Abstract
Background: Rats subjected to bile duct ligation (BDL) exhibit increased systemic oxidative stress and brain dysfunction characteristic of hepatic encephalopathy (HE), including fatigue, neurotransmitter alterations, cognitive and motor impairment, and brain inflammation. The levels of tumor necrosis factor-alpha (TNF-α) and asymmetric dimethylarginine (ADMA) are both increased in plasma and brain in encephalopathy induced by chronic liver failure. This study first determined the temporal profiles of TNF-α and ADMA in the plasma, brain cortex, and hippocampus in young BDL rats. Next, we examined whether etanercept was beneficial in preventing brain damage.Methods: Young rats underwent sham ligation or BDL at day 17 ± 1 for 4 weeks. Treatment group rats were administered etanercept (10 mg/kg) intraperitoneally (IP) three times per week with or without etanercept (100 μg) intrathecally (IT) three times in total.Results: We found increased plasma TNF-α, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble tumor necrosis factor receptor 2 (sTNFR2), and ADMA levels, increased cortical TNF-α mRNA and protein and ADMA, and hippocampal TNF-α mRNA and protein, and spatial defects in young BDL rats. The increase in cortex TNF-α mRNA and ADMA were reduced by IP etanercept or combined IP and IT etanercept. Dually IP/IT etanercept administration reduced the increased cortical and hippocampal TNF-α mRNA and protein level as well as spatial deficits.Conclusions: We conclude that combined intraperitoneal and intrathecal etanercept reduce increased brain TNF-α and ADMA levels and rescues spatial deficits in young rats after BDL.
Highlights
Rats subjected to bile duct ligation (BDL) exhibit increased systemic oxidative stress and brain dysfunction characteristic of hepatic encephalopathy (HE), including fatigue, neurotransmitter alterations, cognitive and motor impairment, and brain inflammation
We conclude that combined intraperitoneal and intrathecal etanercept reduce increased brain TNF-α and asymmetric dimethylarginine (ADMA) levels and rescues spatial deficits in young rats after Bile duct ligation (BDL)
We found that the BDL2W group rats had higher plasma TNF-α (26.8 ± 3.1 pg/mL vs. 11.7 ± 0.6 pg/mL, P = 0.031), soluble tumor necrosis factor receptor 1 (sTNFR1) (294.8 ± 8.7 pg/mL vs. 156.2 ± 8.1 pg/mL, P < 0.001), and soluble tumor necrosis factor receptor 2 (sTNFR2) (3632.5 ± 106.4 pg/mL vs. 1338.5 ± 65.8 pg/mL, P < 0.001) levels as well as higher cortex TNF-α mRNA expression (4.67 ± 1.76 vs. 1.00 ± 0.24, P < 0.001) than the SHAM controls (Figure 2), but there were no significant differences in cortex TNF-α protein levels (0.70 ± 0.06 pg/mg protein vs. 0.70 ± 0.04 pg/mg protein, P = 1.00) or hippocampus TNF-α mRNA expression (0.77 ± 0.15 vs. 1.00 ± 0.15, P = 0.660)
Summary
Rats subjected to bile duct ligation (BDL) exhibit increased systemic oxidative stress and brain dysfunction characteristic of hepatic encephalopathy (HE), including fatigue, neurotransmitter alterations, cognitive and motor impairment, and brain inflammation. The levels of tumor necrosis factor-alpha (TNF-α) and asymmetric dimethylarginine (ADMA) are both increased in plasma and brain in encephalopathy induced by chronic liver failure. Bile duct ligation (BDL) in rats can result in chronic liver failure with accompanying brain dysfunction that are characteristic of HE, including changes in neurotransmitters (Celik et al, 2005; Dhanda and Sandhir, 2015), cognitive and motor impairment (Huang et al, 2009; Magen et al, 2010), and brain inflammation (Rodrigo et al, 2010). Odeh proposes that TNF-α plays a central role in the pathogenesis of HE associated with both acute and chronic liver failure (Odeh, 2007)
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