Acute Liver Failure in Rats Induced Vasogenic Edema and Nitric Oxide Synthase-Nitric Oxide-cGMP Pathway after Differential Regulation of NMDA Receptors in Cerebral Cortex and Cerebellum

Abstract Acute liver failure (ALF) is a complication of severe liver dysfunction resulting from a wide range of factors including alcoholism, drug-abuse, improper medication, viral hepatitis etc., and present with high mortality rate among the human population. ALF led hyperammonemia (HA) induced cerebral dysfunction is considered to be the main cause of death in patients, however, the precise molecular mechanism is not completely understood. The aim of this study was to investigate the status of brain edema and modulation of N-methyl D-aspartate receptors (NMDAR)- Nitric oxide synthase (NOS)- Nitric oxide (NO)- cyclic guanosine monophosphate (cGMP) axis in the cerebral cortex and cerebellum of ALF rats. ALF was induced by intraperitoneal (IP) injection of thioacetamide (TAA). We observed significantly increased brain water content in ALF rats but absence of astrocytes swelling suggested induction of vasogenic edema. Except constant NR2B, down regulation of NR2A, 2C and 2D subunits containing NMDAR genes in cerebral cortex, however, constant NR2A-C but up-regulation of NR2D subunit in cerebellum suggested brain regions specific differential regulation of NMDAR in ALF rats. Significantly increased nNOS gene and protein level were found to be accompanied by the significantly increased level of NO and cGMP in both brain tissues; however, increased eNOS expression in cortex but increased iNOS expression and activity in cerebellum were observed in ALF rats. Together these findings suggested that ALF in rats may trigger differential regulation of NR2A-D subunits containing NMDAR, induction of NOS-NO-cGMP axis and vasogenic edema in cerebral cortex and cerebellum.