Activation of NF-κB Signal Pathway and Downstream IL-1β Expression in Hippocampal Astrocytes of LPS-Induced Aged Rats

Abstract

Background: The activation of nuclear factor-kappa B (NF-κB) signal pathway and downstream expression of IL-1β may play a pivotal role in neuroinflammation and cognitive dysfunction. We previously reported that a single lipopolysaccharide (LPS) dose induces prolonged neuroinflammation which is associated with astrocytic NF-κB signal pathways in aged rats. Blockade of the pathway by pyrrolidine dithiocarbamate (PDTC) in astrocytes could markedly suppress them, which may provide innovative ideas for clinical improvement for postoperative cognitive dysfunction (POCD). Methods: Rats were randomly assigned to vehicle, LPS, LPS+PDTC groups (n = 8 per group, per time point). 1) vehicle control (0.9% NaCl i.p.), 2) LPS (2 mg/kg i.p), 3) LPS + PDTC (LPS and PDTC50 mg/kg i.p.). After injection, whole brain tissues acquired at a series of time points (days 1, 3,7, 15 and 30) was prepared to carry out immunofluorescence, isolated hippocampal tissues were used for enzyme-linked immunosorbent assay (ELISA). NF-κB p65, p-IκBα and IL-1β were detected respectively by immunofluorescence and IL-1β protein levels were determined by ELISA. A separate cohort of rats (n=8-10/group) were tested in a Morris water maze (MWM) for spatial learning and memory. Results: The PDTC treatment suppressed the LPS-induced canonical NF-κB signaling pathway- nuclear translocation of NF-κB p65 and IκBα phosphorylation, positive expression of GFAP and IL-1β in hippocampal astrocytes of aged rats by immunofluorescence and reduced cognitive dysfunction by MWM test; The LPS-induced IL-1β protein increase in hippocampus of aged rats was attenuated by PDTC with ELISA. Conclusion: These findings suggest that NF-κB signaling pathway and downstream IL-1β in senescent astrocytes may play important roles in age-related neuroinflammation and cognitive dysfunction and provide potential discovery tool and therapeutic methods with PDTC for verifying the NF-κB signal pathway and treating cognitive impairment, especially POCD. (Funded by National Clinical Research for Geriatric Disorders of China, and Beijing Municipal Administration of Hospitals' Ascent Plan.)     Citation: Min-Hui Kan, Hui-Qun Fu, Long Fan, Yan Wu, Tian-Long Wang. Activation of NF-κB Signal Pathway and Downstream IL-1β Expression in Hippocampal Astrocytes of LPS-Induced Aged Rats. J Anesth Perioper Med 2017; 4 : 149-61. doi: 10.24015/ JAPM.2017.0051 This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.