Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure

Abstract

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, 100 mg/kg for 10 days) 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. HIGHLIGHTS► Hyperammonemia does not lead independently to brain edema in chronic liver failure. ► Systemic oxidative stress plays a role in brain edema in chronic liver failure. ► Systemic oxidative stress induces brain edema synergistically with hyperammonemia. ► Systemic oxidative stress is an important "first hit" in chronic liver failure.

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

“…Wright et al, using electron microscopy, precisely demonstrated that the BBB is anatomically intact in BDL rats (Wright et al, 2007). Furthermore, in the same model, our group did not find any brain extravasation of Evans Blue or sodium fluorescein (Bosoi et al, 2012), nor any changes in the expression of the tight junction proteins (Huynh et al, 2011). In another rat model of chronic HE, induced by a portacaval anastomosis (PCA), breakdown of the BBB could also not be demonstrated (Alexander et al, 2000).…”

“…Our group recently demonstrated, in six-week BDL rats, that brain edema develops in the presence of systemic, and not cerebral, oxidative stress ( Bosoi et al, 2012). This systemic phenomenon was confirmed as the attenuation of systemic oxidative stress using allopurinol (xanthine oxidase inhibitor) led to a reduction in brain edema ( Bosoi et al, 2012). In the same animal model, our group demonstrated that blood ammonia and oxidative stress are independent factors, and are synergistically implicated in the development of brain edema ( Bosoi et al, 2012).…”

“…However, in the setting of CLD, systemic oxidative stress, rather than cerebral oxidative stress, plays a major role in the onset of brain edema. Our group recently demonstrated, in six-week BDL rats, that brain edema develops in the presence of systemic, and not cerebral, oxidative stress ( Bosoi et al, 2012). This systemic phenomenon was confirmed as the attenuation of systemic oxidative stress using allopurinol (xanthine oxidase inhibitor) led to a reduction in brain edema ( Bosoi et al, 2012).…”

“…This systemic phenomenon was confirmed as the attenuation of systemic oxidative stress using allopurinol (xanthine oxidase inhibitor) led to a reduction in brain edema ( Bosoi et al, 2012). In the same animal model, our group demonstrated that blood ammonia and oxidative stress are independent factors, and are synergistically implicated in the development of brain edema ( Bosoi et al, 2012). Here, BDL rats treated with the oral carbon microspheres (ammonia adsorbent) AST-120 showed an attenuation of ammonia and brain edema, but systemic oxidative stress remained present .…”

“…It has been shown that ammonia applied to cultured astrocytes, at concentrations of 100 and 200 μM, does not induce oxidative stress, while concentrations of ammonia >500 μM result in ROS generation (Görg et al, 2008 andMehrotra andTrigun, 2012). In vivo, blood and brain ammonia levels are significantly lower in CLD rats than in ALF (<250 μM in CLD compared to >800 μM in ALF, ( Bosoi et al, 2012 andJiang et al, 2009c)); however, cerebral oxidative stress was observed only in ALF rats. In support of this, in PCA rats, a model of chronic hyperammonemia with ammonia levels <250 μM, no signs of oxidative stress were observed in the brain ( Bosoi et al, 2012).…”