Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/66332
Title: Preventive effect of genetic knockdown and pharmacological blockade of CysLT(1)R on lipopolysaccharide (LPS)-induced memory deficit and neurotoxicity in vivo
Authors: Chen, F
Ghosh, A
Wu, F
Tang, SS
Hu, M
Sun, HB
Kong, LY
Hong, H
Keywords: Alzheimer's disease
Bcl-2/Bax
Caspase-3
CysLT(1)R
IL-1 beta
Microglia
NF-kappa B p65
Pranlukast
ShRNA
TNF-alpha
Issue Date: 2017
Publisher: Academic Press
Source: Brain, behavior, and immunity, Feb. 2017, v. 60, p. 255-269 How to cite?
Journal: Brain, behavior, and immunity 
Abstract: Previously we reported that cysteinyl leukotrienes (Cys-LTs) and the type 1 receptor for Cys-LTs (CysLT(1)R) are related to amyloid beta (A beta)-induced neurotoxicity. The aim of the current study was to find out the role of CysLT(1)R on lipopolysaccharide (LPS)-induced cognitive deficit and neurotoxicity. shRNA-mediated knockdown or pharmacological blockade (by pranlukast) of CysLT(1)R were performed in ICR mice for 21 days prior to systemic infusion of LPS. From day 22, LPS was administered for 7 days and then a set of behavioral, histopathological and biochemical tests were employed to test memory, neuroinflammation and apoptotic responses in the mouse hippocampus. LPS (only)-treated mice showed poor performance in both Morris water maze (MWM) and Y-maze tests. However, shRNA-mediated knockdown or pranlukast-treated blockade of CysLT(1)R improved performance of the mice in these tests. To find out the possible underlying mechanisms, we assessed several parameters such as microglial activation (by immunohistochemistry), level of CysLT(1)R (by WB and qRT-PCR) and the inflammatory/apoptotic pathways (by ELISA or TUNEL or WB) in the mouse hippocampus. LPS-induced memory impairment was accompanied by activation of microglia, higher level of CysLT(1)R, TNF-alpha and nuclear NF-kappa B p65. LPS also caused apoptosis in the hippocampus as detected by TUNEL staining, further supplemented by detection of increased Caspase-3 and a reduced Bcl-2/Bax ratio. All of these adverse changes in the mouse hippocampus were inhibited by pretreatment with CysLT(1)R-shRNA and pranlukast. Through this study we suggest that CysLT(1)R shares a strong correlation with LPS-associated memory deficit, neuroinflammation and apoptosis and CysLT(1)R could be a novel target for preventive measures to intervene the progression of Alzheimer's disease (AD)-like phenotypes.
URI: http://hdl.handle.net/10397/66332
ISSN: 0889-1591
EISSN: 1090-2139
DOI: 10.1016/j.bbi.2016.10.021
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