Nrf2 transcriptional activity in the mouse affects the physiological response to tribromoethanol

A Kopacz,E Werner,D Kloska,K Hajduk,J Fichna,A Jozkowicz,A Piechota-Polanczyk

doi:10.1016/j.biopha.2020.110317

Abstract

Up to date, there is no information on the influence of 2,2,2-tribromoethanol (TBE; Avertin), a commonly used anaesthetic, on mice with impaired antioxidant capacity. We aimed to analyse the effect of a single dose of Avertin on anaesthesia duration time, inflammatory response, oxidative stress and collagen deposition in the large intestine of Nrf2 transcriptional knockout mice (tNrf2−/−). The studies were performed on six-month-old female mice Nrf2+/+ and tNrf2−/− randomly assigned to Avertin (250 mg/kg b.w. single i.p. injection) or vehicle group. We observed a 2-fold increase in anaesthesia time and longer recovery time (p = 0.015) in tNrf2−/− in comparison to Nrf2+/+. However, no hepato- or nephrotoxicity was detected. Interestingly, we found severe changes in colon morphology of untreated tNrf2-/- mice associated with colon shortening (p = 0.02) and thickening (p = 0.015). Avertin treatment caused colon damage manifested with epithelial layer damage and goblet depletion in Nrf2+/+ mice but not in tNrf2−/− individuals. Additionally, Avertin did not induce oxidative stress in colon tissue, but it increased leukocyte infiltration in Nrf2+/+ mice (p = 0.02). Immunofluorescent staining also revealed enhanced deposition of collagen I and collagen III in the colon of untreated tNrf2−/− mice. Avertin contributed to increased deposition of collagen I in Nrf2+/+ mice but reduced deposition of collagen I and III in tNrf2−/− individuals. In conclusion, tNrf2−/− respond to Avertin with prolonged anaesthesia that is not associated with acute toxicity, inflammatory reaction or enhanced oxidative stress. Avertin does not impair intestine morphology in tNrf2−/− mice but can normalise the enhanced fibrosis.

Highlights

Up to date, there is no information on the influence of 2,2,2-tribromoethanol (TBE; Avertin), a commonly used anaesthetic, on mice with impaired antioxidant capacity
We found that a single dose of Avertin in wild type mice caused a significant increase in ALT at both time points (p = 0.04 for 3 h and p = 0.02 for 6 h; Fig. 2A), a decrease in alkaline phosphatase (ALP) after 3 h (p = 0.04, Fig. 2B) compared to the untreated control
We show in this study that Avertin is non-toxic, yet it causes prolonged anaesthesia in mice with transcriptionally inactive Nrf2

Summary

Introduction

There is no information on the influence of 2,2,2-tribromoethanol (TBE; Avertin), a commonly used anaesthetic, on mice with impaired antioxidant capacity. We aimed to analyse the effect of a single dose of Avertin on anaesthesia duration time, inflammatory response, oxidative stress and collagen deposition in the large intestine of Nrf transcriptional knockout mice (tNrf2−/−). 2,2,2-tribromoethanol (TBE; Avertin) has been used since 1926 as an anaesthetic for dogs, cats, mice and rats [1,2] It was usually injected intraperitoneally in a single dose of 240−250 mg/kg and provided short-term anaesthesia [3]. Avertin may irritate the intestine leading to fibrosis [7] It has been commonly used as a general anaesthetic, since it is easy to prepare and rapidly induces anaesthesia with fast recovery [8], along with low mortality and morbidity rate (< 1%) [9].

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