Obesity induces extracellular vesicle release from the endothelium as a contributor to brain damage after cerebral ischemia in rats.

OBJECTIVES: Cerebral ischemia is the most common cause of disability, the second most common cause of dementia, and the fourth most common cause of death in the developed world [Sveinsson OA, Kjartansson O, Valdimarsson EM. Heilablóðþurrð/heiladrep: Faraldsfræði, orsakir og einkenni [Cerebral ischemia/infarction - epidemiology, causes and symptoms]. Laeknabladid. 2014 May;100(5):271-9. Icelandic. doi:10.17992/lbl.2014.05.543]. Obesity has been associated with worse outcomes after ischemia in rats, triggering proinflammatory cytokine production related to the brain microvasculature. The way obesity triggers these effects remains mostly unknown. Therefore, the aim of this study was to elucidate the cellular mechanisms of damage triggered by obesity in the context of cerebral ischemia. METHODS: We used a rat model of obesity induced by a 20% high fructose diet (HFD) and evaluated peripheral alterations in plasma (lipid and cytokine profiles). Then, we performed cerebral ischemia surgery using two-vessel occlusion (2VO) and analyzed neurological/motor performance and glial activation. Next, we treated endothelial cell line cultures with glutamate in vitro to simulate an excitotoxic environment, and we added 20% plasma from obese rats. Subsequently, we isolated EVs released from endothelial cells and treated primary cultures of astrocytes with them. RESULTS: Rats fed a HFD had an increased BMI with dyslipidemia and high levels of proinflammatory cytokines. Glia from the obese rats exhibited altered morphology, suggesting hyperreactivity related to neurological and motor deficits. Plasma from obese rats induced activation of endothelial cells, increasing proinflammatory signals and releasing more EVs. Similarly, these EVs caused an increase in NF-κB and astrocyte cytotoxicity. Together, the results suggest that obesity activates proinflammatory signals in endothelial cells, resulting in the release of EVs that simultaneously contribute to astrocyte activation.

High fructose diet-induced obesity worsens post-ischemic brain injury in the hippocampus of female rats.

Objectives: Cerebral ischemia is caused by a reduction of the blood flow in a specific area in the brain, triggering cellular cascades in the tissue that result in neuronal death. This phenomenon leads to neurological decline in patients with stroke. The extent of the injury after stroke could be related to the condition of obesity. Thus, we aim to analyze the effect of obesity induced by a high fructose diet (HFD) on the brain after cerebral ischemia in rats.Methods: We induced the obesity model in female Wistar rats with 20% fructose in water for 11 weeks. We then performed cerebral ischemia surgery (2-vessel occlusion), carried out the neurological test 6, 24 and 48 h post-ischemia and analyzed the histological markers.Results: The HFD induced an obese phenotype without insulin resistance. The obese rats exhibited worse neurological performance at 6 h post-ischemia and showed neuronal loss and astroglial and microglial immunoreactivity changes in the caudate putamen, motor cortex, amygdala and hippocampus at 48 h post-ischemia. However, the most commonly affected area was the hippocampus, where we found an increase in interleukin 1ß in the blood vessels of the dentate gyrus, a remarkable disruption of MAP-2+ dendrites, a loss of brain-derived neurotrophic factor and the presence of PHF-tau. In conclusion, a HFD induces an obese phenotype and worsens the neuronal loss, inflammation and plasticity impairment in the hippocampus after cerebral ischemia.

Áreas exofocales de lesión a mediano y largo término post-isquemia cerebral / Exofocal areas of medium- and long-term injury after cerebral ischemia

La isquemia cerebral es el tipo de accidente cerebrovascular más común, generando altas tasas de mortalidad y morbilidad a nivel mundial. El entendimiento de la fisiopatología de la lesión cerebral ha requerido de la implementación de modelos experimentales que permitan evaluar los fenómenos celulares, sobre todo aquellos a largo plazo. Por tal razón, el objetivo del presente trabajo fue evaluar las áreas exofocales a un mes y cuatro meses post-isquemia cerebral en un modelo experimental. Ratas Wistar fueron sometidas a una isquemia focal transitoria (t-MCAo) y un grupo fueron sacrificados al mes y otro grupo a los cuatro meses post-isquemia para su posterior análisis histológico. Los cortes fueron teñidos con Nissl y se realizó inmunohistoquímica de la proteína Tau. Nuestros resultados muestran tres áreas de lesión exofocal tanto al mes como a los cuatro meses post-isquemia: el giro dentado, la amígdala y el tálamo. Estas regiones se han asociado al control emocional, lo cual sugiere que a largo término post-isquemia se tengan en cuenta hallazgos clínicos que evalúen cambios emocionales en los pacientes que han sufrido un evento isquémico cerebral.

Cerebral ischemia is the most common type of stroke, which generates high mortality and morbidity rates worldwide. The understanding of the pathophysiology of brain injury has required the implementation of experimental models that allow the evaluation of cellular phenomena, especially those in the long-term. For this reason, the objective of the present work was to evaluate the exofocal areas at one month and four months after cerebral ischemia. Wistar rats were subjected to transient focal ischemia (t-MCAo) and one group was sacrificed one month and another group at four months' post-ischemia for subsequent histological analysis. The cuts were stained with Nissl and immunohistochemistry of the Tau protein was performed. Our results show three areas of exofocal lesion both one month and four months' post-ischemia: the thalamus, the dentate gyrus, and the amygdala. These regions have been associated with emotional control, which suggests that in the long-term post-ischemia clinical findings that evaluate emotional changes in patients who have suffered a cerebral ischemic event should be considered.