Abstract
SUMMARYBrain ischemia, also termed cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand, leading to tissue death (cerebral infarction) due to poor oxygen supply (cerebral hypoxia). Our group is interested in the protective effects of neuropeptides for alleviating brain ischemia, as well as the underlying mechanisms of their action. The present study was initiated to investigate molecular responses at the level of gene expression in ischemic brain tissue. To achieve this, we used a mouse permanent middle cerebral artery occlusion (PMCAO) model in combination with high-throughput DNA microarray analysis on an Agilent microarray platform. Briefly, the right (ipsilateral) and left (contralateral) hemispheres of PMCAO model mice were dissected at two time points, 6 and 24 hours post-ischemia. Total RNA from the ischemic (ipsilateral) hemisphere was subjected to DNA microarray analysis on a mouse whole genome 4x44K DNA chip using a dye-swap approach. Functional categorization using the gene ontology (GO, MGD/AMIGO) of numerous changed genes revealed expression pattern changes in the major categories of cellular process, biological regulation, regulation of biological process, metabolic process and response to stimulus. Reverse-transcriptase PCR (RT-PCR) analysis on randomly selected highly up- or downregulated genes validated, in general, the microarray data. Using two time points for this analysis, major and minor trends in gene expression and/or functions were observed in relation to early- and late-response genes and differentially regulated genes that were further classified into specific pathways or disease states. We also examined the expression of these genes in the contralateral hemisphere, which suggested the presence of bilateral effects and/or differential regulation. This study provides the first ischemia-related transcriptome analysis of the mouse brain, laying a strong foundation for studies designed to elucidate the mechanisms regulating ischemia and to explore the neuroprotective effects of agents such as target neuropeptides.
Highlights
Brain ischemia, known as cerebral ischemia or ischemic stroke, is the third most common cause of death worldwide, after heart attack and cancer, resulting in major negative social and economic consequences
Changes in gene expressions in the ischemic brain and their functional categorization Using the total RNA in the ischemic hemisphere and the 4x44K mouse whole genome DNA microarray chip in conjunction with a dye-swap approach, genome-wide global gene expression profiles were obtained for ischemia-related genes
On the basis of a highthroughput transcriptomics approach on a 44K DNA microarray chip, we have identified numerous genes with potential involvement in the regulation of brain ischemia, and most of the genes that have previously been reported in targeted studies
Summary
Known as cerebral ischemia or ischemic stroke, is the third most common cause of death worldwide, after heart attack and cancer, resulting in major negative social and economic consequences. Ischemic stroke, which results from cardiac arrest, cerebral arterial occlusion or severe vasospasm after subarachnoid ischemia, causes devastating damage to the brain and represents a serious global health problem. The most common cause of stroke is the sudden occlusion of a blood vessel by a thrombus or embolism, resulting in an almost immediate loss of oxygen and glucose to the cerebral tissue. The obstruction of cerebral blood flow induces time-dependent pathophysiological changes in brain tissue, including tissue necrosis, and can cause death if the situation is not resolved quickly. The most important aspects of therapy for brain ischemia after onset of disease is that the patient adopts a healthy lifestyle (including diet, exercise and rest) and undergoes long-term rehabilitation to improve residual brain function
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