Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats.
OBJECTIVE
Postoperative cognitive dysfunction (POCD) is a growing and largely underestimated problem without defined etiology. Herein, we sought to determine the relationship between cognitive decline, blood-brain barrier (BBB) permeability, and inflammation, namely high mobility group box-1 (HMGB1), after surgery in aged rats.


METHODS
Aged rats were randomly assigned as surgery group (n = 45, splenectomy under general anesthesia), anesthesia (n = 45, 2% isoflurane for 2 h), and naïve control (n = 15). Markers of inflammation were measured in plasma and brain. Blood-brain barrier ultrastructure and permeability were measured by transmission electron microscope (TEM) and IgG immunohistochemistry. Cognitive function was assessed in a reversal learning version of the Morris water maze (MWM).


RESULTS
Surgical trauma under general anesthesia caused distinct changes in systemic and central proinflammatory cytokines. Levels of HMGB1 and the receptor for advanced glycation end products (RAGE) were significantly upregulated in the hippocampus of operated animals. Immunohistochemistry and TEM showed BBB disruption induced by surgery and anesthesia. These molecular changes were associated with cognitive impairment in latency with the MWM up to postoperative day 3.


CONCLUSIONS
HMGB1 and RAGE signaling appear pivotal mediators of surgery-induced cognitive decline and may contribute to the changes in BBB permeability after peripheral surgical trauma.
Department of Anesthesiology, The Third Xiangya Hospital of Central South University, Changsha, China.
Hui-Juan
HJ
He
Yi
Y
Wang
Yuan
Y
Le
Kai-Ming
KM
Duan
Xue-Bin
XB
Yan
Qin
Q
Liao
Yan
Y
Liao
Jian-Bin
JB
Tong
Niccolò
N
Terrando
Wen
W
Ouyang
D000375:Aging / Q000187:drug effects; D000704:Analysis of Variance; D000758:Anesthesia / Q000009:adverse effects; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology* / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000209:etiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D055032:Electron Microscope Tomography; D004660:Encephalitis / Q000139:chemically induced / Q000209:etiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D018782:Maze Learning; D011183:Postoperative Complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D016207:Cytokines; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D012333:RNA, Messenger