Differential Expression of Circular RNAs in the Frontal Cortex of the Rat Brain in Ischemia–Reperfusion

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Ivan V. Mozgovoy¹, Yana Yu. Shpetko¹, Alina E. Denisova², Vasily V. Stavchansky¹, Margarita A. Vinogradina¹, Leonid V. Gubsky^2,3, Lyudmila V. Dergunova¹, Svetlana A. Limborska¹, Ivan B. Filippenkov^1,a*

¹National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia

²Pirogov Russian National Research Medical University, 117997 Moscow, Russia

³Federal Center for the Brain and Neurotechnology, Federal Medical Biological Agency, 117513 Moscow, Russia

^* To whom correspondence should be addressed.

Received: January 31, 2025; Revised: May 6, 2025; Accepted: May 6, 2025

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Circular RNAs (circRNAs) are covalently closed non-coding RNAs with an increased metabolic stability, capable of regulating gene expression. CircRNAs can be potentially used as biomarkers and therapeutic targets in various diseases, including ischemic stroke. Transient middle cerebral artery occlusion (tMCAO) is commonly used as a model in stroke transcriptomics. Here, we used genome-wide RNA sequencing to investigate expression profiles of circRNAs in the frontal cortex of rats 24 h after tMCAO. Sixty-four differentially expressed circRNAs (fold change > 1.5; Padj < 0.05) were identified; most of them were upregulated compared to sham-operated animals. According to on the MRI data, the analyzed region of the frontal cortex included the penumbra, an area containing damaged but viable cells, whose survival is crucial for the poststroke recovery. Based on bioinformatics analysis of identified circRNAs and previously obtained data on differential mRNA expression in this brain region, we predicted regulatory circRNA–microRNA–mRNA networks involved in ischemic stroke. Functional analysis of these networks revealed that genes whose expression in ischemia was presumably regulated by circRNAs, are involved in synaptic signaling and inflammatory response. Our data indicate a significant role of circRNA-mediated transcriptome regulation in the penumbra region in ischemia and suggest circRNA as potential targets in the development of new strategies in the therapy of stroke and poststroke complications.

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KEY WORDS: ischemic stroke, gene expression, non-coding RNAs, circRNAs, microRNAs, regulatory axes, circRNA–microRNA–mRNA network

DOI: 10.1134/S0006297925600280

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