PDF(Pubmed)
Abstract：
UNASSIGNED: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor.
UNASSIGNED: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration.
UNASSIGNED: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals.
UNASSIGNED: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE.
UNASSIGNED: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.
UNASSIGNED: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration.
UNASSIGNED: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals.
UNASSIGNED: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE.
UNASSIGNED: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.
摘要：
■血浆氨浓度升高和随之而来的脑能量代谢中断可能是肝性脑病（HE）的发病机理的基础。脑能量稳态依赖于脑氧合的有效维持，和失调损害神经元功能，导致认知障碍。我们假设HE与脑氧合降低有关，并探讨了氨作为潜在病理生理因素的潜在作用。
■在具有最小HE（mHE;胆管结扎[BDL]）的慢性肝病大鼠模型中，脑组织氧测量，和质子磁共振波谱用于研究高氨血症如何影响中枢神经系统的氧合和代谢底物可用性。鸟氨酸苯乙酸盐（OP，OCR-002；奥塞拉治疗学，CA,美国）用作降低血浆氨浓度的实验处理。
■在BDL动物中，葡萄糖，乳酸，大脑皮层组织氧浓度明显低于假手术对照组。OP治疗纠正了高氨血症并恢复了脑组织氧。虽然BDL动物是低血压的，通过增加动脉血压的治疗，皮质组织氧浓度显著提高。发现BDL动物对外源施加的CO2的脑血管反应性正常。
■这些数据表明高氨血症显著降低皮质氧合，可能损害大脑能量代谢。这些发现对mHE患者的治疗具有潜在的临床意义。
■脑功能障碍是肝硬化的严重并发症，影响约30%的患者；然而，它的治疗仍然是一个未满足的临床需求。这项研究表明，肝硬化动物模型脑中的氧浓度显着降低。低动脉血压和增加的氨（一种在肝衰竭患者中积累的神经毒素）被证明是主要的根本原因。这些异常的实验校正恢复了大脑中的氧浓度，建议探索潜在的治疗途径。
■在具有最小HE（mHE;胆管结扎[BDL]）的慢性肝病大鼠模型中，脑组织氧测量，和质子磁共振波谱用于研究高氨血症如何影响中枢神经系统的氧合和代谢底物可用性。鸟氨酸苯乙酸盐（OP，OCR-002；奥塞拉治疗学，CA,美国）用作降低血浆氨浓度的实验处理。
■在BDL动物中，葡萄糖，乳酸，大脑皮层组织氧浓度明显低于假手术对照组。OP治疗纠正了高氨血症并恢复了脑组织氧。虽然BDL动物是低血压的，通过增加动脉血压的治疗，皮质组织氧浓度显著提高。发现BDL动物对外源施加的CO2的脑血管反应性正常。
■这些数据表明高氨血症显著降低皮质氧合，可能损害大脑能量代谢。这些发现对mHE患者的治疗具有潜在的临床意义。
■脑功能障碍是肝硬化的严重并发症，影响约30%的患者；然而，它的治疗仍然是一个未满足的临床需求。这项研究表明，肝硬化动物模型脑中的氧浓度显着降低。低动脉血压和增加的氨（一种在肝衰竭患者中积累的神经毒素）被证明是主要的根本原因。这些异常的实验校正恢复了大脑中的氧浓度，建议探索潜在的治疗途径。
