Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction

Abstract

Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery that might lead to a decline in learning and memory. Oxidative stress damage is one of the pathogenic mechanisms underlying POCD. Recent studies had shown that the integrated stress response (ISR) is closely related to oxidative stress. The core response of the ISR is phosphorylation of eIF2α. Various cellular stress stimuli trigger activation of eIF2α kinases, thus causing phosphorylation of eIF2α. ISR is associated with many neurodegenerative diseases; however, the relationship between POCD and ISR has not been defined. In the present study, the tibias in 4-month-old male C57BL/6 mice were fractured under isoflurane anesthesia to establish the POCD animal model. Cognitive function was assessed by fear conditioning tests and the Y-maze from 3 to 14 days post-surgery. Western blot was used to determine the levels of PeIF2α, eIF2α, ATF4, GADD34, CHOP, BDNF, proBDNF, and p-NR2B expression. The levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to determine oxidative stress in hippocampal tissues. After tibial fracture surgery in mice, the hippocampus had increased levels of PeIF2α, ATF4, GADD34, and CHOP protein, ROS-positive cells, and average fluorescence intensity, SOD activity was decreased, and the MDA level was increased. The ISR inhibitor, ISRIB, reduced the levels of PeIF2α, ATF4, GADD34, and CHOP protein, and alleviated oxidative stress in the hippocampus of POCD mice. Moreover, ISRIB ameliorated cognitive dysfunction in POCD mice. Our findings suggested that targeting ISR may represent an effective approach to combat POCD.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction

“…Hippocampus is a key brain region for the study of spatial memory and episodic memory [ 45 – 48 ]. Previous studies have demonstrated that spatial memory and hippocampus-dependent memory impairment were found in mice three days after intramedullary fixation of tibial fracture, but hippocampus-independent memory was not affected [ 24 , 25 , 49 ]. Our experiment also proved that the freezing time of mice in the training phase and tone test phase of FC did not show significant statistical difference, but in the context test, the mice in the anesthesia/surgery group showed shorter freezing time.…”

Caffeic Acid Phenethyl Ester Suppresses Oxidative Stress and Regulates M1/M2 Microglia Polarization via Sirt6/Nrf2 Pathway to Mitigate Cognitive Impairment in Aged Mice following Anesthesia and Surgery

“…Oxidative stress and prolonged neuroinflammation have been considered the main pathological factors contributing to POCD development [ 39 , 60 , 61 , 62 ]. A few studies have suggested that anesthesia and surgery resulted in the increase in malondialdehyde and oxidative damage in the elderly brain and antioxidants could attenuate cognitive dysfunction after anesthesia and surgery [ 45 , 63 , 64 , 65 ]. Moreover, emerging evidence suggested that suppression of neuroinflammation could attenuate cognitive deficits caused by laparotomy and cardiopulmonary bypass surgery under isoflurane anesthesia [ 66 , 67 ].…”

Activation of ACE2/Ang-(1-7)/Mas axis improve cognitive dysfunction induced by isoflurane in mice via oxidative stress

“…Clinical studies have shown that oxidative stress is an important mechanism in the development of cognitive impairment, which may contribute to cognitive decline [11] . Our previous research also has provided evidence that oxidative stress is involved in the occurrence of POCD, and both the 6h isoflurane anesthesia model and the tibial fracture model have been shown to increase oxidative stress [12,13] . Multiple cellular mechanisms related to oxidative stress have been implicated in the onset of various neurodegenerative disorders.…”