Noncoding RNAs and Intracerebral Hemorrhage

Author(s): Lingzhi Li, Pingping Wang, Haiping Zhao*, Yumin Luo*

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 3 , 2019

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Graphical Abstract:


Background & Objective: Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke, for which there are few effective interventions. Computed tomography is accepted as the gold standard for diagnosis, whereas surgical evacuation is the main treatment for ICH. However, in emergency rooms, time is limited and information regarding a patient’s clinical status or tolerance is typically not available. Many studies over the last decade have investigated the fundamental mechanisms of ICH and especially hematoma, which not only cause physical damage but also release toxins that have detrimental effects. However, there remain many gaps in our understanding of ICH. Compared to ischemic stroke, there is little known about the ICH pathogenesis and treatment options, and few specific biomarkers are available for monitoring disease progression, which include hematoma enlargement and perihematoma edema. Noncoding RNAs (ncRNAs) are involved in various biological processes and are potential biomarkers and therapeutic tools in central nervous system diseases. Recent studies have examined the role of ncRNAs including microRNAs, long noncoding RNAs, and circular RNAs—the three main subgroups associated with stroke—in ICH models. A deeper understanding of the functions of ncRNAs in different biological processes can provide a basis for developing more effective therapeutic strategies to prevent neuronal damage following ICH. In clinical settings, ncRNAs can serve as biomarkers for predicting the degree of injury resulting from ICH.

Conclusion: In this review, we discuss the current state of knowledge of the role of ncRNAs in ICH.

Keywords: Intracerebral hemorrhage, miRNA, lncRNA, circRNA, exosome, transcriptome.

Members WG, Benjamin EJ, Blaha MJ, et al. Heart disease and stroke statistics-2017 update: a report from the american heart association. Circulation 2017; 131(4): e29.
Dowlatshahi D, Demchuk AM, Flaherty ML, et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology 2011; 76(14): 1238-44.
Balami JS, Buchan AM. Complications of intracerebral haemorrhage. Lancet Neurol 2012; 11(1): 101-18.
Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, et al. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol 2012; 11(4): 307-14.
Morgenstern LB, Hemphill JC, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Neurosurgery 2015; 46(7): 2032-60.
Hemphill JCI, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2015; 46(7): 2032-60.
Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol 2012; 11(8): 720-31.
Wilkinson DA, Pandey AS, Thompson BG, Keep RF, Hua Y, Xi G. Injury mechanisms in acute intracerebral hemorrhageNeuropharmacology 2018; 134(Pt B): 240-8
Ni W, Mao S, Xi G, Keep RF, Hua Y. Role of erythrocyte CD47 in intracerebral hematoma clearance. Stroke 2016; 47(2): 505.
Liu R, Cao SL, Hua Y, Keep RF, Huang YN, Xi GH. CD163 Expression in neurons after experimental intracerebral hemorrhage. Stroke 2017; 48(5): 1369-75.
Zhao XR, Sun GH, Ting SM, et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem 2015; 133(1): 144-52.
Askenase MH, Sansing LH. Stages of the inflammatory response in pathology and tissue repair after intracerebral hemorrhage. Semin Neurol 2016; 36(3): 288-97.
Duris K, Lipkova J. The role of microRNA in ischemic and hemorrhagic stroke. Curr Drug Deliv 2016; 13(999): 1.
Friedman RC, Farh K, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19(1): 92-105.
Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008; 9(2): 102-14.
Lewis BP, Shih IH, Jonesrhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell 2003; 115(7): 787-98.
Zheng H, Wang Y, Lin J, et al. Circulating MicroRNAs as potential risk biomarkers for hematoma enlargement after intracerebral hemorrhage. CNS Neurosci Ther 2012; 18(12): 1003-11.
Guo D, Liu J, Wang W, et al. Alteration in abundance and compartmentalization of inflammation-related mirnas in plasma after intracerebral hemorrhage. Stroke 2013; 44(6): 1739.
Zhu Y, Wang JL, He ZY, Jin F, Tang L. Association of altered serum micrornas with perihematomal edema after acute intracerebral hemorrhage. PLoS One 2015; 10(7): e133783.
Iwuchukwu I, Nguyen D, Sulaiman W. MicroRNA profile in cerebrospinal fluid and plasma of patients with spontaneous intracerebral hemorrhage. CNS Neurosci Ther 2016; 22(12): 1015.
Kong F, Zhou J, Zhou W, Guo Y, Li G, Yang L. Protective role of microRNA-126 in intracerebral hemorrhage. Mol Med Rep 2017; 15(3): 1419.
Wang MD, Wang Y, Xia YP, et al. High serum MiR-130a levels are associated with severe perihematomal edema and predict adverse outcome in acute ICH. Mol Neurobiol 2016; 53(2): 1-12.
Wang Z, Gang L, Sze J, et al. Plasma miR-124 is a promising candidate biomarker for human intracerebral hemorrhage stroke. Mol Neurobiol 2018; 55(7): 1-10.
Rangarajan P, Eng-Ang L, Dheen ST. Potential drugs targeting microglia: current knowledge and future prospects. CNS Neurol Disord Drug Targets 2013; 12(6): 799-806.
Zhen Z, Zhang Z, Hong L, Yang Q, He W, Jian W. Microglial polarization and inflammatory mediators after intracerebral hemorrhage. Mol Neurobiol 2017; 54(3): 1874-86.
Wang M, Mungur R, Lan P, Wang P, Wan S. MicroRNA-21 and microRNA-146a negatively regulate the secondary inflammatory response of microglia after intracerebral hemorrhage. Int J Clin Exp Pathol 2018; 11(7): 3348-56.
Zhang Y, Han B, He Y, et al. MicroRNA-132 attenuates neurobehavioral and neuropathological changes associated with intracerebral hemorrhage in mice. Neurochem Int 2016; 107: 182.
Shu W, Cheng Y, Hang J, et al. Microglia Activation and polarization after intracerebral hemorrhage in mice: the role of protease-activated receptor-1. Transl Stroke Res 2016; 7(6): 1-10.
Min Y, Chen Z, Ouyang Y, et al. Thrombin-induced, TNFR-dependent miR-181c downregulation promotes MLL1 and NF-κB target gene expression in human microglia. J Neuroinflammation 2017; 14(1): 132.
Qian H, Hu K, Xie M, et al. Intracerebroventricular injection of miR-7 inhibits secondary brain injury induced by intracerebral hemorrhage via EGFR/STAT3 pathway in rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2018; 34(2): 141.
Lan X, Han X, Li Q, Yang QW, Wang J. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol 2017; 13(7): 420.
Yu A, Zhang T, Duan H, et al. MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-α pathway in intracerebral hemorrhage. Immunol Lett 2016; 182: 1.
Kim TW, Staschke K, Bulek K, et al. A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. J Exp Med 2007; 204(5): 1025-36.
Yuan B, Shen H, Lin L, Su T, Zhong L, Yang Z. MicroRNA367 negatively regulates the inflammatory response of microglia by targeting IRAK4 in intracerebral hemorrhage. J Neuroinflammation 2015; 12(1): 206.
Yang Z, Zhong L, Xian R, Yuan B. MicroRNA-223 regulates inflammation and brain injury via feedback to NLRP3 inflammasome after intracerebral hemorrhage. Mol Immunol 2015; 65(2): 267-76.
Xu H, Fang X, Zhu S, et al. Glucocorticoid treatment inhibits intracerebral hemorrhage-induced inflammation by targeting the microRNA-155/SOCS-1 signaling pathway. Mol Med Rep 2016; 14(4): 3798-804.
Yu AY, Zhang TX, Zhong WY, et al. miRNA-144 induces microglial autophagy and inflammation following intracerebral hemorrhage. Immunol Lett 2017; 182: 18-23.
Hu YL, Wang H, Huang Q, Wang G, Zhang HB. MicroRNA-23a-3p promotes the perihematomal edema formation after intracerebral hemorrhage via ZO-1. Eur Rev Med Pharmacol Sci 2018; 22(9): 2809.
Ma XL, Li SY, Shang F. Effect of microRNA-129-5p targeting HMGB1-RAGE signaling pathway on revascularization in a collagenase-induced intracerebral hemorrhage rat model. Biomed Pharmacother 2017; 93: 238.
Xi T, Jin F, Zhu Y, et al. MicroRNA-126-3p attenuates blood-brain barrier disruption, cerebral edema and neuronal injury following intracerebral hemorrhage by regulating PIK3R2 and Akt. Biochem Biophys Res Commun 2017; 494(1-2): 144.
Jeong-Min K. The inhibition of microRNA 466b facilitates neurological recovery in a rat intracerebral haemorrhage model by activating insulin-like growth factor pathway. Hum Gene Ther 2017; 28(12): A81.
Kim JH, Choi JS. MicroRNA-34a regulates brain-derived neurotrophic factor in an intracerebral hemorrhage model. Turk J Biol 2017; 41(2): 249-55.
Kamal MA, Mushtaq G, Greig NH. Current update on synopsis of mirna dysregulation in neurological disorders. CNS Neurol Disord Drug Targets 2015; 14(4): 492-501.
Moon J, Kim JM, Byun JI, et al. The therapeutic potential of MicroRNA regulation in a rat intracerebral hemorrhage model. Mol Ther 2013; 211: S229.
Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell 2009; 136(4): 629-41.
Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell 2011; 43(6): 904-14.
Quan Z, Zheng D, Hong Q. Regulatory roles of long non-coding rnas in the central nervous system and associated neurodegenerative diseases. Front Cell Neurosci 2017; 11: 175.
Cui HJ, Tao L, Li PF, et al. Altered long noncoding RNA and messenger RNA expression in experimental intracerebral hemorrhage - a preliminary study. Cell Physiol Biochem 2018; 45(3): 1284-301.
Hung IL, Hung YC, Wang LY, et al. Chinese herbal products for ischemic stroke. Am J Chin Med 2015; 43(7): 1365-79.
Cui H, Liu T, Li P, et al. An intersectional study of lncrnas and mrnas reveals the potential therapeutic targets of buyang huanwu decoction in experimental intracerebral hemorrhage. Cell Physiol Biochem 2018; 46(5): 2173-86.
Liu B, Sun L, Liu Q, et al. A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 2015; 27(3): 370-81.
Jia J, Zhang M, Li Q, Zhou Q, Jiang Y. Long noncoding ribonucleic acid NKILA induces the endoplasmic reticulum stress/ autophagy pathway and inhibits the nuclear factor-k-gene binding pathway in rats after intracerebral hemorrhage. J Cell Physiol 2018; 233(11): 8839-49.
Wen J, Yang CY, Lu J, Wang XY. Ptprj-as1 mediates inflammatory injury after intracerebral hemorrhage by activating NF-kappa B pathway. Eur Rev Med Pharmaco 2018; 22(9): 2817-23.
Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet 2016; 17(5): 272.
Dong B, Zhou B, Sun Z, et al. LncRNA-FENDRR mediates VEGFA to promote the apoptosis of brain microvascular endothelial cells via regulating miR-126 in mice with hypertensive intracerebral hemorrhage. Microcirculation 2018; e12499.
Ebbesen KK, Kjems J, Hansen TB. Circular RNAs: identification, biogenesis and function. Biochimica Et Biophysica Acta 2016; 1859(1): 163-8.
Venø MT, Hansen TB, Venø ST, et al. Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol 2015; 16(1): 245.
Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 2015; 25(8): 981-4.
Grasso M, Piscopo P, Confaloni A, Denti MA. Circulating miRNAs as biomarkers for neurodegenerative disorders. Molecules 2014; 19(5): 6891.
Lu D, Xu A. Mini review: circular RNAs as potential clinical biomarkers for disorders in the central nervous system. Front Genet 2016; 7: 53.
Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013; 495(7441): 384-8.
Ashwal-Fluss R, Meyer M, Pamudurti NR, et al. circRNA Biogenesis Competes with Pre-mRNA Splicing. Mol Cell 2014; 56(1): 55-66.
Mehta SL, Pandi G, Vemuganti R. Circular RNA expression profiles alter significantly in mouse brain after transient focal ischemia. Stroke 2017; 48(9): 2541.
Liu C, Zhang C, Yang J, et al. Screening circular RNA expression patterns following focal cerebral ischemia in mice. Oncotarget 2017; 8(49): 86535-47.
Bai Y, Zhang Y, Han B, et al. Circular RNA DLGAP4 ameliorates ischemic stroke outcomes by targeting mir-143 to regulate endothelial-mesenchymal transition associated with blood-brain barrier integrity. J Neurosci 2018; 38(1): 32-50.
Han B, Zhang Y, Zhang Y, et al. Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke. Autophagy 2018; 14(7): 1164-84.
Mcgough IJ, Vincent JP. Exosomes in developmental signalling. Development 2016; 143(14): 2482-93.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654.
Farooqi AA, Desai NN, Qureshi MZ, et al. Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds. Biotechnol Adv 2018; 36(1): 328-34.
Chen K, Chen C, Wallace CG, et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 2016; 7(46): 74537-56.
Carvallo P, Astudillo P. Therapeutic effect of exosomes on ischemic stroke in experimental animals. Int J Morphol 2016; 34(4): 1300-7.
Kaiser EE, Jurgielewicz BJ, Spellicy SE, et al. Neural stem cell derived exosome treatment promotes recovery in a porcine model of ischemic stroke. Xenotransplantation 2017; 24(5)
Chen YJ, Song YY, Huang J, et al. Increased circulating exosomal mirna-223 is associated with acute ischemic stroke. Front Neurol 2017; 8: 57.
Ji QH, Ji YH, Peng JW, et al. Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients. PLoS One 2016; 11(9)
Jiang M, Wang HR, Zin MM, et al. Exosomes from MiR-30d-5p-ADSCs reverse acute ischemic stroke-induced, autophagy-mediated brain injury by promoting M2 Microglial/Macrophage polarization. Cell Physiol Biochem 2018; 47(2): 864-78.
Otero-Ortega L, de Frutos M, Laso-Garcia F, et al. Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab 2018; 38(5): 767-79.
Shen HT, Yao XY, Li HY, et al. Role of exosomes derived from mir-133b modified mscs in an experimental rat model of intracerebral hemorrhage. J Mol Neurosci 2018; 64(3): 421-30.
Marbán E. The secret life of exosomes: what bees can teach us about next-generation therapeutics. J Am Coll Cardiol 2018; 71(2): 193-200.
Sharma S, Taliyan R, Sarathlal KC. Epigenetics in neurodegenerative diseases: the role of histone deacetylases. CNS Neurol Disord Drug Targets 2018.
Bourassa MW, Ratan RR. The interplay between microRNAs and histone deacetylases in neurological diseases. Neurochem Int 2014; 77: 33-9.

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Year: 2019
Page: [205 - 211]
Pages: 7
DOI: 10.2174/1871527318666190204102604
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