Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Feb 27:25:1526-1536.
doi: 10.12659/MSM.912658.

A Mouse Model of Hepatic Ischemia-Reperfusion Injury Demonstrates Potentially Reversible Effects on Hippocampal Neurons and Postoperative Cognitive Function

Weiwei Wu  1   2 , Yan Wu  3 , Gao Cheng  2 , Chi Zhang  4 , Hongxian Wang  1 , Yuanhai Li  1
Affiliations

A Mouse Model of Hepatic Ischemia-Reperfusion Injury Demonstrates Potentially Reversible Effects on Hippocampal Neurons and Postoperative Cognitive Function

Weiwei Wu et al. Med Sci Monit. .

Abstract

BACKGROUND This study aimed to investigate cognitive function, hippocampal neuronal changes, and the expression of inflammatory cytokines in a mouse model of hepatic ischemia-reperfusion injury. MATERIAL AND METHODS Sixty mice were divided into the sham group, which underwent surgery without vascular occlusion; the I/R1 group, with occlusion of the left hepatic artery and portal vein for 20 min, and reperfusion for 30 min; and the I/R2 group, with occlusion of the left hepatic artery and portal vein for 40 min, and reperfusion for 30 min. At postoperative day 4 and 11, ten mice from each group underwent the Morris water maze (MWM) task. Hippocampal tissues were stained for Nissl bodies. Expression of nuclear factor-κB (NF-κB) and choline acetyltransferase (ChAT) were quantified by immunohistochemistry. Serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Groups I/R1 and I/R2 showed a significantly increased latency in the MWM test between days 5-9, compared with the sham group (P<0.05), with no difference by day 11; the I/R2 group had an initial lower crossing frequency (P<0.05), with no difference by day 18. The I/R2 group showed reduced numbers of Nissl bodies in hippocampal neurons. The I/R1 and I/R2 groups had increased expression of NF-κB, TNF-α, and IL-1β and decreased ChAT. No differences between the groups were found in levels of NF-κB, TNF-α, IL-1β, or ChAT by day 18. CONCLUSIONS A mouse model of hepatic ischemia-reperfusion injury showed transient and reversible cognitive dysfunction, changes in hippocampal neurons, and expression of inflammatory cytokines.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

None.

Figures

Figure 1
Figure 1
Cell morphology of the mouse hepatocytes in the mouse model groups with hepatic ischemia-reperfusion injury and the sham group. (A) Electron microscopy shows the subcellular morphology of the mouse hepatocytes. Magnification ×10,000. (B) Photomicrographs of the light microscopy of the liver tissues in the three mouse study groups. Hematoxylin and eosin (H&E). Magnification ×100. (a1, a2) The sham group, consisting of mice that underwent anesthesia, surgery, and separation of the hepatic artery and vein, but without occlusion. (b1, b2) The I/R1 group, in which the left hepatic artery and portal vein were clamped for 20 min, followed by reperfusion for 30 min. (c1, c2) The I/R2 group, in which the left hepatic artery and portal vein were clamped for 40 min followed by reperfusion for 30 min. M – mitochondria; RER – rough endoplasmic reticulum.
Figure 2
Figure 2
(A, B) Latency in navigation assay of in the mouse model groups with hepatic ischemia-reperfusion injury and the sham group. The three mouse study groups included: the sham group, consisting of mice that underwent anesthesia, surgery, and separation of the hepatic artery and vein, but without occlusion; the I/R1 group, in which the left hepatic artery and portal vein were clamped for 20 min, followed by reperfusion for 30 min; and the I/R2 group, in which the left hepatic artery and portal vein were clamped for 40 min followed by reperfusion for 30 min. Comparison with the sham group (* P<0.05). Comparison with the I/R1 group (# P<0.05).
Figure 3
Figure 3
Photomicrographs of the Nissl histochemical stain for Nissl bodies (blue/violet), or rough endoplasmic reticulum (RER), in the motor neurons of the hippocampus in the mouse model groups with hepatic ischemia-reperfusion injury and the sham group. (A) Photomicrograph of the light microscopy shows hippocampal Nissl bodies at 11 days postoperatively. Nissl stain. Magnification ×100. (B) Photomicrograph of the light microscopy shows hippocampal Nissl bodies at 18 days postoperatively. Nissl stain. Magnification ×100. (a1, a2) The sham group, consisting of mice that underwent anesthesia, surgery, and separation of the hepatic artery and vein, but without occlusion. (b1, b2) The I/R1 group, in which the left hepatic artery and portal vein were clamped for 20 min, followed by reperfusion for 30 min. (c1, c2) The I/R2 group, in which the left hepatic artery and portal vein were clamped for 40 min followed by reperfusion for 30 min. Data are presented as the mean ±SD (n=10). (C) Comparison between the sham group at day 11 after surgery, and the I/R2 group at day 18 after surgery (* P<0.05). Arrows show the Nissl bodies.
Figure 4
Figure 4
Photomicrographs of the immunohistochemical staining for the expression of choline acetyltransferase (ChAT) in the mouse hippocampal CA3 region in the mouse model groups with hepatic ischemia-reperfusion injury and the sham group. (A) Light microscopy of the immunohistochemical staining for choline acetyltransferase (ChAT) in tissue sections of the mouse hippocampal CA3 region at 11 days postoperatively. Magnification ×100. (B) Light microscopy of the immunohistochemical staining for ChAT in tissue sections of the mouse hippocampal CA3 region at 18 days postoperatively. Magnification ×100. (a1, a2) The sham group, consisting of mice that underwent anesthesia, surgery, and separation of the hepatic artery and vein, but without occlusion. (b1, b2) The I/R1 group, in which the left hepatic artery and portal vein were clamped for 20 min, followed by reperfusion for 30 min. (c1, c2) The I/R2 group, in which the left hepatic artery and portal vein were clamped for 40 min followed by reperfusion for 30 min. Data are presented as the mean ±SD (n=10). (C) Comparison between with sham group at day 11 with day 18 after surgery (* P<0.05). Comparison between the I/R1 group at day 11 after surgery with day 18 after surgery (# P<0.05). Arrows indicate the positively stained cells.
Figure 5
Figure 5
Photomicrographs of the immunohistochemical staining for the expression of nuclear factor-κB (NF-κB) in the mouse hippocampal CA3 region in the mouse model groups with hepatic ischemia-reperfusion injury and the sham group. (A) Light microscopy of the immunohistochemical staining for nuclear factor-κB (NF-κB) in tissue sections of the mouse hippocampal CA3 region at 11 days postoperatively. Magnification ×100. (B) Light microscopy of the immunohistochemical staining for NF-κB in tissue sections of the mouse hippocampal CA3 region at 18 days postoperatively. Magnification ×100. (a1, a2) The sham group, consisting of mice that underwent anesthesia, surgery, and separation of the hepatic artery and vein, but without occlusion. (b1, b2) The I/R1 group, in which the left hepatic artery and portal vein were clamped for 20 min, followed by reperfusion for 30 min. (c1, c2) The I/R2 group, in which the left hepatic artery and portal vein were clamped for 40 min followed by reperfusion for 30 min. Data are presented as the mean ±SD (n=10). (C) Comparison between with sham group at day 11 with day 18 after surgery (* P<0.05). Comparison between the I/R1 group at day 11 after surgery with day 18 after surgery (# P<0.05). Arrows indicate the positive cells.
Figure 6
Figure 6
Serum levels of the inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were determined using an enzyme-linked immunosorbent assay (ELISA) in the mouse model groups with hepatic ischemia-reperfusion injury and the sham group. Serum was isolated from mice in each of the three study groups, followed by measuring the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) using an enzyme-linked immunosorbent assay (ELISA) kit. Data are presented as the mean ±SD (n=10). Comparison of the cytokine levels in the sham group at day 11 after surgery with day 18 after surgery (* P<0.05). Comparison between the I/R1 group at day 11 after surgery with day 18 after surgery (# P<0.05).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Evered LA, Silbert BS. Postoperative cognitive dysfunction and noncardiac surgery. Anesth Analg. 2018;127(2):496–505. - PubMed
    1. Feinkohl I, Winterer G, Spies CD, Pischon T. Cognitive reserve and the risk of postoperative cognitive dysfunction. Dtsch Arztebl Int. 2017;114(7):110–17. - PMC - PubMed
    1. Umholtz M, Nader ND. Anesthetic immunomodulation of the neuroinflammation in postoperative cognitive dysfunction. Immunol Invest. 2017;46(8):805–15. - PubMed
    1. Qiao Y, Feng H, Zhao T, et al. Postoperative cognitive dysfunction after inhalational anesthesia in elderly patients undergoing major surgery: The influence of anesthetic technique, cerebral injury and systemic inflammation. BMC Anesthesiol. 2015;15:154. - PMC - PubMed
    1. Huang C, Martensson J, Gogenur I, Asghar MS. Exploring postoperative cognitive dysfunction and delirium in noncardiac surgery using MRI: A systematic review. Neural Plast. 2018;2018 1281657. - PMC - PubMed