Hyperammonemia, brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication

Abstract

Aim: To study the blood-brain barrier integrity, brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication.

Methods: Adults male Wistar rats were divided into four groups. Group I: sham operation; II: Prehepatic portal hypertension, produced by partial portal vein ligation; III: Acetaminophen intoxication and IV: Prehepatic portal hypertension plus acetaminophen. Acetaminophen was administered to produce acute hepatic injury. Portal pressure, liver serum enzymes and ammonia plasma levels were determined. Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity. Reflexes and behavioral tests were recorded.

Results: Portal hypertension was significantly elevated in groups II and IV. Liver enzymes and ammonia plasma levels were increased in groups II, III and IV. Prehepatic portal hypertension (group II), acetaminophen intoxication (group III) and both (group IV) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia. Cortical edema was present in rats with acute hepatic injury in groups III and IV. Behavioral test (rota rod) was altered in group IV.

Conclusion: These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (cytotoxic). Group IV, with behavioral altered test, can be considered as a model for study at an early stage of portal-systemic encephalopathy.

Figure 1

Significantly increased ammonia plasma levels in all groups of rats ^aP<0.05 and ^bP<0.01 when compared with sham group.

Figure 2

Liver Microscopy. A: Shows a normal liver histology corresponding to a rat in sham group (HE, 100 ×); B: Minimal focal necrosis in group II (HE, asterisk, 500 ×); C: Diffuse hem-orrhagic necrosis in group III (HE, arrows, 400 ×); D: Focal hem-orrhagic confluent necrosis in group IV (HE, asterisk, 400 ×).

Figure 3

Significantly increased brain water content in groups III and IV ^dP < 0.01, ^bP < 0.001 when compared with sham group.

Figure 4

Trypan blue and BBB. A: Trypan blue dye in hippocam-pus of a sham rat. No breakdown of BBB was observed. Trypan blue was only positive in vascular space (100 ×); B: Trypan blue dye diffusion due to the breakdown of BBB as an example of what was observed in hippocampus in groups II, III and IV (100 ×).