Comprehensive ceRNA Network Analysis Reveals Regulatory Mechanisms of mRNA, miRNA, circRNA, and lncRNA in Methcathinone-Induced Neurotoxicity

Abstract Methcathinone, a synthetic cathinone derivative similar to amphetamine, has raised public health concerns due to its addictive properties and health risks associated with neurotoxicity. Low-dose, medium-dose, and high-dose methcathinone-induced neurotoxicity models were established. Learning and memory functions were assessed using the Morris water maze, and changes in hippocampal synaptic morphology and structure were examined using electron microscopy and Golgi staining. Whole-transcriptome sequencing was then used to characterize the expression of mRNAs, miRNAs, circRNAs, and lncRNAs. Differentially expressed mRNAs(DEmRNAs), miRNAs(DEmiRNAs), circRNAs (DEcircRNAs), and lncRNAs (DElncRNAs) were identified, and circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA networks were constructed. Compared with the control group, 784 DEmRNAs, 32 DEmiRNAs, 391 DElncRNAs and 749 DEcircRNAs were identified in the low-concentration group, 607 DEmRNAs, 28 DEmiRNAs, 369 DElncRNAs and 728 DEcircRNAs were identified in the medium-concentration group, and 501 DEmRNAs, 23 DEmiRNAs, 371 DElncRNAs and 753 DEcircRNAs were identified in the high-concentration group. Multiple genes in the immediate-early gene system and the IGF system were affected by methcathinone concentrations, including c-Fos, Nr4a1, Arc, Egr1, Egr2, Npas4, Igf1, and Igf2. These genes were regulated by rno-miR-92a-3p, rno-miR-211-5p, rno-miR-378a-3p, rno-miR-182, rno-miR-336-5p, rno-miR-21-3p, rno-miR-96-5p, rno-miR-183-5p, and rno-miR-143-3p. These miRNAs were competitively bound by 95 lncRNAs and 146 circRNAs participating in the ceRNA network by regulating these nine miRNAs. This result provides new insights into the regulatory mechanisms of mRNA, miRNA, lncRNA, and circRNA in methcathinone-induced neurotoxicity.