Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice

Abstract

Aims Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be the most important mechanisms especially during the postoperative period. The GABAergic system is easily disrupted by neuroinflammation. This study investigated the impact of the GABAergic system on PND after anesthesia and surgery. Methods An animal model of laparotomy with inhalation anesthesia in 16‐month‐old mice was addressed. Effects of the GABAergic system were assessed using biochemical analysis. Pharmacological blocking of α5GABAARs or P38 mitogen‐activated protein kinase (MAPK) were applied to investigate the effects of the GABAergic system. Results After laparotomy, the hippocampus‐dependent memory and long‐term potentiation were impaired, the levels of IL‐6, IL‐1β and TNF‐α up‐regulated in the hippocampus, the concentration of GABA decreased, and the protein levels of the surface α5GABAARs up‐regulated. Pharmacological blocking of α5GABAARs with L655,708 alleviated laparotomy induced cognitive deficits. Further studies found that the P38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunctions. Conclusions Anesthesia and surgery caused neuroinflammation in the hippocampus, which consequently disrupted the GABAergic system, increased the expressions of surface α5GABAARs especially through the P38 MAPK signaling pathway, and eventually led to hippocampus‐dependent memory dysfunctions.

Effect of basal forebrain somatostatin and parvalbumin neurons in propofol and isoflurane anesthesia

“…Future study should divide these neurons into different subgroups according to different subregions, such as the wake‐active Kv2.2‐expressing GABAergic neurons 46,47 . Additionally, some experiments indicated that the GABAergeic system could be affected by anesthetics, and this effect is related to age 48,49 . Therefore, in our study, we only included young mice (8–12 weeks) to avoid any possible effects caused by aging.…”

Update on the Mechanism and Treatment of Sevoflurane-Induced Postoperative Cognitive Dysfunction

“…Tang et al, 2020;Xu and Qian, 2020 AChE, ACh Sevoflurane upregulates the expression of AChE, decreases the concentration of Ach, and downregulates the cholinergic anti-inflammatory pathway. Yin et al, 2019 GABA, GABAA receptors Sevoflurane decreases the concentration of GABA and potentiates GABAA receptors Cabrera et al, 2020;Zhang et al, 2020 Dopamine, dopamine receptors Sevoflurane accelerates dopamine turnover in the brain and increases the expression levels of the dopamine receptor genes Hayase et al, 2016;Taharabaru et al, 2018 Serotonin, SDM Sevoflurane sequesters acrolein and may promote the production of SDM that depletes local serotonin and enhances neuronal vulnerability Roberts et al, 2007;Miller et al, 2010;Brownrigg et al, 2011 NF-κB, nuclear factor-kappa B; IL, interleukin; PPAR-γ, peroxisome proliferator-activated receptor-γ; ROS, reactive oxygen species; NLRP3, Nod-like receptor protein 3; SIRT1, sirtuin 1; BDNF, brain-derived neurotrophic factor; AChE, acetylcholinesterase; Ach, acetylcholine; GABA, γ-aminobutyric acid; GABAA, GABA type A; SDM, serotonin-derived melanoid. The κ-opioid receptor agonist, oxycodone, an opioid widely used for postoperative pain, can downregulate the expression of inflammatory factors and attenuate POCD (Gan et al, 2020;Fan et al, 2021).…”

“…The GABAA receptors are the main targets of sevoflurane; such binding is related to the development of cognitive memory deficits after anesthesia ( Zurek et al, 2012 ; Li T. et al, 2019 ). After mice undergo inhalation anesthesia, their concentration of GABA decreases and their level of surface GABAA receptor proteins increases ( Zhang et al, 2020 ). The Na–K–Cl–1 cotransporter (NKCC1) is a chloride importer that maintains high intracellular chloride levels, establishing a concentration gradient across neuronal membranes that drives a chloride efflux upon GABAA receptor activation.…”

GLP-1R Activation Ameliorate Novel-object Recognition Function via Hippocampal AMPK/NF-κB Signaling Pathway in Neuropathic Pain Mice

“…The NORT was conducted as previously described [9]. Brie y, the mice were handled for 1minute a day continuing 6 days before the test.…”

“…Read Full License neuroin ammaton is a critical factor contributing to hippocampus-dependent memory impairment [9].Neuropathic pain can alos cause the release of pro-in ammatory cytokines in the hippocampus [3].…”