J Anesth Perioper Med. 2017;4(4):149-161. https://doi.org/10.24015/ebcmed.japm.2017.0051
From the 1Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China; 2Department of Anatomy, Capital Medical University, Beijing, China.
Correspondence to Dr. Tian-Long Wang at firstname.lastname@example.org.
EBCMED ID: ebcmed.japm.2017.0051 DOI: 10.24015/ebcmed.japm.2017.0051
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).
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.
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.
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.)
Declaration of Interests
The authors declare no other conflicts of competing interest for this work.
This work has been funded by grants from National Clinical Research for Geriatric Disorders, Xuanwu Hospital of Capital Medical University (No. 20170026) and Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20150802).
The authors gratefully acknowledge the kind help of Mr. Yi-Zhi Song for excellent technical assistance.
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