Circular RNA Expression in the Brain of a Neonatal Rat Model of Periventricular White Matter Damage

Abstract

Background/Aims: Periventricular white matter damage (PWMD) is the predominant neurologic lesion in preterm infants who survive brain injury. In this study, we assessed the global changes in and characteristics of the transcriptome of circular RNAs (circRNAs) in the brain tissues of rats with PWMD. Methods: We compared the expression profiles of circRNAs in brain samples from three rats with PWMD and three paired control tissues using deep RNA sequencing. Bioinformatics analysis was applied to investigate these differentially expressed circRNAs, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis was performed to confirm the results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict associated cell signaling pathways and functions. Network analysis was performed to predict circRNAs-microRNAs, and target genes related to PWMD. Results: A total of 2151 more reliable circRNAs were dysregulated in the brain tissues of rats with PWMD, indicating a potential role in the condition. Of the 98 circRNAs significantly differentially expressed in rat brains with PWMD (P< 0.05), 52 were significantly over-expressed and 46 were significantly under-expressed. The expression profiles of seven of 10 randomly selected circRNAs were confirmed by qRT-PCR analysis. The glutamatergic synapse pathway and the VEGF signaling pathway, both associated with hypoxia/ischemia induced brain damage, were inriched. Relationship between miRNA (rno-miR-433-3p and rno-miR-206-3p) and HIF-1α were evident and potential associations between chr6: 48820833|48857932 and their target genes (rno-miR-433-3p and rno-miR-206-3p) were identified. Conclusion: The distinct expression patterns of circRNAs in the brain tissues of rats with PWMD suggest that circRNAs actively respond to hypoxia-ischemia. These findings could assist the development of novel diagnostic and therapeutic targets for PWMD therapy.

Pleiotrophin ameliorates white matter injury of neonatal rats by activating the mTOR/YY1/Id4 signaling pathway

“…Several studies have used a P3 neonatal rat WMI model, so we chose P3 rats. 28,29,40,41 Furthermore, in our study, we only selected male rats because other studies indicated that male neonatal rats had more severe brain damage than female rats under the same conditions. 42 Moreover, clinical studies have shown that the severity of brain injuries in male newborns is higher than that in female newborns, and the recovery ability of males is lower than that of females.…”

“…The development of the brain white matter in P2‐5 neonatal rats is similar to that in human preterm infants with a gestational age of 23–32 weeks. Several studies have used a P3 neonatal rat WMI model, so we chose P3 rats 28,29,40,41 . Furthermore, in our study, we only selected male rats because other studies indicated that male neonatal rats had more severe brain damage than female rats under the same conditions 42 .…”

“…To establish a neonatal rat model that could mimic WMI in human premature infants, first, in the WMI group, P3 rats were placed under anesthesia using inhaled isoflurane. The right common carotid arteries of P3 rats were isolated, ligated, and interrupted using a scalpel (keeping the interrupted condition to the end of this experiment), followed by exposure to a hypoxic environment (6% O 2 + 94% N 2 ) for 2 h. [28][29][30] In the Sham group, the right common carotid arteries of the rats were isolated without ligation, interruption, or exposure to a hypoxic environment. After the WMI model was established for 24 h, rats were administered PTN (20,40,80 μg/kg, R&D Systems) for 5 min through the lateral ventricle to establish the WMI + PTN group, and rats in the WMI + PBS group were injected with the same quantity of PBS.…”

Hypoxia-Induced circRNAs in Human Diseases: From Mechanisms to Potential Applications

“…Mechanistically, circPTK2 inhibits SOCS-1 expression by competitively binding to miR-29b, consequently upregulating JAK2/STAT3 signaling and suppressing IL-1β expression, thereby promoting neuronal apoptosis [74]. Similarly, hypoxia-related circRNAs are differentially expressed in heat adaptation, hypoxic-ischemic brain damage, and moyamoya disease [82][83][84][85].…”

Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson’s Disease in a Mouse Model

“…This indicates that circRNA participates in endogenous RNA to bind miRNA specifically, which thus is involved in the development of many diseases by regulating the expression of miRNA downstream target gene [22,23]. CircRNA is also involved in the pathogenesis of many neurological diseases, including Moyamoya disease [24], Alzheimer's disease [25], periventricular white matter damage [26], and blood-brain-barrier integrity [27]. These studies have shown that circRNAs may be involved in the pathogenesis of neurological diseases, but more studies are needed to confirm this hypothesis.…”