Identification of the Potential Gene Regulatory Networks and Therapeutics in Aged Mice With Postoperative Neurocognitive Disorder

Abstract

Postoperative neurocognitive disorder (PND) is one of the most common postoperative neurological complications in aged patients, characterized by mental disorder, anxiety, personality changes, and impaired memory. At present, the molecular mechanism of PND remains largely unclear, and the ideal biomarker for clinical diagnosis and prognosis are lacking. Circular RNA (circRNA) and microRNA (miRNA), as unique non-coding RNAs, affecting the regulation of miRNAs on genes and further intervening in the progression of diseases through the sponge action between the two. Besides, it could be served as novel biomarkers in various diseases. In order to detect the differential expression profiles of genes caused by PND, a total of 26 18-month-old male C57BL/6 mice were randomly assigned to control group and PND group. Behavioral tests showed that mice in the PND group had impaired cognitive function compared with the control group. Three mice in each group were randomly selected to harvest the brain for analysis the expressions of circRNAs, miRNAs, and mRNAs in the prefrontal cortex by next-generation sequencing (NGS) technology. Differentially expressed genes, including 1192 circRNAs, 27 miRNAs, and 266 mRNAs were identified, and its accuracy was further confirmed by qRT-PCR. Bioinformatics analysis results suggested that neuroinflammation was the main pathological mechanism of PND. The construction of competitive endogenous RNA (ceRNA) networks and the identification of hub genes provided possible therapeutic targets for PND. Cinnarizine and Clemastine were predicted to have the potential therapeutic effects on PND. This is the first study to explore the differential expression profiles of genes and their regulation mechanisms in PND, our results provided new clues and targets for the treatment of this refractory disease.

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

“…Previous studies have shown that dysregulation of the WNT/β-catenin pathway is closely related to PND ( Hu et al, 2016 ). Our previous sequencing results showed the expression of WNT10B were significantly up-regulated in aged mice with PND ( Wu et al, 2021 ), indicating that PND might induce the overactivation of the WNT/β-catenin pathway. Besides, previous studies demonstrated that the overactivation of WNT/β-catenin pathway leads to the decrease of OLIG2 ( Huang et al, 2020 ; Jiang et al, 2020 ).…”

“…But locomotor activity and postoperative anxiety behavior were not affected. In our previous study, the differentially expressed genes in the brain tissues of aged PND mice were identified by next-generation sequencing, and clematine was predicted to have the potential to treat this refractory disease ( Wu et al, 2021 ). In the present study, we found that clemastine treatment ameliorated the impaired hippocampal-related memories caused by surgical and anesthetic factors.…”

“…The gene expression profile data (accession number GSE174413) which we previously obtained through next-generation sequencing was downloaded from the Gene Expression Omnibus (GEO) database. It contains the gene expression profiles of the brain tissues of three aged male C57BL/6 mice in the PND group and the CON group, respectively ( Wu et al, 2021 ). Limma package in R software was applied to screen differentially expressed genes of PND with p -value < 0.05, | log2 (Fold Change) | ≥ 1.…”

“…Surgery was also performed with isoflurane inhalation anesthesia and lasted 30 min. As shown in our previous study, mice received this surgery with isoflurane inhalation anesthesia had no hypoxia, heart rates and respiratory rates were kept within the normal ranges (Wu et al, 2021). During the whole process, an anesthesia monitor (B450, GE, United States) was used to dynamically monitor the depth of anesthesia and maintain the anesthesia level when toe pinch and surgery did not respond.…”

“…However, the effect of clemastine on PND is unknown. In our previous study, clematine was predicted to have a potential therapeutic effect on PND through next-generation sequencing combined with bioinformatics analysis ( Wu et al, 2021 ).…”