Salutary Effect of Pre-Treatment With an Nrf2 Inducer on Ischemia Reperfusion Injury in The Rat Liver

Yuichi Masuda, Nostratola D. Vaziri, Chie Takasu, Shiri LI, Lourdes Robles, Lourdes Robles, Christine Pham, Christine Pham, Aimee Le, Aimee Le, Kelly Vo, Kelly Vo, Seyed H. Farzaneh, Seyed H. Farzaneh, Michael J Stamos, Michael J Stamos, Hirohito Ichii, Hirohito Ichii


BACKGROUND: Ischemia–reperfusion injury (IRI) is a common phenomenon occurring during liver surgery, transplantation, and trauma. IRI causes oxidative stress which plays a critical role in causing organ damage. The Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Nrf2 dysfunction has been implicated in the pathogenesis of several inflammatory disorders, cancer, and aging. This study was undertaken to investigate the effect of Nrf2 pathway activator (dh404) on warm liver IRI in a rodent model.
METHODS: Ten Sprague-Dawley rats were treated with dh404 or vehicle. Dh404 was dissolved in sesame oil and was given orally (1.5mg/kg) the night before and 5 hours before procedures. Rat livers were subjected to 60 minutes of 70% ischemia followed by 3 hours of reperfusion. Serum ALT and Malondialdehyde (MDA) were determined and liver tissue was processed for histological examination, and determination of apoptosis, myeloperoxidase (MPO) activity, ADP/ATP ratio, and expressions of Nrf2, eNOS, anti-oxidant enzymes, and inflammatory mediators.
RESULTS: Serum ALT and MDA levels and tissue MPO activity were significantly lower, expression of the anti-oxidant enzyme, glutamate cysteine ligase was significantly higher, whereas expression of NFkB and COX-2 was unchanged in the dh404-treated group. Although the total Suzuki histology score did not 

differ significantly, the extent of sinusoidal congestion, vacuolization, and apoptosis was significantly reduced in the dh404 treated compared to the untreated group (P<0.01).
CONCLUSION: Pre-treatment with dh404 resulted in partial attenuation of hepatic ischemia reperfusion injury in rats.


Liver; Ischemia reperfusion injury; Reactive oxygen species; Oxidative stress; Bardoxolone methyl analogue; Inflammation

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