Perioperative neurocognitive disorders (PNDs) are common neurological complications after anesthesia in the elderly. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates signal transducer and activator of transcription protein 3 (STAT3) signaling to control inflammation in certain organs, but its role in PNDs remains unknown. Herein, we constructed a PND model in 18-month-old rats by treating them with sevoflurane. PND rats developed neuroinflammation, along with a significant decrease in PTPN2 expression and a rise in STAT3 phosphorylation in the hippocampus. Ptpn2 overexpression alleviated the behavioral disorders of PND rats, ameliorated neuronal injury, inhibited neuroinflammation, inflammasome activation, microglial activation, and microglial phenotype switching. Similar results were observed in sevoflurane-treated HMC3 microglia with PTPN2 overexpression, while PTPN2 silencing showed the opposite results. Additionally, PTPN2 seems to be a target of T-box transcription factor 2 (TBX2). These results contribute to the evidence supporting the idea that PTPN2 is a regulatory factor in PND progression.
Perioperative neurocognitive disorder (PND) frequently occurs in elderly patients following anesthesia, and is associated with pro-inflammatory activation of microglia in hippocampus. In this study, sevoflurane , a commonly used inhaled anesthetic in clinic, was used to induce PND-like symptoms in aged SD rats (18–20 months). Data from novel object recognition and Y-maze tests first confirmed that aged SD rats exposed to 2% sevoflurane for 5 h developed cognitive impairment . Microglia preferred to polarizing towards pro-inflammatory M1 subtype (iNOS+Iba-1 +) in rat hippocampus post sevoflurane exposure, but not anti-inflammatory M2 subtype (Arg-1 +Iba-1 +). Microarray data identified interferon regulatory factor 6 (Irf6) as one (Fold change = −2.52, p = 0.006) of the 15 downregulated genes in hippocampus of the rats exposed to sevoflurane. Co-immunofluorescence data further illustrated that sevoflurane decreased Irf6 expression in hippocampal microglia. In vitro, sevoflurane enhanced lipopolysaccharide-induced M1 polarization of BV-2 cells and inhibited interleukin-4 induced M2 polarization. Interestingly, manipulation of Irf6 expression hardly affected M1 polarization. However, Irf6 overexpression further augmented the inhibitory effects on M2 polarization, and its silencing showed opposite effects. In addition, such M2 polarization-promoting effects of Irf6 knockdown may be associated with induction of peroxisome proliferator activated receptor gamma expression. Collectively, these findings suggest that Irf6 downregulation in hippocampal microglia may be a compensatory mechanism against sevoflurane-induced PND in the elderly.
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