The Role of Circular RNAs in Brain Injury

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The Role of Circular RNAs in Brain Injury

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Huaxin Zhu, a,b Zelong Xing, a Yueyu Zhao, a Zheng Hao a and Meihua Li a*

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a

Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang 330006, Jiangxi, China

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Department of Preventive Medicine, Jiujiang University, No. 57, Xiangyang East Road, Yuyang District, Jiujiang 332000, Jiangxi, China

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Abstract—Circular RNAs are an increasingly important topic in non-coding RNA biology, drawing considerable attention in recent years. Accumulating evidence suggests a critical role for circular RNAs in both early and latent stages of disease pathogenesis. Circular RNAs are abundantly expressed in brain tissue, with significant implications for neural development and disease progression. Disruption of these processes, including those seen in response to brain injury, can have serious consequences such as hemiplegia, aphasia, coma, and death. In this review, we describe the role of circular RNAs in the context of brain injury and explore the potential connection between circular RNAs, brain hypoxic ischemic injury, ischemia–reperfusion injury, and traumatic injury. Ó 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

Key words: circular RNAs, brain injury, hypoxic ischemic injury, ischemia–reperfusion injury, traumatic brain injury.

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INTRODUCTION

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Circular RNAs, a special type of non-coding RNA (ncRNA) characterized by a covalently closed loop structure, were first discovered in the 1970s (Sanger et al., 1976). Once regarded as a nonfunctional byproduct of RNA processing with no apparent function, these ncRNAs have been shown to play important roles in mRNA stability and function via their activity as microRNA (miR) sponges, translation modulators, and biomarkers (Burd et al., 2010; Hansen et al., 2013; Memczak et al., 2013; Zhang et al., 2013). Given their high level of expression in neural tissues, circular RNAs are thought to play an important role in the development of the adult brain (Rybak-Wolf et al., 2015). The brain is the most delicate organ in the human body, serving as a seat of human consciousness, dominating the ways in which we act, feel, speak, and more (Zeki and Shipp, 1988; Tononi et al., 1998; Friston, 2002). Any injury to the brain comes with the potential for serious consequences, including the possibility of permanent damage that can lead to heavy burdens

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*Corresponding author. E-mail address: [email protected] (M. Li). Abbreviations: AD, Alzheimer’s disease; BBB, blood brain barrier; ciRNAs, circular intron RNAs; CNS, central nervous system; ecircRNAs, exon circRNAs; EIciRNA, sexon intron circRNAs; EndoMT, endothelial-mesenchymal transition; GO, Gene Ontology; HIE, hypoxic ischemic encephalopathy; IRI, ischemia–reperfusion injury; KEGG, Kyoto Encyclopedia of Genes and Genomes; lncRNA, long noncoding RNA; miRNAs, microRNAs; OGD/R, oxygen-glucose deprivation/reoxygenation; pre-mRNA, precursor mRNA; RBPs, RNA binding proteins; TBI, traumatic brain injury; TLE, temporal lobe epilepsy.

on the patient’s family (Steyerberg et al., 2008; Brazinova et al., 2016). Furthermore, once brain injuries have occurred, there are no efficient pharmacotherapeutic options to attenuate or slow tissue injury and organ dysfunction (Sobrino and Shafi, 2013; Brazinova et al., 2016; Cancelliere et al., 2017). For example, conditions such as ischemic stroke can lead to widespread paralysis, while traumatic brain injuries may lead to a coma and death (Steyerberg et al., 2008; Zhang et al., 2019). Many studies have shown that circular RNAs are important for brain disorders such as Alzheimer’s disease, Parkinson’s disease, and glioma (Huang et al., 2017; Akhter, 2018). In this review, we explore the connection between circular RNAs and brain injury, and the potential role circular RNAs play in the pathogenesis of brain damage.

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BIOGENESIS OF CIRCULAR RNA

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Circular RNAs are classified into three categories: exon circRNAs (ecircRNAs), exon intron circRNAs (EIciRNAs), and circular intron RNAs (ciRNAs) (Table1). EcircRNAs mainly localized in cytoplasm, generate by back-splicing and have multiple functions. EIciRNAs are considered an intermediate product in the production of ecircRNAs and localized in nucleus (Li et al., 2015a,b). ciRNAs are considered a byproduct of back-splicing and canonical splicing and localized in nucleus (Zhang et al., 2013). Both EIciRNAs and ciRNAs might affect parental genes (Lu et al., 2015; Li et al., 2017). Back-splicing includes intron pairing-driven circularization, exon skipping and RNA-binding proteins (RBPs).

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https://doi.org/10.1016/j.neuroscience.2019.12.018 0306-4522/Ó 2020 IBRO. Published by Elsevier Ltd. All rights reserved. 1 Please cite this article in press as: Zhu H et al. The Role of Circular RNAs in Brain Injury. Neuroscience (2020), https://doi.org/10.1016/j.neuroscience.2019.12.018

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Table 1. circRNA categories circRNA forms

Location

Biogenesis

Function

exon circRNAs (ecircRNAs)

cytoplasm

Back-splicing*

circular intron RNAs (ciRNAs) exon intron circRNAs (EIciRNAs)

nucleus nucleus

Back-splicing* and canonical splice Back-splicing*

EcircRNAs might compete with the canonical splice of pre-mRNAs, act as a sponge for miRNAs, be translated and as biomarkers CiRNAs might affect parental genes EIciRNAs might affect parental genes

*Back-splicing includes intron pairing-driven circularization, exon skipping and RNA-binding proteins (RBPs).

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Intron pairing-driven circularization 0

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Almost every exon has splicing signals at its 5 and 3 ends that are capable of forming circular RNAs; however, due to the extremely low efficiency of backsplicing, only a small number of back-splicing events are induced in cells (Zhang et al., 2013, 2014, 2016). The majority of observed circular RNAs contain 2–3 exons, with all relevant introns having been lost during routine processing. Back-splicing events typically do not require a particular sequence; however, they do require base pairing interactions between flanking intronic elements (Wilusz, 2018). As the introns flanking circularized exons are typically longer than average, Jeck et al. (2013) were able to identify Alu repetitive elements in these regions that play a crucial role in intron pairing-driven cyclization. Using CRISPR-Cas9 expression plasmids to remove intronic repeats from endogenous gene loci has proven that base pairing between intronic repeats is essential for circular RNA production (Liang and Wilusz, 2014; Zhang et al., 2014, 2016; Kramer et al., 2015; Starke et al., 2015). Alternatively, when base pairing occurs across different introns, back-splicing is induced to generate a circular RNA composed of the intervening exon (Fig. 1a). Although there is competition between canonical-splicing and back-splicing, 100 nt of each repeat is sufficient for exon circularization (Kramer et al., 2015; Liang et al., 2017). At some gene loci, short (30-nt) intronic repeats provide sufficient base pairing to promote RNA circularization (Liang and Wilusz, 2014; Kramer et al., 2015). Depending on how the repetitive elements base pair to one another, one precursor mRNA (pre-mRNA) has the potential to generate very different spliced isoforms and circular RNAs (Zhang et al., 2014).

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Exon skipping

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Recent studies have identified a new mechanism of circular RNA production in which the 30 splice site of the exon upstream of the pre-mRNA combines with the 50 splice site of the downstream exon (Kelly et al., 2015). This form of circularization requires at least one exon between the outside splicing exons, resulting in the production of an intron lariat containing one or more exons and a linear mRNA (Talhouarne and Gall, 2014; Barrett et al., 2015). This lariat is then re-spliced to product a mature circular RNA (Fig. 1b). The mRNA generated by exon skipping is expressed at a very low level and only can be detected by RT-PCR, suggesting that exon skipping is not the main mechanism of circular RNA biogene-

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sis (Conn et al., 2017). However, exon skipping provides a mechanism for generating circular RNAs in the absence of intronic repeats (Wilusz, 2018).

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RNA-binding proteins (RBPs)

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RBPs are vital regulators of circular RNAs capable of producing tissue-specific expression patterns from the same loci (Westholm et al., 2014; Rybak-Wolf et al., 2015; Maass et al., 2017) (Fig. 1c). For example, the RNA helicase DExH-Box Helicase 9 (DHX9) binds to double-stranded RNAs and inhibits back-splicing by unwinding the RNA pairs flanking circularized exons or by recruiting the enzyme adenosine deaminase 1 acting on RNA (ADAR1), resulting in the suppression of circular RNA expression via the conversion of adenosines to inosines and diminishing the complementarity and stability of these RNA pairs (Salzman et al., 2013; Westholm et al., 2014; Maass et al., 2017). On the other hand, the splicing factor Quaking (QKI) takes part in the human epithelial–mesenchymal transition (EMT) and upregulates the expression of numerous circular RNAs (Conn et al., 2015). This increased production is mediated by the binding of QKI to flanking introns and bringing the circularized exons closer together via dimerization, resulting in augmented circular RNA formation (Conn et al., 2015). Muscleblind, a splicing factor derived from the Mbl gene, was the first example of an RBP capable of controlling the levels of circular RNAs derived from its second exon by binding both flanking introns (AshwalFluss et al., 2014). FUS regulates circular RNA biogenesis by binding introns flanking the back-splicing junctions, as well as acting as both an activator and repressor of splicing (Errichelli et al., 2017). Circular RNAs are thus controlled in a complex manner with intronic repeats offering the opportunity for back-splicing to occur, with a variety of factors regulating the efficiency of this process.

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FUNCTIONS OF CIRCULAR RNAS

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Circular RNAs can affect parental genes

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The course of circular RNA formation can influence canonical splicing of their precursor transcripts, resulting in altered gene expression levels (Zhang et al., 2014). Despite the low efficiency of the process, back-splicing requires both 50 and 30 splice sites, which can compete with the canonical splicing of pre-mRNAs, resulting in lower levels of linear mRNA expression with exon inclusion (Fig. 2a) (Ashwal-Fluss et al., 2014; Zhang et al.,

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Fig. 1. Biogenesis of circular RNA. (A) Base pairing between intronic repeats can facilitates back-splicing events. (B) Exon skipping can directly participate in circular RNA production. (C) RBPs are involved in the generation of circular RNA and as a regulator. (D) Though canonical splice, the pre-mRNA can generate a mature mRNA. exon circRNA: ecircRNA, exon intron circRNA: EIciRNA, circular intron RNA: ciRNA.

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2014; Kelly et al., 2015). The more exons that are circularized, the fewer the number of mRNAs that can theoretically be generated. However, not every skipped exon can produce circular RNAs, suggesting that additional regulators could affect exon circularization or skipping in linear isoforms (Kelly et al., 2015). The majority of circular RNAs are located in the cytoplasm, but circular RNAs produced from processed intron lariats (ciRNAs) or from back-splicing with retained introns (EIciRNAs) are restricted to the nucleus in human cells (Fig. 2) (Salzman et al., 2012; Jeck et al., 2013; Zhang et al., 2013; Li et al., 2015a,b). Furthermore, some nuclearlocalized circular RNAs may modulate gene expression at both the transcription and splicing levels (Fig. 2b), including CircSEP3, derived from exon 6 of SEPALLATA3, which can modulate the splicing of its linear counterpart (Lu et al., 2015; Li et al., 2017).

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Circular RNAs act as a sponge for miRNAs

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Circular RNAs have been hypothesized to act as sponges for miRNAs (Fig. 2c), small (21-nt) RNAs that function post-transcriptionally by binding with mRNAs and suppressing protein translation and/or enhancing mRNA degradation (Bartel, 2009). Recent studies have shown that several abundant circular RNAs can function as miRNA sponges. For example, Cdr1as (ciRS-7) is a circularized long noncoding RNA (lncRNA) that is highly abundant in the mammalian brain, with minimal to no expression in other tissues, and it contains more than 70 binding sites for miR-7 (Hansen et al., 2013; Memczak et al., 2013). The miR-7 binding sites are only partially complementary to ciRS-7 to avoid degradation by Argonaute2 (AGO2) bound to miR-7. In contrast, Cdr1as also contains an almost fully complementary binding site for miR-671 enabling active degradation of the Cdr1as-miR-671 complex (Hansen et al., 2011). MiR-7

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and miR-671 are post-transcriptionally deregulated in Cdr1as knockout rat brains (Piwecka et al., 2017). In addition, circular RNA sex-determining region Y (Sry) serves as a sponge for miR-138, thereby preventing miR-138 from interacting with its target genes (Hansen et al., 2013). Further, circITCH promotes the expression of ITCH by acting as a sponge for miR-214 and inhibiting Wnt/b-catenin signaling, thereby inhibiting tumor cell proliferation (Huang et al., 2015).

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Circular RNAs can be translated

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Linear mRNA translation normally requires a 50 end 7methylguanosine (m7G) cap structure and a 30 poly (A) tail. As circular RNAs lack both an m7G cap and poly (A) tail, they are unable to be recognized by ribosomes and translated into functional proteins. However, with the discovery of internal ribosome entry sites (IRESs), IRES-containing RNAs (including circular RNAs) can be translated both in vitro and in vivo in a cap-independent manner (Fig. 2d) (Kozak, 1979; Chen and Sarnow, 1995; Abe et al., 2015; Kramer et al., 2015; Wang and Wang, 2015; Li et al., 2017). Human circZNF609 was found to take part in the regulation of myoblast proliferation due to the presence of a 753-nt open reading frame (ORF), which is capable of encoding a protein; however, it is still not known whether this peptide contributes directly to myoblast proliferation (Legnini et al., 2017). In addition to IRESs, N6-methyladenosine (m6A) residues are enriched in circular RNAs and can drive circular RNA translation (Yang et al., 2017). The impact of peptides encoded by circular RNAs remains largely unknown, but different cell conditions could affect their translation, as seen in cases of cellular starvation, which promotes the translation of circMbl (Pamudurti et al., 2017).

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Fig. 2. Functions of circular RNA. (A) Production of circular RNA by back-splcing can compete with the canonical splice of pre-mRNAs. (B) Nuclear localized circular RNA can effect gene expression. (C) Circular RNAs can act as sponges of miRNAs (microRNAs). (D) circular RNAs can be translated. (E) circRNAs are promising biomarkers. exon circRNA: ecircRNA, exon intron circRNA: EIciRNA, circular intron RNA: ciRNA.

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Circular RNAs as biomarkers

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The closed ring structure of circular RNAs contains neither a 50 cap nor a 30 tail; this prevents it from being degraded by RNA exonucleases, enabling it to maintain stable expression both inside cells and in the extracellular space and plasma (e.g., blood and saliva) (Fig. 2e) (Bahn et al., 2015; Li et al., 2015a,b; Memczak et al., 2015). This particular stability may enable the use of circular RNAs in the diagnosis of numerous diseases, but further research is needed to prove it.

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CIRCULAR RNAS AND THE NERVOUS SYSTEM

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The development of the central nervous system (CNS) starts early in embryogenesis, and is extremely important for human development (Yang et al., 2018a,b, c,d). Many studies have shown that circular RNAs are specifically enriched in brain tissue and are closely connected with neuronal development. The proliferation and differentiation of neural stem cells (NSCs) are critical steps in CNS development (van Rossum et al., 2016). Yang et al. (2018a,b,c,d) identified 12 circular RNAs associated with mouse NSC differentiation. Gene Ontology (GO) enrichment analysis found that these circular RNAs may have a regulatory role in NSC differentiation, and the expression profiles of circular RNAs were different from those of mRNAs, suggesting that circular RNA–mRNA mechanisms might regulate NSC differentiation, though more work is needed to validate these observations (Yang et al., 2018a,b,c,d). The expression of circular RNAs is not equally distributed throughout the

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CNS, with significant differences seen among various brain regions and developmental stages. Regions of the brain with high circular RNA expression include the cerebellum, cortex, striatum, olfactory bulbs, and hippocampus. Circular RNAs are highly abundant and dynamically expressed in a spatio-temporal manner in porcine fetal brain, suggesting important potential functions during mammalian brain development (Veno et al., 2015). Moreover, miR-138 is a potential molecular regulator of human memory function. As circular RNA Sry acts as a sponge for miR-138, this circular RNA may play a special role in modulating memory formation (Tatro et al., 2013; Schroder et al., 2014). Circular RNAs not only serve physiological functions in the CNS, they also have a complex connection with brain diseases. b-Amyloid precursor protein (APP) can be cleaved by b-site APP-cleaving enzyme 1 (BACE1), resulting in the generation of b-amyloid peptide (Ab), a key molecule in Alzheimer’s disease (AD) pathogenesis (Zhao et al., 2016; Shi et al., 2017). Cdr1as can inhibit the translation of nuclear factor-jB (NF-jB) and induce its cytoplasmic localization, thus down-regulating ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) expression, which promotes APP and BACE1 degradation (Shi et al., 2017). CircFBXW7 can be translated to FBXW7185aa, which could induce a cell cycle arrest and reduce proliferation in glioma cells, as well as inhibit the expression of c-Myc, thus decreasing cellular proliferation and inhibiting cell cycle acceleration (Yang et al., 2018a,b,c, d). In temporal lobe epilepsy (TLE), circ-EFCAB2 binds to miR-485-5p to increase expression of the ion channel chloride channel 6 (CLCN6), while circ-DROSHA inter-

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acts with miR-1252-5p to decrease the expression level of the alpha 2 subunit of the Na+/K+ ATPase (ATP1A2) (Li et al., 2018). Together, these processes strongly affect the pathogenesis of TLE (Li et al., 2018).

CIRCULAR RNAS AND BRAIN HYPOXIC ISCHEMIC INJURY Hypoxia-ischemia of the brain can lead to neuronal damage and function loss, and may even be fatal, as stroke remains a leading cause of hypoxic-ischemic injury (Baltan et al., 2013, Acosta et al., 2015; Denorme and De Meyer, 2016). Ischemic stroke results in the obstruction of blood flow and a lack of oxygen in the affected tissue that could ultimately induce tissue injury and brain infarction (Catanese et al., 2017). Without efficient therapeutic interventions, affected individuals may never fully recover (Fisher and Schaebitz, 2000). Studies have shown that brain damage caused by stroke is mediated by several synergistic pathophysiologic mechanisms, including autophagy, mitochondrial dysfunction, oxidative stress, apoptosis, endoplasmic reticulum stress, and inflammation (Balog et al., 2016, Kim and Vemuganti, 2017). The therapeutic potential of regulating specific miRNAs after stroke is well confirmed, including inhibiting the miRNAs miR-181a, let-7f, miR-479, and miR-145, all of which have been shown to protect the brain after ischemia (Dharap et al., 2009; Yin et al., 2010; Selvamani et al., 2012; Dharap et al., 2015; Xu et al., 2015). Mehta et al. (2017) identified circular RNA profiles in rat brains with middle cerebral artery occlusion and found that the expression of circular RNAs was different from that in the normal group. Altered circular RNAs after stroke can remarkably change the function of miRNAs and their ability to regulate target mRNAs (Mehta et al., 2017). Thus, the downstream translation of proteins encoded by target mRNAs may play an important role in the pathogenesis of ischemic stroke. Gene-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that mitogen-activated protein kinase signaling, the cell cycle, regulation of the actin cytoskeleton, and focal adhesion are core pathways associated with circular RNAs (Mehta et al., 2017). Blood brain barrier (BBB) integrity damage is not only a consequence of but also a contributor to the progression of stroke, while the endothelial–mesenchymal transition (EndoMT) is believed to be involved in the disruption of BBB integrity (Derada et al., 2016; Hu et al., 2017). Bai et al. (2018) found that circDLGAP4 can bind to miR143 and inhibit its activity, resulting in increased expression of the miR-143 target HECTD1, which may underlie the regulation of the EndoMT (Fig. 3a). Another study also reported that circHECW2 was involved in the EndoMT, resulting in damage to the BBB via the suppression of miR-30D activity and subsequent downstream activation of ATG5 (Fig. 3a) (Yang et al., 2018a,b,c,d). Bazan et al. (2017) reported that in patients suffering from an acute carotid-related ischemic stroke event, the ratio of circulating circR-284 to miR-221 in serum was elevated, suggesting that circular RNAs represent a potential diagnostic biomarker for cerebrovascular ischemia (Fig. 3c).

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Hypoxic ischemic encephalopathy (HIE) can also cause neonatal morbidity and mortality. Jiang et al. (2019a,b) found that circular RNAs were significantly altered in the hippocampus following brain hypoxic ischemic injury compared with a sham control, and chr1: 200899066-201028171 might bind to miR-9a, an important regulator of hypoxia-induced neuronal apoptosis (Fig. 3b) (Wachtel and Hendricks-Munoz, 2011). Periventricular white matter damage is the predominant neurologic lesion in preterm infants who survive a brain injury, often resulting in changes to the expression of circular RNAs, suggesting that circular RNAs might actively respond to hypoxia–ischemia (Volpe, 2009; Liu et al., 2013; Zhu et al., 2018). Many circular RNAs have been implicated in the pathogenesis of brain hypoxic ischemic injury, providing a potential therapeutic and prognostic target, but further investigation is needed.

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CIRCULAR RNAS AND BRAIN ISCHEMIA– REPERFUSION INJURY (IRI)

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Cerebral IRI refers to the pathological phenomena of further brain injury induced by restored blood flow to an ischemic area, and is associated with high morbidity, mortality, and disability rates (Lu et al., 2014; Zhao et al., 2015). Cerebral IRI often occurs secondary to thrombolytic therapy in acute ischemic stroke followed by the restoration of spontaneous circulation after cardiopulmonary resuscitation (Lin et al., 2016). When oxygenated blood is restored, ischemic damage is increased rather than decreased, resulting in enlarged lesions and more severe damage to the BBB, often leading to brain edema and even hemorrhage (Mizuma and Yenari, 2017). Proper postconditioning for IRI is therefore vital to attenuate pathology and promote effective recovery. Lin et al. (2016) showed that mmu-circRNA-015947 is involved in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuron injury and might bind to the miRNAs mmu-miR-188-3p, mmu-miR-329-5p, mmumiR-3057-3p, mmu-miR-5098, and mmu-miR-683, thereby enhancing the expression of their target genes. KEGG pathway analysis predicts that mmu-circRNA015947 may participate in apoptosis-related, metabolism-related, and immune-related pathways, all of which are known to underlie IRI pathogenesis, but the exact role of mmu-circRNA-015947 remains uncertain (Fig. 3d) (Lin et al., 2016). Astrocyte activity can aggravate inflammation and neuronal tissue damage, or it can promote immune suppression and tissue repair, depending on the timing and stage of the brain pathology (Colombo and Farina, 2016; Liu and Chopp, 2016). Han et al. (2018) reveal that circHECTD1 functions as an endogenous miR-142 sponge and reduces miR-142 activity. This suppression of miR-142 results in the inhibition of TIPARP expression with subsequent inhibition of astrocyte activation via macroautophagy/autophagy, indicating that circHECTD1 and its coupling mechanism are involved in cerebral ischemia–reperfusion (Fig. 3e) (Han et al., 2018). Another survey reported that circ-008018 expression is increased following cerebral IRI, and inhibiting circ-008018 can alle-

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Fig. 3. Circular RNAs with brain hypoxic ischemic injury and ischemia–reperfusion injury. (A) CircDLGAP4 and circHECW2 can sponge miR-143 and miR-30D, respectively, to involve in the EndoMT (endothelial-mesenchymal transition), thus effect the BBB (Blood Brain Barrier) which is both the consequence and contributor of brain injury. (B) Chr1: 200899066-201028171 can act as a sponge of miR-9a which has been reported to associate with hypoxia-induced neuronal apoptosis. (C) CircR-284 can sponge to miR-221 and is increased in serum to be a biomarker of carotidrelated ischemic stroke. (D) mmu-circRNA-015947 might absorb mmu-miR-188-3p, miR-329-5p, miR-3057-3p, miR-5098, miR-683 and participate in apoptosis-related, metabolism-related and immune-related pathways, but further study is needed. (E) CircHECTD1 can sponge miR-142 and reduces miR-142 activity result in the inhibition of TIPARP expression with subsequent inhibition of astrocyte activation via macroautophagy/ autophagy. (F) Circ-008018 can sponge miR-99a via Akt and GSK3b signaling thereby regulate the apoptosis.

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viate the injury by enhancing miR-99a expression via Akt and GSK3b signaling, suggesting that circ-008018 may be a new target in protecting against subsequent neurological damage (Fig. 3f) (Yang et al., 2018a,b,c,d).

CIRCULAR RNAS AND TRAUMATIC BRAIN INJURY (TBI) TBI is a significant cause of morbidity and mortality worldwide. Numerous pharmacotherapeutic interventions have been developed to protect the brain after injury; however, none of these therapies have proven successful at improving TBI outcomes (Rubiano et al., 2015; Brazinova et al., 2016; Cancelliere et al., 2017). Recent studies have reported that circular RNA expression profiles are different between TBI brains and normal brains both within the cell and in the extracellular space, indicating that circular RNAs might participate in the pathogenesis of TBI and act as a regulator (Xie et al., 2018; Zhao et al., 2018; Chen et al., 2019; Jiang et al., 2019a,b). Jiang et al. (2019a,b) analyzed altered circular RNAs in the TBI cortex, revealing the downregulation of circular RNA-16895. This circular RNA is able to bind mmu-miR-214-3p, thereby releasing its target mRNA My010-004 and enriching the Fc gamma Rmediated phagocytosis pathway, indicating that circular RNA-16895 may be involved in brain immune response regulation after TBI through an miR-214-dependent pathway (Fig. 4a) (Jiang et al., 2019a,b). MiR-214 has been shown to be closely regulated within the CNS and able to modulate early human neurogenesis, regulating depressive-like behaviors, microglial morphology, and

inflammation by influencing ERK/AKT signaling or bcatenin (Saika et al., 2017; Mellios et al., 2018; Deng et al., 2019). MiR-27a is down-regulated in the injured cortex, thus inducing neuronal death with increased expression of the proapoptotic Bcl-2 family members Noxa, Puma, and Bax, and it is connected with hypoxiainduced neuronal apoptosis (Sabirzhanov et al., 2014). In contrast, raising the expression of this miRNA could alleviate neural damage (Sabirzhanov et al., 2014). Rno-circRNA-010705 is predicted to bind miR-27a and may be an important regulator of the pathogenesis of TBI, though the exact role of rno-circRNA-010705 remains unknown and needs further investigation (Fig. 4b) (Xie et al., 2018). Another study reported significant increases in circular RNA chr8-87859283–87904548, with important implications due to its role as a pro-inflammatory mediator (Chen et al., 2019). Strong activation of these processes may be deleterious to neurological restoration after TBI (Chen et al., 2019). Circular RNA chr887859283-87904548 can competitively bind mmu-let-7a5p, resulting in higher production of CXCR2, a highaffinity ligand for interleukin-8 (IL-8) receptor. Signaling through IL-8 receptor has been shown to rapidly mobilize neutrophils during early stages of acute inflammation (Fig. 4c) (Marchelletta et al., 2015; Bajrami et al., 2016). Zhao et al. (2018) demonstrated that traumatically injured brain tissues could release exosomes to the cerebral extracellular space, consistent with observations that circular RNAs in exosomes are differentially expressed. KEGG pathway analysis revealed that hypoxia-inducible factor-1 (HIF-1) signaling, Wnt signaling, and Notch sig-

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gery is its own major trauma; more conservative treatments may be effective, though the success of these interventions is difficult to predict. The pharmacotherapeutics available for the treatment of brain injuries are limited, highlighting the need for a greater understanding of these injuries at the molecular level. Circular RNAs have great potential in the process of brain injury, with regulatory circular RNAs (e.g., circDLGAP4 and circHECW2) playing vital roles in the EndoMT and the maintenance of BBB integrity in brain ischemic injury (Bai et al., 2018; Yang et al., 2018a,b,c,d). This provides a new platform from which to understand the underlying mechanisms of brain injury and study specific therapies to attenuate the development of injury and minimize brain dysfunction. Although many studFig. 4. Circular RNAs with traumatic brain injury. (A) Circ-16895 can sponge mmu-miR-214-3p thereby release the it’s target mRNA My010-004, and enrich Fc gamma R-mediated phagocytosis ies have reported an involvement pathway, thus modulate immune response. (B) MiR-27a can regulate the expression levels of the of circular RNAs in brain injury, proapoptotic Bcl-2 family members Noxa, Puma, and Bax, thereby involved in neuronal apoptosis, the specific role of those circular rno-circRNA-010705 is predicted to be a sponge to bind miR-27a and participate in regulating the RNAs is largely unknown. The cirpathogenesis of TBI, but need further verification. (C) Circular RNA chr8-87859283-87904548 can cular RNA-miRNA-mRNA-protein captures mmu-let-7a-5p to produce more CXCR2 protein which takes part in inflammation response in TBI. pathway network might play a crucial role in disease pathology; hownaling all activate the proliferation and differentiation of ever, further investigation is needed. neural stem cells through the generation of stem cell regCircular RNAs contain another function when ulatory factors, hence the promotion of neural regeneratranslated into peptides; however, due to the low tion and repair are connected with altered circular RNAs expression level and difficulty in detecting these and might participate in regulating the process of TBI products, few studies have directly explored the (Michaelidis and Lie, 2008; Pierfelice et al., 2011). Accurelationship between circular RNA-peptides and mulating evidence has verified that tropomyosin-related diseases (Chen and Sarnow, 1995). Zhang et al. (2018) kinase B (TrkB) might activate endogenous protective reported that circ-SHPRH could be translated into a promechanisms after TBI against secondary injury via the tein, SHPRH-146aa, which can protect full-length SHPRH PI3K/Akt signaling pathway (Hetman et al., 1999). The from ubiquitination and promote the degradation of prolifPI3K/Akt pathway is the major TrkB-mediated survival erating cell nuclear antigen (PCNA), thus suppressing pathway, acting as a key regulator of neuronal survival glioma proliferation and tumorigenesis. Although the funcand having a potential relationship with altered circular tions of most peptides encoded by circular RNAs are RNAs in the extracellular space (Hetman et al., 1999; ambiguous, it may still be a viable way to comprehend Zhao et al., 2018). Although many pathways have been the special role of circular RNAs in diseases. documented to be involved in the pathogenesis of TBI, a specific circular RNA-miRNA-mRNA-protein pathway ACKNOWLEDGEMENT network is unclear and requires further investigation. The brain remains in the cranial cavity and is well Not applicable. protected by the skull; however, in cases of cerebral injury, the skull might become the primary barrier for FUNDING treatment. In cases of ischemic stroke, we have thrombolytic therapy to restore vessels; however, once This work was supported by the National Natural Science the hypoxic ischemic injury has happened, the Foundation of China (NSFC): 81860225. pathogenesis cannot be reversed and the resulting ischemia–reperfusion will cause secondary damage that COMPETING INTERESTS can aggravate the brain injury (Oda and Kawai, 2012). The same can be said for TBI, in which the injured brain The authors declare that they have no competing tissue often needs be eliminated by surgery, but brain surinterests.

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(Received 12 May 2019, Accepted 10 December 2019) (Available online xxxx)

Please cite this article in press as: Zhu H et al. The Role of Circular RNAs in Brain Injury. Neuroscience (2020), https://doi.org/10.1016/j.neuroscience.2019.12.018

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