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

• Published in: Free radical biology & medicine Vol. 178; pp. 295 - 307
• Main Authors: Pierzchala, K., Simicic, D., Sienkiewicz, A., Sessa, D., Mitrea, S., Braissant, O., McLin, V.A., Gruetter, R., Cudalbu, C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2022
• Subjects: Animals; Antioxidants; Bile Ducts; Brain; Central nervous system; CNS and Systemic oxidative stress; Disease Models, Animal; Hepatic encephalopathy; Hepatic Encephalopathy - etiology; Inflammation; Oxidative Stress; Rats; Rats, Wistar; Antioxidants; CNS and Systemic oxidative stress; Inflammation; Hepatic encephalopathy; Central nervous system
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.12.011

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.
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•Longitudinal tracking of both CNS and systemic oxidative stress in a rat model of type C HE using ex-vivo and in-vitro EPR spin-trapping.•Synergistic participation of CNS oxidative stress and inflammation in the progression of type C HE.•Increased oxidative stress is not due to the decline of antioxidant activity but rather to an increase in ROS production.