Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Montréal, QC H2X 1P1, Canada.
Free Radic Biol Med. 2012 Apr 1;52(7):1228-35. doi: 10.1016/j.freeradbiomed.2012.01.006. Epub 2012 Jan 24.
Chronic liver failure leads to hyperammonemia, a central component in the pathogenesis of hepatic encephalopathy (HE); however, a correlation between blood ammonia levels and HE severity remains controversial. It is believed oxidative stress plays a role in modulating the effects of hyperammonemia. This study aimed to determine the relationship between chronic hyperammonemia, oxidative stress, and brain edema (BE) in two rat models of HE: portacaval anastomosis (PCA) and bile-duct ligation (BDL). Ammonia and reactive oxygen species (ROS) levels, BE, oxidant and antioxidant enzyme activities, as well as lipid peroxidation were assessed both systemically and centrally in these two different animal models. Then, the effects of allopurinol (xanthine oxidase inhibitor, 100mg/kg for 10days) on ROS and BE and the temporal resolution of ammonia, ROS, and BE were evaluated only in BDL rats. Similar arterial and cerebrospinal fluid ammonia levels were found in PCA and BDL rats, both significantly higher compared to their respective sham-operated controls (p<0.05). BE was detected in BDL rats (p < 0.05) but not in PCA rats. Evidence of oxidative stress was found systemically but not centrally in BDL rats: increased levels of ROS, increased activity of xanthine oxidase (oxidant enzyme), enhanced oxidative modifications on lipids, as well as decreased antioxidant defense. In PCA rats, a preserved oxidant/antioxidant balance was demonstrated. Treatment with allopurinol in BDL rats attenuated both ROS and BE, suggesting systemic oxidative stress is implicated in the pathogenesis of BE. Analysis of ROS and ammonia temporal resolution in the plasma of BDL rats suggests systemic oxidative stress might be an important "first hit", which, followed by increases in ammonia, leads to BE in chronic liver failure. In conclusion, chronic hyperammonemia and oxidative stress in combination lead to the onset of BE in rats with chronic liver failure.
慢性肝衰竭导致血氨升高，这是肝性脑病（HE）发病机制的一个重要组成部分；然而，血氨水平与 HE 严重程度之间的相关性仍存在争议。据信氧化应激在调节血氨升高的影响方面发挥作用。本研究旨在确定两种 HE 大鼠模型（门腔静脉分流术（PCA）和胆管结扎术（BDL））中慢性高氨血症、氧化应激和脑水肿（BE）之间的关系。在这两种不同的动物模型中，系统和中枢评估了氨和活性氧（ROS）水平、BE、氧化剂和抗氧化酶活性以及脂质过氧化。然后，仅在 BDL 大鼠中评估了别嘌呤醇（黄嘌呤氧化酶抑制剂，100mg/kg，10 天）对 ROS 和 BE 的影响以及氨、ROS 和 BE 的时间分辨率。在 PCA 和 BDL 大鼠中发现了相似的动脉和脑脊液氨水平，与各自的假手术对照相比，这两种水平均显著升高（p<0.05）。在 BDL 大鼠中检测到 BE（p < 0.05），但在 PCA 大鼠中未检测到。在 BDL 大鼠中发现了系统性氧化应激的证据，但在中枢神经系统中未发现：ROS 水平升高、黄嘌呤氧化酶（氧化剂酶）活性增加、脂质的氧化修饰增强以及抗氧化防御能力降低。在 PCA 大鼠中，证明了氧化还原平衡得到了维持。在 BDL 大鼠中用别嘌呤醇治疗可减轻 ROS 和 BE，表明系统性氧化应激与 BE 的发病机制有关。对 BDL 大鼠血浆中 ROS 和氨时间分辨率的分析表明，系统性氧化应激可能是一个重要的“第一击”，随后氨的增加导致慢性肝衰竭中的 BE。总之，慢性高氨血症和氧化应激的结合导致慢性肝衰竭大鼠发生 BE。
