Hepatic Encephalopathy (HE) is a severe complication of acute or chronic liver diseases with a broad spectrum of neurological symptoms including motor disturbances and cognitive impairment of different severity. Contrary to former beliefs, a growing number of studies suggest that cognitive impairment may not fully reverse after an acute episode of overt HE in patients with liver cirrhosis. The reasons for persistent cognitive impairment in HE are currently unknown but recent observations raise the possibility that astrocyte senescence may play a role here. Astrocyte senescence is closely related to oxidative stress and correlate with irreversible cognitive decline in aging and neurodegenerative diseases. In line with this, surrogate marker for oxidative stress and senescence were upregulated in ammonia-exposed cultured astrocytes and in post mortem brain tissue from patients with liver cirrhosis with but not without HE. Ammonia-induced senescence in astrocytes involves glutamine synthesis-dependent formation of reactive oxygen species (ROS), p53 activation and upregulation of cell cycle inhibitory factors p21 and GADD45α. More recent studies also suggest a role of ROS-induced downregulation of Heme Oxygenase (HO)1-targeting micro RNAs and upregulation of HO1 for ammonia-induced proliferation inhibition in cultured astrocytes. Further studies are required to identify the precise sequence of events that lead to astrocyte senescence and to elucidate functional implications of senescence for cognitive performance in patients with liver cirrhosis and HE.
Keywords: ARE, Antioxidant Response Elements; BDNF, Brain-Derived Neurotrophic Factor; Eph, Ephrine; EphR, Ephrine Receptor; GADD45α, Growth Arrest and DNA Damage Inducible 45α; GS, Glutamine Synthetase; HE, Hepatic Encephalopathy; HO1, Heme Oxygenase 1; LOLA, l-Ornithine-l-Aspartate; MAP, Mitogen Activated Protein Kinases; NAPDH, Reduced Form of Nicotinamide Adenine Dinucleotide Phosphate; Nox, NADPH Oxidase; Nrf2, Nuclear Factor-Like 2; PBR, Peripheral-Type Benzodiazepine Receptor; PTN, Protein Tyrosine Nitration; RNOS, Reactive Nitrogen and Oxygen Species; ROS, Reactive Oxygen Species; SA-β-Gal, Senescence-Associated β-d-Galactosidase; TSP, Trombospondin; TrkBT, Truncated Tyrosine Receptor Kinase B; ZnPP, Zinc Protoporphyrin; ammonia; astrocytes; heme oxygenase 1; hepatic encephalopathy; mPT, Mitochondrial Permeability Transition; miRNAs; nNOS, Neuronal-Type Nitric-Oxide Synthase; oxidative stress.