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.

Oclusión de la arteria cerebral media en ataque cerebrovascular isquémico agudo / Middle cerebral artery occlusion in acute ischaemic cerebrovascular attack

El ataque cerebrovascular isquémico (ACV) es una de las principales causas de morbimortalidad a nivel mundial y nacional. Se estudiaron 35 pacientes identificándose que las arterias que presentaron mayor frecuencia de oclusión en el ACV isquémico agudo fueron la arteria cerebral media y la arteria cerebral posterior. Consideramos necesario que los especialistas puedan localizaran atómicamente los ACV para la aplicación de terapias neuroprotectoras mejorando las opciones de tratamiento y previniendo obstrucciones secundarias.

Ischaemic stroke (CVA) is one of the leading causes of morbidity and mortality at a global and national level. We studied 35 patients, determined the arteries that presented a higher frequency of occlusion in acute ischemic stroke and identified the middle cerebral artery and the posterior cerebral artery. We consider it necessary that specialists can locate anatomically strokes in order to apply neuroprotective therapies to improve treatment options and preventing secondary obstructions.

Does the side of middle cerebral artery compromise matters in the mortality after thrombolysis in ischemic stroke? / O lado acometido da artéria cerebral média interfere na mortalidade do acidente vascular isquêmico pós trombólise?

The impact of the side in middle cerebral artery (MCA) ischemic stroke is not well established. Our aim was to analyze the differences between right (RMCA) and left middle cerebral artery (LMCA) stroke in patients submitted to intravenous thrombolysis and the influence of the affected side in the patient’s mortality after 3 months. Method Patients with MCA ischemic stroke submitted to intravenous thrombolysis from March 2010 to December 2011 at two Brazilian Stroke Centers were included. Differences between patients with RMCA and LMCA stroke were identified by univariate analysis. Results Forty-five patients with RMCA stroke and 67 with LMCA stroke were analyzed. Patients with LMCA had a higher incidence of atrial fibrillation (p = 0.031), although patients with RMCA more often had a previous ischemic stroke (p = 0.034). The mortality over 3 months was similar for either side (OR = 1.20 ;0.37 - 4.29, p = 0.772). Conclusion The side of the MCA ischemic stroke did not influence the patients mortality. .

O impacto do lado de acometimento da artéria cerebral média (ACM) não é bem estabelecido. Nosso objetivo é analisar as diferenças entre pacientes com acidente vascular isquêmico (AVCi) de ACM direita (ACMD) e esquerda (ACME) submetidos à trombólise endovenosa e a influência do lado acometido na mortalidade em 3 meses. Método Pacientes com AVCi ACMD e ACME submetidos à trombólise endovenosa entre Março de 2010 a Dezembro de 2012 em duas Unidades de AVC brasileiras foram incluídos. Diferenças entre AVCi ACMD e ACME foram identificadas pela análise univariada. Resultados Quarenta e cinco pacientes com AVCi de ACMD e 67 de ACME foram analisados. Pacientes com AVCi de ACME tiveram maior incidência de fibrilação atrial (p = 0,031), enquanto de ACMD maior de AVCi prévio (p = 0,034). A mortalidade em 3 meses foi similar em ambos os grupos (OR = 1,20; 0,37 -4,29, p = 0,772). Conclusão O lado de acometimento da ACM no AVCi não influencia na mortalidade. .

A forced running wheel system with a microcontroller that provides high-intensity exercise training in an animal ischemic stroke model

We developed a forced non-electric-shock running wheel (FNESRW) system that provides rats with high-intensity exercise training using automatic exercise training patterns that are controlled by a microcontroller. The proposed system successfully makes a breakthrough in the traditional motorized running wheel to allow rats to perform high-intensity training and to enable comparisons with the treadmill at the same exercise intensity without any electric shock. A polyvinyl chloride runway with a rough rubber surface was coated on the periphery of the wheel so as to permit automatic acceleration training, and which allowed the rats to run consistently at high speeds (30 m/min for 1 h). An animal ischemic stroke model was used to validate the proposed system. FNESRW, treadmill, control, and sham groups were studied. The FNESRW and treadmill groups underwent 3 weeks of endurance running training. After 3 weeks, the experiments of middle cerebral artery occlusion, the modified neurological severity score (mNSS), an inclined plane test, and triphenyltetrazolium chloride were performed to evaluate the effectiveness of the proposed platform. The proposed platform showed that enhancement of motor function, mNSS, and infarct volumes was significantly stronger in the FNESRW group than the control group (P<0.05) and similar to the treadmill group. The experimental data demonstrated that the proposed platform can be applied to test the benefit of exercise-preconditioning-induced neuroprotection using the animal stroke model. Additional advantages of the FNESRW system include stand-alone capability, independence of subjective human adjustment, and ease of use.

Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia / La atorvastatina protege las neuronas gabérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Materials and methods: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. Results: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Conclusion: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Introducción. La isquemia cerebral es la tercera causa de muerte y la primera de discapacidad permanente en el mundo. La atorvastatina es un fármaco neuroprotector prometedor para el tratamiento de la apoplejía; sin embargo, su acción sobre las poblaciones neuronales del sistema nigroestriatal después de la isquemia aún se desconoce. Objetivo. Evaluar el efecto de la atorvastatina sobre poblaciones gabérgicas y dopaminérgicas en regiones exofocales en un modelo de oclusión transitoria de la arteria cerebral media. Materiales y métodos. Se utilizaron 28 ratas Wistar macho de ocho semanas de edad. Los ejemplares con isquemia simulada y los ejemplares sometidos a isquemia fueron tratados con atorvastatina (10 mg/kg) y carboximetilcelulosa (placebo) administrados por medio de sonda a las 6, 24, 48 y 72 horas después de la reperfusión. Se analizó la inmunorreacción de la descarboxilasa del ácido glutámico y de la tirosina hidroxilasa en el globo pálido, el putamen caudado y la sustancia negra. Resultados. Los datos confirmaron el daño neurológico y la pérdida celular en el putamen caudado. Se incrementó la inmunorreacción de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata , disminuyendo la inmunorreacción de la descarboxilasa del ácido glutámico en el globo pálido lateral de los animales isquémicos tratados con placebo; sin embargo, el tratamiento con atorvastatina pudo revertirla, lo que logró una disminución significativa de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata y aumentando los niveles de descarboxilasa del ácido glutámico en el globo pálido lateral. Conclusión. Nuestros datos sugieren que la atorvastatina en el tratamiento posterior a la isquemia ejerce neuroprotección en las zonas exofocales, modulando las poblaciones neuronales gabérgicas y dopaminérgicas del sistema nigroestriatal, lo que podría prevenir trastornos neurológicos.

Stroke associated with left atrial mass: Association of cerebral aneurysm with left atrial myxoma.

Association of LA myxoma with cerebral aneurysm is rare. We describe a patient who had LA mass and cerebral aneurysm and developed stroke. The patient underwent clipping of the cerebral aneurysm. We discuss the pathology of the association and the anesthetic management.

Transplantation of mouse embryonic stem cell after middle cerebral artery occlusion / Transplante de células-tronco embrionárias de camundongo após a oclusão da artéria cerebral média

PURPOSE: Stem cell transplantation has been extensively studied as individual therapies for ischemic stroke. The present investigation is an initial effort to combine these methods to achieve increased therapeutic effects after brain ischemia. Cell transplantation may recover massive neuronal loss by replacing damaged brain cells. METHODS: Undifferentiated mouse embryonic stem (mES) cells were used to induce differentiation in vitro into neuron-like cells with good cell viability for use a graft. In this study, middle cerebral artery occlusion (MCAO) was induced in rats using intra-luminal vascular occlusion, and infused mES cells after MCAO. The animals were examined behaviorally using motor and sensory test with neurological assessment. RESULTS: Motor function of the recipients was gradually improved, whereas little improvement was observed in control rats. This result may suggest that the grafted cells have synaptic connection in the recipient brain. Our study revealed that stem cell transplantation can have a positive effect on behavioral recovery and reduction of infarct size in focal ischemic rats. Consequently after euthanasia, rats were histochemically investigated to explore graft survival with green fluorescent protein (GFP). CONCLUSION: The mouse embryonic stem cells may have advantage for use as a donor source in various neurological disorders including motor dysfunction.

OBJETIVO: O transplante de células-tronco tem sido extensivamente estudado como terapias individuais para o AVC isquêmico. A presente investigação é um esforço inicial para combinar estes métodos para alcançar aumento de efeitos terapêuticos após a isquemia cerebral. O transplante de células pode recuperar a perda neuronal intensa, substituindo as células do cérebro danificado. MÉTODOS: Células tronco embrionárias indiferenciadas de camundongo foram utilizadas para induzir in vitro a diferenciação de células como neurônio com boa viabilidade para utilizar como enxerto. Neste estudo foi induzida a oclusão da artéria cerebral média em camundongos, usando a oclusão vascular intraluminal e células embrionárias infundidas. Os animais foram examinados comportamentalmente utilizando motor e teste sensorial com avaliação neurológica. RESULTADOS: A função motora dos receptores melhorou gradualmente, ao passo que pouca melhora foi observada nos animais controle. Este resultado pode sugerir que as células enxertadas têm conexão sináptica no cérebro receptor. Nosso estudo revelou que o transplante de células-tronco pode ter um efeito positivo na recuperação do comportamento e na redução do tamanho do infarto na isquêmica focal em camundongos. Após a eutanásia foi realizada análise histoquímica para avaliar a sobrevida do enxerto com proteína fluorescente verde (GFP). CONCLUSÃO: As células embrionárias de camundongo podem ser utilizadas como enxerto em várias desordens neurológicas, incluindo disfunção motora.

Expression of HSP70 in cerebral ischemia and neuroprotetive action of hypothermia and ketoprofen / Expressão de HSP70 na isquemia cerebral e a ação neuroprotetora da hipotermia e do cetoprofeno

Heat shock proteins (HSPs) are molecular chaperones that bind to other proteins to shepherd them across membranes and direct them to specific locations within a cell. Several injurious stimuli can induce Hsp70 expression, including ischemia. This study aimed to investigate the pattern of expression of protein (immunohistochemistry) and gene (real-time PCR) Hsp70 in experimental focal cerebral ischemia in rats by occlusion of the middle cerebral artery for 1 hour and the role of neuroprotection with hypothermia (H) and ketoprofen (K). The infarct volume was measured using morphometric analysis defined by triphenyl tetrazolium chloride. It was observed increases in the protein (p=0.0001) and gene (p=0.0001) Hsp70 receptor in the ischemic areas that were reduced by H (protein and gene: p<0.05), K (protein: p<0.001), and H+K (protein: p<0.01 and gene: p<0.05). The Hsp70 increases in the ischemic area suggests that the Hsp70-mediated neuroexcitotoxicity plays an important role in cell death and that the neuroprotective effect of both, H and K are directly involved with the Hsp70.

Proteínas de choque térmico (HSPs) são chaperones moleculares que se ligam a outras proteínas para atravessar as membranas e encaminhá-las para locais específicos dentro de uma célula. Vários estímulos nocivos podem induzir a expressão de Hsp70, incluindo isquemia. Este estudo teve como objetivo investigar o padrão de expressão protéica (imunohistoquímica) e gênica (PCR em tempo real) de Hsp70 na isquemia cerebral focal experimental em ratos pela oclusão da artéria cerebral média durante 1 hora e o papel da neuroproteção com hipotermia (H) e cetoprofeno (C). O volume de infarto foi calculado através da análise morfométrica definido por cloreto de trifenil tetrazólio. Foi observado aumento na expressão proteína (p=0,0001) e gênica (p=0,0001) de Hsp70 nas áreas isquêmicas que foram reduzidas pela H (proteína e gene: p<0,05), C (proteína: p<0,001) e H+K (proteína: p<0,01 e gene: p<0,05). O aumento de Hsp70 na área isquêmica sugere que a neuroexcitotoxicidade mediada pela Hsp70 desempenha um papel importante na morte celular e que o efeito neuroprotetor tanto da H quanto do C está diretamente envolvido com a Hsp70.

Effect of central microinjection of carbenoxolone in an experimental model of focal cerebral ischemia

Previous experimental studies have shown the protective effects of CBX on brain ischemic injures in global and in vitro models of ischemia. However, effects of CBX in temporary model of focal cerebral ischemia are not clear. Hence, the aim of this study was to investigate the effects of central micro injection of CBX on post-ischemic reperfusion injuries in a temporary model of focal cerebral ischemia. Transient focal cerebral ischemia was induced in rats by 60 min middle cerebral artery occlusion [MCAO], followed by 23 h reperfusion. CBX was administered into the right ventricle at doses of 1, 12, 25, 50 and/or 100 micro g/kg at the beginning of MCAO. Cortical and striatal infarct volumes and motor dysfunctions were assessed 24 h after MCAO. Administration of CBX at doses of 1, 12, 25 and/or 50 micro g/kg significantly reduced cortical infarct volumes by 35%, 49%, 41% and 43%, respectively [P<0.001]. In addition, CBX only at dose of 25 micro g/kg significantly reduced striatal infract volume and improved neurological dysfunctions [P<0.01]. Our findings indicated that central microinjection of CBX has protective effect on against ischemic reperfusion injuries in a transient model of focal cerebral ischemia

Evaluation of the neuroprotective effect of ketoprofen on rats submitted to permanent focal brain ischemia

OBJECTIVE: To study the neurobehavioral, biochemical and histopathological consequences of permanent focal brain ischemia, and the putative neuroprotective action of ketoprofen. METHOD: One-hundred-and-three Wistar rats divided into groups A and B were respectively submitted to 48 hours and 15 days of ischemia. Each group was divided into 4 subgroups: ischemic not treated, ischemic treated, sham not treated, and sham treated. Ischemic animals had the left middle cerebral artery coagulated. Ketoprofen was administered to treated subgroups 15 minutes before arterial coagulation (manipulation in the sham group). RESULTS: Exploratory activity and defecation were reduced in all ischemic animals in the first postoperative days and constant histopathological changes were observed in each group. The total brain glutamate levels were higher in treated animals 48 hours after surgery. CONCLUSION: No clear parallelism among behavioral, biochemical and histopathological findings was observed. Ketoprofen demonstrated no neuroprotective effect on the behavioral or histopathological aspects of focal permanent brain ischemia.

OBJETIVO: Estudar as conseqüências comportamentais, bioquímicas e histopatológicas da isquemia cerebral focal permanente e o possível efeito neuroprotetor do cetoprofeno. MÉTODO: Foram utilizados 103 ratos Wistar, divididos em grupos A e B, submetidos, respectivamente, a 48 horas e a 15 dias de isquemia. Cada grupo foi dividido em 4 subgrupos: isquêmico não tratado; isquêmico tratado; sham não tratado; sham tratado. Nos animais isquêmicos foi coagulada a artéria cerebral média esquerda. Os subgrupos tratados receberam cetoprofeno 15 minutos antes da oclusão ou manipulação arterial. RESULTADOS: Os animais isquêmicos reduziram a atividade exploratória e as evacuações nos primeiros dias pós-operatórios e mostraram alterações histopatológicas constantes em cada grupo. As concentrações do glutamato total 48 horas após a cirurgia foram maiores nos animais tratados. CONCLUSÃO: Não houve um paralelismo entre os achados comportamentais, bioquímicos e histopatológicos. O cetoprofeno não apresentou efeito protetor contra isquemia cerebral focal permanente, nos aspectos comportamentais e histopatológicos.

An early continuous experimental study on magnetic resonance diffusion-weighted image of focal cerebral ischemia and reperfusion in rats / 华中科技大学学报（医学）（英德文版）

The chronological and spatial rules of changes during focal cerebral ischemia and reperfusion in different brain regions with magnetic resonance diffusion-weighted imaging (DWI) in a model of occlusion of middle cerebral artery (MCAO) and the development of cytotoxic edema in acute phase were explored. Fifteen healthy S-D rats with MCA occluded by thread-emboli were randomly divided into three groups. 15 min after the operation, the serial imaging was scanned on DWI for the three groups. The relative mean signal intensity (RMSI) of the frontal lobe, parietal lobe, lateral cauda-putamen, medial cauda-putamen and the volume of regions of hyperintense signal on DWI were calculated. After the last DWI scanning, T2 WI was performed for the three groups. After 15 min ischemia, the rats was presented hyperintense signals on DWI. The regions of hyperintense signal were enlarged with prolonging ischemia time. The regions of hyperintense signal were back to normal after 60 min reperfusion with a small part remaining to show hyperintense signal. The RMSIs of parietal lobe and lateral cauda-putamen were higher than that of the frontal lobe and medial cauda-putamen both in ischemia phase and recanalization phase. The three groups were normal on T2 WI imaging. DWI had good sensitivity to acute cerebral ischemia, which was used to study the chronological and spatial rules of development of early cell edema in ischemia regions.