The adenosine A_2Areceptor alleviates postoperative delirium‐like behaviors by restoring blood cerebrospinal barrier permeability in rats

Abstract

Postoperative delirium (POD) is a common post‐operative complication in elderly patients that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains unknown. The blood–cerebrospinal fluid barrier (BCB) and brain–blood barrier (BBB) are composed of tight junctions between cells that form physical barriers, and BBB damage plays an important role in the neuropathogenesis of POD. Nevertheless, the role of BCB in POD remains to be elucidated. Herein, we investigated the effect of adenosine A2A receptor (A2AR), a key regulator of the permeability of barriers, on surgery‐induced increased permeability of BCB and POD‐like behaviors. Open field, buried food, and Y maze tests were used to evaluate behavioral changes in rats after surgery. Levels of tight junction proteins, adherens junction proteins, A2AR, GTP‐RhoA, and ROCK2 in the choroid plexus were assessed by western blotting. The concentrations of NaFI and FITC‐dextran in the cerebrospinal fluid (CSF) were detected by fluorescence spectrophotometry. Transmission electron microscopy was applied to observe the ultrastructure of the choroid plexus. Surgery/anesthesia decreased the levels of tight junction (e.g., ZO‐1, occludin, and claudin1) proteins, increased concentrations of NaFI and FITC‐dextran in CSF, damaged the ultrastructure of choroid plexus, and induced POD‐like behaviors in rats. An A2AR antagonist alleviated POD‐like behaviors in rats. Furthermore, the A2AR antagonist increased the levels of tight junction proteins and restored the permeability of BCB in rats with POD. Fasudil, a selective Rho‐associated protein kinase 2 (ROCK2) inhibitor, ameliorated POD‐like behaviors induced by A2AR activation. Moreover, fasudil also abolished the increased levels of GTP‐RhoA/ROCK2, decreased levels of tight junction proteins, and increased permeability of BCB caused by A2AR activation. Our findings demonstrate that A2AR might participate in regulating BCB permeability in rats with POD via the RhoA/ROCK2 signaling pathway, which suggests the potential of A2AR as a therapeutic target for POD.

Reactive oxygen species contribute to delirium-like behavior by activating CypA/MMP9 signaling and inducing blood-brain barrier impairment in aged mice following anesthesia and surgery

“…Studies are underway to evaluate BBB dysfunction as a risk factor for postoperative delirium. Several animal models have reported that anesthesia/surgery can decrease the levels of TJ proteins, and increase the leakage of BBB or blood-cerebrospinal barrier (BCB) accompanied by delirium-like behavior ( Yang et al, 2017 ; Wen et al, 2020 ; Chen et al, 2021 ; Li et al, 2021 ). The present study reconfirmed that BBB disruption was associated with anesthesia/surgery-induced delirium-like behavior.…”

Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions

“…Currently, it is still uncertain whether POD and dNCR are distinct pathologies or "two sides of the same coin" (Olotu, 2020), mainly because of the lack of animal models of POD. Peng et al used 4-month-old mice to determine the effects of anesthesia/surgery on natural and learned behaviors, and the results suggested that this mouse model could exhibit acute onset and a fluctuating course of behaviors similar to POD (Peng et al, 2016;Chen et al, 2021). Illendula et al used 18to 20-month-old mice to examine anesthesia, surgery, and the intensive care unit environment and found that these insults impaired mouse behaviors that depend on attention, memory, and thought organization.…”

Adenosine A2A Receptor Antagonist Improves Cognitive Impairment by Inhibiting Neuroinflammation and Excitatory Neurotoxicity in Chronic Periodontitis Mice

“…The OFT was used to evaluate locomotion and anxiety-like behavior of the rodents [ 5 , 10 ]. The open field chamber was placed in a quiet and dim environment, and mice were placed in the center of chamber and allowed to explore freely for 5 min.…”

“…Adenosine is an endogenous purine nucleoside that regulates numerous physiological functions by activating the four G protein-coupled receptors A 1 , A 2A , A 2B and A 3 [ 9 , 10 ]. CD73 (ecto-5-nucleoditase) plays an important role in the immune inflammatory response against various diseases.…”