Sheen Jiunn-Ming, Chen Yu-Chieh, Hsu Mei-Hsin, Tain You-Lin, Yu Hong-Ren, Huang Li-Tung
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang Gung University College of MedicineKaohsiung, Taiwan.
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan.
Front Cell Neurosci. 2016 Jun 23;10:167. doi: 10.3389/fncel.2016.00167. eCollection 2016.
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.
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.
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.
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.
胆管结扎（BDL）大鼠表现出全身氧化应激增加和肝性脑病（HE）特征性的脑功能障碍，包括疲劳、神经递质改变、认知和运动障碍以及脑炎症。在慢性肝衰竭诱发的脑病中，血浆和脑中肿瘤坏死因子-α（TNF-α）和不对称二甲基精氨酸（ADMA）水平均升高。本研究首先确定了年轻BDL大鼠血浆、大脑皮层和海马中TNF-α和ADMA的时间变化情况。接下来，我们研究了依那西普是否有助于预防脑损伤。
在第17±1天，将年轻大鼠进行假结扎或BDL手术，持续4周。治疗组大鼠每周腹腔注射（IP）依那西普（10mg/kg）3次，或联合鞘内注射（IT）依那西普（100μg），共3次。
我们发现年轻BDL大鼠的血浆TNF-α、可溶性肿瘤坏死因子受体1（sTNFR1）、可溶性肿瘤坏死因子受体2（sTNFR2）和ADMA水平升高，皮层TNF-α mRNA和蛋白以及ADMA增加，海马TNF-α mRNA和蛋白增加，且存在空间缺陷。腹腔注射依那西普或联合腹腔和鞘内注射依那西普可降低皮层TNF-α mRNA和ADMA的增加。腹腔/鞘内联合注射依那西普可降低皮层和海马TNF-α mRNA和蛋白水平的升高以及空间缺陷。
我们得出结论，腹腔和鞘内联合使用依那西普可降低年轻BDL大鼠脑中升高的TNF-α和ADMA水平，并挽救空间缺陷。
