Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy

K Pierzchala; D Simicic; A Sienkiewicz; D Sessa; S Mitrea; O Braissant; V A McLin; R Gruetter; C Cudalbu

doi:10.1016/j.freeradbiomed.2021.12.011

Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy

Free Radic Biol Med. 2022 Jan:178:295-307. doi: 10.1016/j.freeradbiomed.2021.12.011. Epub 2021 Dec 8.

Authors

K Pierzchala¹, D Simicic², A Sienkiewicz³, D Sessa⁴, S Mitrea⁵, O Braissant⁶, V A McLin⁴, R Gruetter⁷, C Cudalbu⁵

Affiliations

¹ Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland. Electronic address: katarzyna.pierzchala@epfl.ch.
² Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland.
³ Laboratory for Quantum Magnetism, Institute of Physics, EPFL, Lausanne, Switzerland; ADSresonances Sàrl, Préverenges, Switzerland.
⁴ Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland.
⁵ Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁶ Service of Clinical Chemistry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁷ Center for Biomedical Imaging, EPFL, Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland.

PMID: 34890769
DOI: 10.1016/j.freeradbiomed.2021.12.011

Abstract

The role and coexistence of oxidative stress (OS) and inflammation in type C hepatic encephalopathy (C HE) is a subject of intense debate. Under normal conditions the physiological levels of intracellular reactive oxygen species are controlled by the counteracting antioxidant response to maintain redox homeostasis. Our previous in-vivo¹H-MRS studies revealed the longitudinal impairment of the antioxidant system (ascorbate) in a bile-duct ligation (BDL) rat model of type C HE. Therefore, the aim of this work was to examine the course of central nervous system (CNS) OS and systemic OS, as well as to check for their co-existence with inflammation in the BDL rat model of type C HE. To this end, we implemented a multidisciplinary approach, including ex-vivo and in-vitro electron paramagnetic resonance spectroscopy (EPR) spin-trapping, which was combined with UV-Vis spectroscopy, and histological assessments. We hypothesized that OS and inflammation act synergistically in the pathophysiology of type C HE. Our findings point to an increased CNS- and systemic-OS and inflammation over the course of type C HE progression. In particular, an increase in the CNS OS was observed as early as 2-weeks post-BDL, while the systemic OS became significant at week 6 post-BDL. The CNS EPR measurements were further validated by a substantial accumulation of 8-Oxo-2'-deoxyguanosine (Oxo-8-dG), a marker of oxidative DNA/RNA modifications on immunohistochemistry (IHC). Using IHC, we also detected increased synthesis of antioxidants, glutathione peroxidase 1 (GPX-1) and superoxide dismutases (i.e.Cu/ZnSOD (SOD1) and MnSOD (SOD2)), along with proinflammatory cytokine interleukin-6 (IL-6) in the brains of BDL rats. The presence of systemic inflammation was observed already at 2-weeks post-surgery. Thus, these results suggest that CNS OS is an early event in type C HE rat model, which seems to precede systemic OS. Finally, our results suggest that the increase in CNS OS is due to enhanced formation of intra- and extra-cellular ROS rather than due to reduced antioxidant capacity, and that OS in parallel with inflammation plays a significant role in type C HE.

Keywords: Antioxidants; CNS and Systemic oxidative stress; Central nervous system; Hepatic encephalopathy; Inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Ducts
Brain
Disease Models, Animal
Hepatic Encephalopathy* / etiology
Inflammation
Oxidative Stress
Rats
Rats, Wistar