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

Zhang, Wen, Xiong, Bing-Rui, Zhang, Long-Qing, Huang, Xian, Zhou, Wen-Chang, Zou, Qian, Manyande, Anne ORCID: https://orcid.org/0000-0002-8257-0722, Wang, Jie, Tian, Xue-Bi and Tian, Yu-Ke (2020) Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice. CNS Neuroscience & Therapeutics. ISSN 1755-5930

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Manyande_etal_CNS_Neuroscience_&_Therapeutics_2020_Disruption_of_the_GABAergic_System_Contributes_to_the_Development_of_Perioperative_Neurocognitive_Disorders_after_Anesthesia_and_Surgery_in_Aged_Mice.pdf - Accepted Version
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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) was applied to investigate the effect 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 upregulated 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. A further study found that the P38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunction.
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.

Item Type: Article
Uncontrolled Keywords: neuroinflammation, perioperative neurocognitive disorders, GABAergic system, α5GABAA receptors, mitogen-activated protein kinase
Subjects: Medicine and health
Depositing User: Camille Regnault
Date Deposited: 17 Apr 2020 15:52
Last Modified: 24 Jul 2020 13:46
URI: http://repository.uwl.ac.uk/id/eprint/6859

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