miR-34b-3p Inhibition of eIF4E Causes Post-stroke Depression in Adult Mice / 神经科学通报·英文版

Post-stroke depression (PSD) is a serious and common complication of stroke, which seriously affects the rehabilitation of stroke patients. To date, the pathogenesis of PSD is unclear and effective treatments remain unavailable. Here, we established a mouse model of PSD through photothrombosis-induced focal ischemia. By using a combination of brain imaging, transcriptome sequencing, and bioinformatics analysis, we found that the hippocampus of PSD mice had a significantly lower metabolic level than other brain regions. RNA sequencing revealed a significant reduction of miR34b-3p, which was expressed in hippocampal neurons and inhibited the translation of eukaryotic translation initiation factor 4E (eIF4E). Furthermore, silencing eIF4E inactivated microglia, inhibited neuroinflammation, and abolished the depression-like behaviors in PSD mice. Together, our data demonstrated that insufficient miR34b-3p after stroke cannot inhibit eIF4E translation, which causes PSD by the activation of microglia in the hippocampus. Therefore, miR34b-3p and eIF4E may serve as potential therapeutic targets for the treatment of PSD.

Efecto terapéutico de los exosomas en el ACV isquémico en animales de experimentación / Therapeutic effect of exosomes on ischemic stroke in experimental animals

La posibilidad de que los exosomas funcionen como una nueva forma de comunicación intercelular para establecer y mantener circuitos cerebrales está comenzando a ser explorada. Los exosomas son liberados desde células e interactúan con otras células receptoras para mediar cambios fisiológicos. Todas las células cerebrales liberan exosomas incluyendo las celulas madre neuronales, las neuronas, astrocitos, microglia, oligodendrocitos y las celulas endoteliales. El objetivo de esta revisión es reunir evidencia actualizada sobre las funciones de protección, antiinflamación y regeneración de los exosomas en el ataque cerebrovascular (ACV) isquémico en ratas. Se realizó una búsqueda sistemática de la literatura sensible y específica en base de datos Medline, EMBASE, Web of Science, Scopus, TRIP database, SciELO y LILACS con términos libres y meSH. Los exosomas generados de CSMs pueden ser utilizados para el tratamiento del ACV. Los exosomas de oligodendrocitos también ejercen una variedad de efectos sobre las neuronas receptoras e influencian un amplio espectro de la fisiología neuronal. En conjunto estos resultados sugieren que los exosomas de las CSMs mediados con miR-133b se transfieren a astrocitos y neuronas, las que regulan la expresión génica, beneficiando tanto la remodelación de neuritas, como la recuperación funcional despues de un ACV. Sería importante en el futuro desarrollar métodos para cuantificar y caracterizar los exosomas en el cerebro con isquemia. Esto permitiría correlacionar entre la cantidad de exosomas en el cerebro y la recuperación funcional entregando información sobre sus mecanismos de acción.

The possibility that exosomes function as a new form of inter cellular communication to establish and maintain brain circuits is beginning to be investigated. Exosomes are released from cells and interact with other receptor cells to mediate physiological changes. All brain cells release exosomes including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes and endothelial cells. The aim of this review is to gather current evidence on the protective, anti-inflammatory and regenerative functions of exosomes in ischemic stroke in rats. A systematic search of sensitive and specific literature was carried out in the following database search engines: Medline, EMBASE, Web of Science, Scopus, TRIP database, SciELO and LILACS with free and MeSH terms data. MSC generated exosomes can be used in the treatment of stroke. Oligodendrocyte exosomes also exert a variety of effects on receptor neurons and influence a wide spectrum of neuronal physiology. Together these results suggest that MSC exosome-mediated transfer of miR-133b to astrocytes and neurons, thus regulating gene expression, benefiting both neurite remodeling, such as functional recovery following a stroke. It would be important in the future to develop methods to quantify and characterize exosomes in brain ischemia. This would allow correlation between the amount of exosomes in the brain and functional recovery providing information relevant to its action mechanisms.

Ischemic Stroke in Rats Enhances Bone Resorption in Vitro

We hypothesized that the formation and differentialtion of osteoclasts are accelerated and the potential of bone resorption is increased in the hemiplegic bone marrow in the early stage of stroke. We randomly divided white female Sprague-Dawley (SD) rats (n = 30) into two groups, stroke (n = 15) and sham group (n = 15). On the 7th day after stroke, after cutting away the epiphyses of the femurs and tibias, diaphyseal channels were flushed using alpha-minimum essential medium (alpha-MEM) and bone marrow cells were collected. Bone marrow stem cells, which were extracted from the femur and tibia, were cultured on the 7th day after middle cerebral artery occlusion. We then estimated the ratio of non-adherent cells to total bone marrow cells that included osteoclast precursor cells. After culturing these cells separately, cells that tested positive on the tartrate resistant acid phosphatase (TRAP) were counted and bone resorption was evaluated by using the OAAS(TM) plate. In comparison to the control group, the stroke group showed a higher increase of non-adherent cells in the hemiplegic side bone marrow. In addition, after the primary culture, the stroke group showed an increased number of TRAP positive cells and a higher degree of bone resorption estimated by OAAS(TM) plate. As a result, osteoclastogenesis and osteoclast differentiation are accelerated and the potential of bone resorption is increased in the hemiplegic bone marrow and these changes are detected as early as within the first week after middle cerebral artery occlusion in SD rats.

Functional and Histologic Changes After Repeated Transcranial Direct Current Stimulation in Rat Stroke Model

Transcranial direct current stimulation (tDCS) is associated with enhancement or weakening of the NMDA receptor activity and change of the cortical blood flow. Therefore, repeated tDCS of the brain with cerebrovascular injury will induce the functional and histologic changes. Sixty-one Sprague-Dawley rats with cerebrovascular injury were used. Twenty rats died during the experimental course. The 41 rats that survived were allocated to the exercise group, the anodal stimulation group, the cathodal stimulation group, or the control group according to the initial motor function. Two-week treatment schedules started from 2 days postoperatively. Garcia, modified foot fault, and rota-rod performance scores were checked at 2, 9, and 16 days postoperatively. After the experiments, rats were sacrificed for the evaluation of histologic changes (changes of the white matter axon and infarct volume). The anodal stimulation and exercise groups showed improvement of Garcia's and modified foot fault scores at 16 days postoperatively. No significant change of the infarct volume happened after exercise and tDCS. Neuronal axons at the internal capsule of infarct hemispheres showed better preserved axons in the anodal stimulation group. From these results, repeated tDCS might have a neuroprotective effect on neuronal axons in rat stroke model.

Early Motor Balance and Coordination Training Increased Synaptophysin in Subcortical Regions of the Ischemic Rat Brain

The aim of this study was to evaluate the effect of early motor balance and coordination training on functional recovery and brain plasticity in an ischemic rat stroke model, compared with simple locomotor exercise. Adult male Sprague-Dawley rats with cortical infarcts were trained under one of four conditions: nontrained control, treadmill training, motor training on the Rota-rod, or both Rota-rod and treadmill training. All types of training were performed from post-operation day 1 to 14. Neurological and behavioral performance was evaluated by Menzies' scale, the prehensile test, and the limb placement test, at post-operation day 1, 7, and 14. Both Rota-rod and treadmill training increased the expression of synaptophysin in subcortical regions of the ischemic hemisphere including the hippocampus, dentate gyrus, and thalamus, but did not affect levels of brain-derived neurotrophic factor or tyrosin kinase receptor B. The Rota-rod training also improved Menzies' scale and limb placement test scores, whereas the simple treadmill training did neither. The control group showed significant change only in Menzies' scale score. This study suggests that early motor balance and coordination training may induce plastic changes in subcortical regions of the ischemic hemisphere after stroke accompanied with the recovery of sensorimotor performance.

Homocisteína e transtornos psiquiátricos / Homocysteine and neuropsychiatric disorders

O autor apresenta uma visão geral da literatura atual sobre homocisteína como um fator de risco para os transtornos neuropsiquiátricos. Foram pesquisados os bancos de dados MEDLINE, Current Contents e EMBASE (entre 1966 e 2002) para publicações em língua inglesa utilizando as palavras-chave Homocisteína e AVC; Doença de Alzheimer; Déficit Cognitivo, Epilepsia, Depressão ou Doença de Parkinson. Artigos individuais foram pesquisados para referências cruzadas relevantes. É biologicamente plausível que altos níveis de homocisteína possam causar lesão cerebral e transtornos neuropsiquiátricos. A homocisteína é pró-aterogênica e pró-trombótica. Dessa forma, aumenta o risco de acidente vascular cerebral, podendo ter um efeito neurotóxico direto. Evidências de que a homocisteína seja um fator de risco para doença microvascular cerebral são conflitantes, mas justificam maiores estudos. Estudos transversais e alguns longitudinais suportam a crescente prevalência de acidente vascular cerebral e demência vascular em indivíduos com hiper-homocisteinemia. As evidências de crescente neurodegeneração estão se acumulando. A relação com a depressão ainda é experimental, da mesma forma como com a epilepsia. Atualmente, estudos sobre tratamentos são necessários para colocar as evidências sobre bases mais sólidas. Os pacientes de alto risco também devem ser pesquisados para hiper-homocisteínemia, cujo tratamento deve ser feito com ácido fólico. Mais evidências são necessárias antes que pesquisas populacionais possam ser recomendadas.

Surface Expression of P-selectin on Platelets Is Related with Clinical Worsening in Acute Ischemic Stroke

Platelet activation has a critical role in arterial disorders. In this study, we showed that the upregulation of P-selectin expression on platelets was related with clinical worsening in acute ischemic stroke. We serially (within 24 hr, at 72 hr, and 7 days) measured the expression of P-selectin on platelets in patients with acute ischemic stroke (n=45) and investigated the correlation between their extents and clinical severity of ischemic stroke. A significant relationship between the P-selectin expressions and National Institute of Health Stroke Scale (NIHSS) was observed at 72 hr and 7 days after ischemic stroke onset. Patients with clinical deterioration showed significantly increased expression of P-selectin on platelets as compared to those without deterioration. These results suggest that the P-selectin expression on platelets may contribute to the aggravation of clinical course in acute ischemic stroke. Thus, adequate manipulation of activated platelets is an important therapeutic strategy in acute ischemic stroke.