Abstract
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.
Highlights
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]
Circulating miR-16-5p, miR-101a-3p, miR-218a-5p, and miR-27b-3p Are Upregulated in the Plasma of Rats 3 h After middle cerebral artery occlusion (MCAO) Onset
Among the 15 microRNAs selected from the microarray analysis, 11 miRNAs showed no significant difference in plasma samples at all times assessed after cerebral ischemia compared to the control group (Figures 2A–C,E–J,L,O)
Summary
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]. The only effective pharmacological treatment for ischemic stroke is limited to the use of recombinant tissue plasminogen activator (rtPA) [7], endovascular therapy has emerged as an effective treatment for acute ischemic stroke [8]. The emergency treatment of hemorrhagic stroke focuses on controlling bleeding and reducing pressure in the brain [1, 2]. 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; 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]. The use of rt-PA is contraindicated in the case of hemorrhagic stroke, as it would worsen the hemorrhage
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