Abstract
Background An excessive neuroinflammatory response involved in the pathogenesis of postoperative cognitive dysfunction (POCD), which increases morbidity and mortality. However, the precise mechanism remains unclear. Trichostatin A (TSA), a histone deacetylase inhibitor, has been shown to be anti-inflammatory. Therefore, we aimed to explore whether TSA can inhibit the surgery-induced neuroinflammation and improve POCD and further reveal the complex neuropathogenesis underlying POCD. Methods To explore the molecular mechanisms by which surgery-induced POCD in aged rats, TSA (1 mg/kg) was intraperitoneally injected, and hippocampal microglial activation and neuroinflammation were observed. We investigated changes in the protein profile of the hippocampus using a proteomics approach [isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano liquid chromatography-mass spectrometry] at the peak of surgery-induced neuroinflammation, and significant alterations of proteins were verified using western blotting and immunofluorescence. Then, proteins associated with signaling pathways in the surgery + TSA and surgery groups were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results After laparotomy, aged rats had prolonged escape latencies on days 4 and 5 postsurgery, spent less time in the target quadrant than control rats (p < 0.05), and exhibited excessive hippocampal microglia activation and IL-1β and TNF-α release. iTRAQ and bioinformatics analyses at 6 h after surgery showed that neurofilaments (NFs), including the NEFH, NEFM and NEFL proteins, were significantly upregulated, and TSA pretreatment could mitigate these changes. Subsequently, KEGG analysis revealed that nine pathways were enriched in the surgery + TSA group vs. the surgery group (p < 0.05). Among them, two signaling pathways, “focal adhesion” and “ECM-receptor interaction”, were associated with significant upregulation of collagen and downregulation of NF proteins, indicating these as possibly important pathways involved in NF degradation in the hippocampus of aged brains after surgery-induced POCD. Conclusion Surgery-induced neuroinflammation upregulated NFs, resulting NF degradation and aggregation in the hippocampus of aged rats, which might lead to hippocampus-independent learning and memory impairment, contributing to POCD. Additionally, TSA diminished surgery-induced neuroinflammatory responses and modulated the NF-associated changes in cognitive dysfunction in aged brains, which might be related to activation of the “focal adhesion” and “ECM-receptor interaction” pathways.
Acute pre-operative ibuprofen improves cognition in a rat model for postoperative cognitive dysfunction
