Alogliptin abates memory injuries of hepatic encephalopathy induced by acute paracetamol intoxication via switching-off autophagy-related apoptosis

Abstract

AimsHepatic encephalopathy (HE) is a complex neuropsychiatric syndrome. Paracetamol (APAP) causes, in high doses, a hepatic injury. Alogliptin (ALO), with its 100% oral bioavailability, may be able to reverse the acute hepatic injury and memory impairments. Materials and methodsForty rats were divided into four groups as follows; Normal Control Group, APAP intoxicated group, ALO and SIL groups. Behavioral tests (Morris water maze, Y-maze spontaneous alteration, and novel object recognition test) were performed together with evaluating HE score. Neurotransmitters (gamma-aminobutyric acid, glutamate, dopamine, serotonin, norepinephrine and acetylcholine), as well as acetylcholinesterase activity, were determined in the hippocampus. Also, hepatotoxicity markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and ammonia) were measured in blood. Additionally, transforming growth factor beta 1, tumor necrosis factor alpha, cytochrome c, granzyme B and caspase-3, coiled-coil Moesin-like BCL-interacting protein 1 “beclin-1”, cellular FLICE-like inhibitory protein, protein 53, TNF-α related apoptosis-inducing ligand, Fas-ligand and alpha-smooth muscle actin were measured in liver homogenate. Moreover, the histopathological investigation was performed. Key findingsAPAP was able to disturb neurotransmitters which were mirrored in the performance of rats in the behavioral test. Most hepatotoxicity, apoptosis and inflammation indicators were elevated after APAP administration, while beclin-1 (autophagy marker) was declined. The tested drugs, both, reversed most of the last mentioned parameters but ALO was more efficient in reducing TGF-β1, α-SMA, TNF-α and ALP as well as increasing % alteration. SignificanceALO and SIL elicited anti-apoptotic, anti-inflammatory and autophagic effects on paracetamol-damaged liver cells and improved memory impairments of HE.