Neurofilament degradation is involved in laparotomy-induced cognitive dysfunction in aged rats.

Lijun Ma,Jiao Yang,Zhengqian Li,Xinning Mi,Aihua Qi,Ning Yang,Xiangyang Guo,Aizhong Wang,Taotao Liu,Yiyun Cao

doi:10.18632/aging.104172

Abstract

Excessive neuroinflammatory responses play important roles in the development of postoperative cognitive dysfunction (POCD). Neurofilaments (NFs) were essential to the structure of axon and nerve conduction; and the abnormal degradation of NFs were always accompanied with degenerative diseases, which were also characterized by excessive neuroinflammatory responses in brain. However, it is still unclear whether the NFs were involved in the POCD. In this study, the LC-MS/MS method was used to explore the neuroinflammatory response and NFs of POCD in aged rats. Moreover, trichostatin A (TSA), an inflammation-related drug, was selected to test whether it could improve the surgery-induced cognitive dysfunction, inflammatory responses and NFs. Evident cognitive dysfunction, excessive microglia activation, neuroinflammatory responses and upregulated NFs in hippocampus were observed in the POCD group. TSA pretreatment could significantly mitigate these changes. The KEGG analysis revealed that nine pathways were enriched in the TSA + surgery group (versus the surgery group). Among them, two signaling pathways were closely related with the changes of NFs proteins. In conclusion, surgery could impair the cognitive function and aggravate neuroinflammation and NFs. The TSA could significantly improve these changes which might be related to the activation of the “focal adhesion” and “ECM-receptor interaction” pathways.

Highlights

Postoperative cognitive dysfunction (POCD) commonly occurs in older adults after surgery and is frequently under-recognized
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 tumor necrosis factor-alpha (TNF-α) release. isobaric tags for relative and absolute quantitation (iTRAQ) and bioinformatics analyses at 6 h after surgery showed that neurofilaments (NFs), including the neurofilament heavy chain (NEFH), neurofilament medium chain (NEFM) and neurofilament light chain (NEFL) proteins, were significantly upregulated, and Trichostatin A (TSA) pretreatment could mitigate these changes
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 “extracellular matrix (ECM)-receptor interaction” pathways

Summary

Introduction

Postoperative cognitive dysfunction (POCD) commonly occurs in older adults after surgery and is frequently under-recognized. Development of POCD has been associated with worse outcomes, longer hospital stays, decreased quality of life, increased mortality and risk of dementia. The precise pathophysiology of POCD remains unclear. Our previous studies revealed that laparotomy could increase the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) in the hippocampus and cause cognitive dysfunction to persist for several weeks in aged rats [7]. The precise mechanism of this neuroinflammatory reaction, which has been confirmed to be a key factor mediating the development of POCD, and its extensive cross-reaction with other elements in hippocampal neurons remain elusive and need to be further explored. An excessive neuroinflammatory response involved in the pathogenesis of postoperative cognitive dysfunction (POCD), which increases morbidity and mortality.

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