1. Academic Validation
  2. TLR4-mediated hippocampal MMP/TIMP imbalance contributes to the aggravation of perioperative neurocognitive disorder in db/db mice

TLR4-mediated hippocampal MMP/TIMP imbalance contributes to the aggravation of perioperative neurocognitive disorder in db/db mice

  • Neurochem Int. 2020 Nov;140:104818. doi: 10.1016/j.neuint.2020.104818.
Yang Zhang 1 Hailin Liu 2 Zixuan Chen 1 Min Yu 1 Jiaxin Li 3 Hongquan Dong 1 Nana Li 1 Xiahao Ding 1 Yahe Ge 1 Cunming Liu 1 Tengfei Ma 3 Bo Gui 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, 1st Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
  • 2 Department of Anesthesiology, Huai'an First People's Hospital, Huai'an, Jiangsu, 223300, China.
  • 3 Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 4 Department of Anesthesiology and Perioperative Medicine, 1st Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. Electronic address: guibosy@163.com.
Abstract

Although type 2 diabetes is an important predictor of perioperative neurocognitive disorder (PND), little is currently known about its mechanism of action. Adult male db/db and db/m mice were subjected to four different treatments, including either sham or tibial fracture surgery as well as intraperitoneal injection of vehicle or TAK-242 (the selective inhibitor of TLR4) at 1, 24, and 48 h after surgery. The fear conditioning test was performed to detect cognitive impairment on post-operative day (POD) 3. The hippocampus was collected on POD 1 for western-blots and on POD 3 for western-blots, transmission electron microscopy, and electrophysiological experiments. Toll-like Receptor 4 (TLR4) inhibition reversed more profound decline in the freezing behavior of db/db mice on POD 3. The surgery reduced the slope of hippocampal field excitatory postsynaptic potentials, and induced blood-brain barrier (BBB) damage in db/db mice on POD 3. The surgery also increased protein levels of TLR4, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, albumin, matrix metalloproteinase (MMP)-2, and MMP-9, and decreased protein levels of claudin-5, occludin, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2 in the hippocampus of db/db and db/m mice. These changes were all reversed by TAK-242 treatment. At last, compared with those in post-operative db/m mice, the surgery increased protein levels of TLR4, TNF-α, and IL-1β, decreased protein levels of claudin-5 and occludin, and sustained the MMP/TIMP imbalance in the hippocampus of db/db mice on POD 3. Our results suggest that TLR4-mediated aggravated hippocampal MMP/TIMP imbalance, BBB disruption, sustained inflammatory cytokine release, and impairment of long-term potentiation play a key role in tibial fracture surgery-induced persistent PND in db/db mice.

Keywords

Blood-brain barrier; Db/db mice; Matrix metalloproteinase; Perioperative neurocognitive disorders; Tissue inhibitors of matrix metalloproteinase; Toll-like receptor 4.

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