Anesthesia and Surgery Impair Blood–Brain Barrier and Cognitive Function in Mice

Abstract

Blood–brain barrier (BBB) dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment. However, the effects of anesthesia and surgery on BBB permeability, the underlying mechanisms, and associated cognitive function remain largely to be determined. Here, we assessed the effects of surgery (laparotomy) under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h on BBB permeability, levels of junction proteins and cognitive function in both 9- and 18-month-old wild-type mice and 9-month-old interleukin (IL)-6 knockout mice. BBB permeability was determined by dextran tracer (immunohistochemistry imaging and spectrophotometric quantification), and protein levels were measured by Western blot and cognitive function was assessed by using both Morris water maze and Barnes maze. We found that the anesthesia/surgery increased mouse BBB permeability to 10-kDa dextran, but not to 70-kDa dextran, in an IL-6-dependent and age-associated manner. In addition, the anesthesia/surgery induced an age-associated increase in blood IL-6 level. Cognitive impairment was detected in 18-month-old, but not 9-month-old, mice after the anesthesia/surgery. Finally, the anesthesia/surgery decreased the levels of β-catenin and tight junction protein claudin, occludin and ZO-1, but not adherent junction protein VE-cadherin, E-cadherin, and p120-catenin. These data demonstrate that we have established a system to study the effects of perioperative factors, including anesthesia and surgery, on BBB and cognitive function. The results suggest that the anesthesia/surgery might induce an age-associated BBB dysfunction and cognitive impairment in mice. These findings would promote mechanistic studies of postoperative cognitive impairment, including postoperative delirium.

Sevoflurane anesthesia impairs metabotropic glutamate receptor‐dependent long‐term depression and cognitive functions in senile mice

“…A number of molecular mechanisms have been proposed to account for the cognitive decline induced by sevoflurane, among which the neuroinflammation induced by anesthesia combined with surgery is generally believed to serve as the trigger and is supported by several reports . For instance, Yang et al reported that anesthesia/surgery impaired the permeability of the blood–brain barrier, and caused an elevated production of interleukin‐6 in an age‐associated manner, accompanied by the prominent deficits in cognitive functions . Furthermore, data generated from both human patients and model animals indicated that sevoflurane administration was related to the levels of pro‐inflammatory mediators, such as tumor necrosis factor‐alpha and interleukin‐6 .…”

“…For instance, a study on a group of older adults undergoing major non‐cardiac surgeries determined that risk factors for POCD included carrying the apolipoprotein E4 genotype, using highly anticholinergic or sedative‐hypnotic agents before surgery, and receiving anesthetics . Consistently, it was found in animal models that general anesthetics indeed initiated neurotoxic events and caused a number of alterations to the hippocampus, the essential structure in cognitive functions . Therefore, cautious choice of anesthetics, as well as better operative techniques, have been proposed as strategies to prevent POCD.…”

Combination of isoflurane and propofol as general anaesthesia during orthopaedic surgery of perioperative cerebral hypoperfusion rats to avoid cognitive impairment Anaesthesia during perioperative cerebral hypoperfusion

“…Taking incidence into account, we therefore used ligation of the CCA to induce CH in ageing rats in this study. As it is di cult to separate clinical anaesthesia and surgery, and our main purpose was to explore the combined effects of the two factors, no separate anaesthesia group was used, which is consistent with most recent studies [34][35][36].…”

Neuroprotectin D1 Protects Against Postoperative Delirium-like Behaviors in Aged Mice by Regulating Neuroinflammation Induced by Surgical Trauma

“…The method is based on the established BBB dye-injection assay with slight modi cation [28,29]. Speci cally, 6 h after surgery, each mouse was injected intravenously through tail veins with 100 µl 10-kDa dextran Texas Red (Invitrogen, D1863 Spectrophotometric quanti cation of extravascular 10-kDa dextran Texas Red was carried out with extracts of the hippocampus and prefrontal cortex at 6 hours after surgery.…”

“…The breakdown of blood-brain barrier (BBB) has been reported to be associated with delirium and perioperative neurocognitive disorders [35,36], herein we employed a well-established dye injection assay to investigate the integrity of BBB [28,29] under the treatment of surgery/anesthesia with or without NPD1.…”