Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream

Even when figured out is this going to be faster than these other fast options?

TIME IS BRAIN, you know, so  I'd suggest these much much faster options.

Maybe you want these much faster objective diagnosis options.

Hats off to Helmet of Hope - stroke diagnosis in 30 seconds; February 2017

Microwave Imaging for Brain Stroke Detection and Monitoring using High Performance Computing in 94 seconds March 2017

 

New Device Quickly Assesses Brain Bleeding in Head Injuries - 5-10 minutes April 2017

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Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream

Pasquale Cepparulo¹, Ornella Cuomo¹, Antonio Vinciguerra¹, Monica Torelli¹, Lucio Annunziato² and Giuseppe Pignataro^1*

• ¹Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy
• ²Istituto di Ricovero e Cura a Carattere Scientifico SDN Napoli, Naples, Italy

To date, the only effective pharmacological treatment for ischemic stroke is limited to the clinical use of recombinant tissue plasminogen activator (rtPA), although endovascular therapy has also emerged as an effective treatment for acute ischemic stroke. Unfortunately, the benefit of this treatment is limited to a 4.5-h time window. Most importantly, the use of rtPA is contraindicated in the case of hemorrhagic stroke. Therefore, the identification of a reliable biomarker to distinguish hemorrhagic from ischemic stroke could provide several advantages, including an earlier diagnosis, a better treatment, and a faster decision on ruling out hemorrhage so that tPA may be administered earlier. microRNAs (miRNAs) are stable non-coding RNAs crucially involved in the downregulation of gene expression via mRNA cleavage or translational repression. In the present paper, taking advantage of three preclinical animal models of stroke, we compared the miRNA blood levels of animals subjected to permanent or transient middle cerebral artery occlusion (MCAO) or to collagenase-induced hemorrhagic stroke. Preliminarily, we examined the rat miRNome in the brain tissue of ischemic and sham-operated rats; then, we selected those miRNAs whose expression was significantly modulated after stroke to create a list of miRNAs potentially involved in stroke damage. These selected miRNAs were then evaluated at different time intervals in the blood of rats subjected to permanent or transient focal ischemia or to hemorrhagic stroke. We found that four miRNAs—miR-16-5p, miR-101a-3p, miR-218-5p, and miR-27b-3p—were significantly upregulated in the plasma of rats 3 h after permanent MCAO, whereas four other different miRNAs—miR-150-5p, let-7b-5p, let-7c-5p, and miR-181b-5p—were selectively upregulated by collagenase-induced hemorrhagic stroke. Collectively, our study identified some selective miRNAs expressed in the plasma of hemorrhagic rats and pointed out the importance of a precise time point measurement to render more reliable the use of miRNAs as stroke biomarkers.

Introduction

Cerebral ischemia results from the interruption of blood flow to a brain region caused by two possible events: a hemorrhagic break or an ischemic occlusion of a cerebral vessel (1, 2). Hemorrhagic stroke accounts for 15% of all strokes, whereas ischemic stroke accounts for 85% of cases. According to the Global Burden of Disease Study, performed from 1990 to 2013, stroke is the second main cause of death (representing 11.8% of all deaths worldwide) and the third leading cause of disability-adjusted life years worldwide (3–6).

To date, the only effective pharmacological treatment for ischemic stroke is limited to the use of recombinant tissue plasminogen activator (rtPA) (7), although endovascular therapy has also emerged as an effective treatment for acute ischemic stroke (8). By contrast, the emergency treatment of hemorrhagic stroke focuses on controlling bleeding and reducing pressure in the brain (1, 2). Unfortunately, the benefit of rtPA treatment for ischemic stroke is time dependent, limited to a 4.5-h therapeutic time window, a largely recognized useful time for penumbra restoring; therefore, the majority of patients cannot benefit from this therapy (9, 10) due to the longer average time needed to carry out an effective diagnosis and therapeutic directioning (11). Most importantly, the use of rt-PA is contraindicated in the case of hemorrhagic stroke, as it would worsen the hemorrhage.

Modern neuroimaging tools, such as computed tomography (CT) or magnetic resonance imaging (MRI), are now used to diagnose a stroke and identify its subtype (12, 13). However, some hospitals do not yet provide MRI and CT service, and many patients cannot benefit from these techniques in the diagnostic process. Moreover, the time required to reach the medical center and to prepare the patients for imaging tests often does not match with the urgency of an early diagnosis for an immediate therapy. In addition, the application of these imaging tools weighs on stroke care costs (14). For all these reasons, the search of biomarkers is critically important to speed up the diagnosis of stroke and selectively distinguish cerebral ischemia from hemorrhagic damage in order to ensure therapeutic interventions in a very short time frame from the onset of the disease.

microRNAs (miRNAs) are evolutionarily conserved non-coding RNAs consisting of 20–22 nucleotides (15), crucially involved in the downregulation of gene expression via mRNA cleavage or translational repression (16). Over the last 10 years, the role of miRNAs in stroke has been widely discussed and evaluated, focusing attention on the regulation of stroke risk factors (17) and the mechanisms activated and elicited by the ischemic insult (18).

For the first time, in the last decade, miRNAs have been observed outside the cells, including in various body fluids (19). Several release mechanisms have been hypothesized: one of these consists in microRNA release by cells through microvesicles that originate by outward budding and fission of the plasma membrane (20). Moreover, a specific type of vesicle with a characteristic process of biogenesis, called exosomes, is shown to be enriched of miRNA and involved in the phenomena of cell-to-cell communication (21). Alternative mechanisms of miRNA transport concern the activity of apoptotic bodies, formed during the programmed cell death, and high-density lipoproteins. In this scenario, circulating microRNAs become important mediators of cell communication by altering the gene expression of recipient cells, and the modification of their release in biofluids reflects the expression changes occurring in the origin cells (22).

Whatever the origin of miRNA is, the presence of microRNA in blood and the ability to measure their levels in a non-invasive way have opened new doors in the search for peripheral biomarkers for the diagnosis and prognosis of diseases such as brain ischemia. Indeed the expression levels of miRNAs in blood are reproducible and indicative of several diseases (23). Since the recommended therapeutic window is very limited, the biomarkers for stroke have the potential to expedite diagnosis and the institution of treatment.

In the present comparative report, the plasma microRNA levels were assessed in both rat models of ischemic and hemorrhagic stroke in order to characterize a specific signature of microRNA potentially useful to distinguish among stroke subtypes.