Hyperammonemia enhances the function and expression of P-glycoprotein and Mrp2 at the blood-brain barrier through NF-κB.

Abstract

Ammonia is considered to be the main neurotoxin responsible for hepatic encephalopathy resulting from liver failure. Liver failure has been reported to alter expression and activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) at the blood-brain barrier (BBB). The aim of this study was to investigate whether ammonia is involved in abnormalities of expression and activity of P-gp and Mrp2 at the BBB. Hyperammonemic rats were developed by an intraperitoneal injection of ammonium acetate (NH4 Ac, 4.5 mmol/kg). Results showed that Mrp2 function markedly increased in cortex and hippocampus of rats at 6 h following NH4 Ac administration. Significant increase in function of P-gp was observed in hippocampus of rats. Meanwhile, such alterations were in line with the increase in mRNA and protein levels of P-gp and Mrp2. Significant increase in levels of nuclear amount of nuclear factor-κB (NF-κB) p65 was also observed. Primarily cultured rat brain microvessel endothelial cells (rBMECs) were used for in vitro study. Data indicated that 24 h exposure to ammonia significantly increased function and expression of P-gp and Mrp2 in rBMECs, accompanied with activation of NF-κB. Furthermore, such alterations induced by ammonia were reversed by NF-κB inhibitor. In conclusion, this study demonstrates that hyperammonemia increases the function and expression of P-gp and Mrp2 at the BBB via activating NF-κB pathway. Hyperammonemia, a proverbial main factor responsible for neurocognitive disorder and blood-brain barrier (BBB) dysfunction resulting from liver failure, could increase the expression and activity of P-glycoprotein and multidrug resistance-associated protein 2 (Mrp2) at the BBB both in vivo and in vitro. Furthermore, the NF-κB activation stimulated by hyperammonemia may be the potential mechanism underlying such abnormalities induced by hyperammonemia.

• Authors: Ji Zhang, Mian Zhang, Binbin Sun, Ying Li, Ping Xu, Can Liu, Li Liu, Xiaodong Liu
• Journal: Journal of neurochemistry (J Neurochem) Vol. 131 Issue 6 Pg. 791-802 (Dec 2014) ISSN: 1471-4159 [Electronic] England
• PMID: 25200138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 International Society for Neurochemistry.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• NF-kappa B

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Biological Transport (physiology)
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Endothelium, Vascular (metabolism)
• Gene Expression Regulation (physiology)
• Hyperammonemia (metabolism)
• Male
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (metabolism)
• NF-kappa B (metabolism)
• Rats, Sprague-Dawley
• Signal Transduction (physiology)