¹ H NMR based Metabolic Signatures in Liver and Brain in Rat Model of Hepatic Encephalopathy

Hepatic Encephalopathy (HE) is a debilitating neuropsychiatric complication associated with acute and chronic liver failure. It is characterized by diverse symptoms with variable severity that includes cognitive and motor deficits. The aim of the study is to assess metabolic alterations in brain and liver using nuclear magnetic resonance (NMR) spectroscopy and subsequent multivariate analyses to characterize metabolic signatures associated with HE. HE was developed by bile duct ligation (BDL) that resulted in hepatic dysfunctions and cirrhosis as shown by liver function tests. Metabolic profiles from control and BDL rats indicated increased levels of lactate, branched chain amino acids (BCAAs), glutamate and choline in liver, whereas levels of glucose, phenylalanine and pyridoxine were decreased. In case of brain, the levels of lactate, acetate, succinate, citrate and malate were increased, while glucose, creatine, isoleucine, leucine and proline levels were decreased. Furthermore, neurotransmitters such as glutamate and GABA were increased, whereas choline and myo-inositol were decreased. The alterations in neurotransmitter levels resulted in cognitive and motor defects in BDL rats. A significant correlation was found between alterations in NAA/choline, choline/creatine and NAA/creatine with behavioural deficits. Thus, the data suggests impairment in metabolic pathways such as tricarboxylic acid (TCA) cycle, glycolysis and ketogenesis in liver and brain of animals with HE. The study highlights that metabolic signatures could be potential marker to monitor HE progression and to assess therapeutic interventions.