortalidade. MÉTODO: Pacientes com duas glicemias acima de 150 mg/dL nas primeiras 12 horas após admissão foram randomizados para insulinoterapia intensiva (Grupo 1) ou tratamento convencional (Grupo 2). Avaliamos um subgrupo de pacientes com injuria cerebral aguda admitidos de julho/2004 a junho/2006. RESULTADOS: O Grupo 1 (n=31) recebeu 70,5 (45,1-87,5) unidades de insulina/dia enquanto o Grupo 2 (n=19) recebeu 2 (0,6-14,1) unidades/dia (p<0,0001). A glicemia mediana foi comparável nos dois grupos (p=0,16). Hipoglicemia ocorreu em 2 pacientes (6,4 por cento) no Grupo 1 e em 1 paciente (5,8 por cento) no Grupo 2. A mortalidade no Grupo 1 foi 25,8 por cento contra 35,2 por cento no Grupo 2 (redução relativa de 27 por cento). A evolução neurológica foi semelhante nos dois grupos. CONCLUSÃO: Insulinoterapia intensiva com controle mais flexível da glicemia reduz a incidência de hipoglicemia mantendo os benefícios do tratamento.

Neuroprotective effects of vitamin E in cold induced cerebral injury in guinea pigs.

Significant reduction in hemorrhage (10 v/s 13), necrosis (2 v/s 4), cavitations (7 v/s 13), neuronal degeneration, perivascular and parenchymal inflammatory infiltrate (7 v/s 11) were observed in Vitamin E treated cold induced head injury in guinea pigs, evaluated post injury using the modified Benderson's scale. The results suggest that Vitamin E is highly effective in promoting clinical and histopathological recovery in cold induced head injury in guinea pigs.

Neuroprotective Effect of Ginseng Total Saponins in Experimental Traumatic Brain Injury

In the present study, we investigated whether ginseng total saponins (GTSs) protect hippocampal neurons after experimental traumatic brain injury (TBI) in rats. A moderate-grade TBI was made with the aid of a controlled cortical impact (CCI) device set at a velocity of 3.0 m/sec, a deformation of 3.0 mm, and a compression time of 0.2 sec at the right parietal area for adult male Sprague-Dawley rats. Shamoperated rats that underwent craniectomy without impact served as controls. GTSs (100 and 200 mg/kg) or saline was injected intraperitoneally into the rats immediately post-injury. Twenty-four hours after the injury, the rats underwent neurological evaluation. Contusion volume and the number of hippocampal neurons were calculated with apoptosis evaluated by TUNEL staining. 24 hr post-injury, salineinjected rats showed a significant loss of neuronal cells in the CA2 region of the right hippocampus (53.4%, p<0.05) and CA3 (34.6%, p<0.05) compared with contralateral hippocampal region, a significant increase in contusion volume (34 +/-8microliter), and significant increase in neurologic deficits compared with the GTSs groups. Treating rats with GTSs seemed to protect the CCI-induced neuronal loss in the hippocampus, decrease cortical contusion volume, and improve neurological deficits.

Eficacia de la optimización de la presión de perfusión cerebral durante la fibrobroncoscopía en pacientes con traumatismo encefalocraneano grave / Effectiveness of the cerebral perfusion pressure optimization during fiberoptic bronchoscopy

Objetivo: Evaluar la utilidad de la optimización de la PPC antes, durante y después de la realización de FB, analizando las diferentes variables hemodinámicas cerebrales. Material y método: Estudio prospectivo, del 01/07/96 al 31/07/97. Ingresaron todos los pacientes con TEC con Glasgow ó 8 a los que se les relizó FB tanto para lavado broncoalveolar (BAL) como para resolución de atelectasias. Todos los pacientes se encotraban intubados, sedados y relajados, con asistencia respiratoria mecánica (ARM) y monitorizados con: catéter de fibra óptica para la medición de Presión Intracraneana (PIC), oximetría cerebral (rSO2) y de pulso (SaO2), capnografía (ETCO2) y catéteres arterial y venoso central. Se calculó: PPC (TAM-PIC), contenido arterial y venoso de O2, diferencia arterio-venosa de O2 cerebral (Dav02C), índice de extracción de O2 cerebral (SaO2-rSO2), consumo metabólico de O2 cerebral (CMO2C) (PCO2xDavO2C). Previo a la FB se mantuvo una PPC = 70 mmHg, una SaO2 = 95 por ciento, una ETCO2 ó 35mmHg y una rSO2 > 55 por ciento. Todas las variables se midieron y calcularon antes de comenzar la FB, luego de la optimización, en el momento de mayor PIC y 30 minutos después de la FB. El análisis estadístico se realizó con el test de Student y el test de correlación de Pearson. Valores de p ó 0,05 o de r2 >0,5, fueron considerados significativos...

The effects of methylprednisolone on prevention of brain edema after experimental moderate diffuse brain injury in rats: comparison between dosage, injection time, and treatment methods

Our study was designed to determine whether methylprednisolone exerts a beneficial effect after experimental moderate diffuse brain injury and whether this possible beneficial effect is affected by the dosage, the timing of administration, and the methods of treatment. A total of 200 anesthetized adult rats were injured utilizing a weight-drop device through a Plexiglas guide tube. These rats were divided into eight groups: Group 1 (n=35) was assigned to receive no methylprednisolone after impact (control group), Group 2 (n=25) received an initial intraperitoneal administration of methylprednisolone with a dose of 5 mg/kg at 1hour after cranial impact, followed by administration with a maintenance dose of 5 mg/kg/4 hours. Group 3 (n=25), group 5 (n=25), and group 7 (n=20) received an initial 30 mg/kg at 1 hour, 4 hours, and 8 hours, respectively without a maintenance dose. Group 4 (n=25), group 6 (n=25), and group 8 (n=20) received an initial 30 mg/kg at 1 hour, 4 hours, and 8 hours after impact, with a maintenance dose of 15 mg/kg/4 hours. Measured water content of brain tissue expressed the amount of water as the difference between fresh and dry weight. At 48 hours after impact, the water content in group 4 and 6 were significantly lower than group 1. Mean SD was 61.4 0.37% in group 4 (p0.1), group 3 (p>0.5), group 5 (p>0.6), group 7 (p>0.1), and group 8 (p>0.5). Groups treated with mega dose before 4hours after head injury, including maintenance dose, showed beneficial effects. Our study suggests that the efficacy of methylprednisolone in head injury was related to the dosage, the timing of administration, and method of treatment.

Edema cerebral en traumatismo craneoencefálico severo en niños tratados con y sin dexametasona: estudio comparativo U.T.I. Hospital de Niños J.M. De Los Rios, Caracas / Brain edema in severe head injury on children treated instead in not dexametasone: comparative study U.T.I. Hospital de Niños J.M. De Los Rios, Caracas

Se realizó un estudio prospectivo de los resultados obtenidos al tratar con y sin Dexametasona a niños con traumatismo craneoencefálico severo, que ingresaron a la U.T.I. del Hospital de Niños "J.M. De Los Rios", durante el período comprendido en los meses de Enero a Mayo de 1986. Se dividieron en dos grupos de cinco cada uno distribuídos al azar simple por el método de la lotería. Ambos grupos fueron comparables estadísticamente. Se distribuyeron por fecha de ingreso, edad, sexo, procedencia, peso, escala de Glasgow de ingreso y salida. Se comparó la vigilancia hemodinámica, metabólica, respiratoria, hematológica e infecciosa. Llamó la atención 4 hechos importantes: 1) La evolución en ambos grupos estudiados fue igual con el uso o no de Dexametasona, si se mantiene una vigilancia hemodinámica, respiratoria y metabólica adecuada. 2) La mortalidad fue discretamente mayor en el grupo con dexametasona, 20%. 3) La función pulmonar se encontró más deteriorada en el grupo que recibió Dexametasona. 4) El porcentaje de hemocultivos sin desarrollo bacteriano (SDB) fue menor en el grupo que recibió Dexametasona

Traumatismo craniencefálico / Skull injuries

Procura-se mostrar ao médico generalista os aspectos básicos do paciene traumatizado de crânio, visando o diagnóstico precoce e o tratamento adequado. Foram analisadas as várias condiçöes clínicas, abrangendo desde as lesöes de couro cabeludo até o traumatismo craniencefálico grave