Hepatic Encephalopathy and Astrocyte Senescence

Abstract

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 GADD45a. 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.

Ammonia inhibits energy metabolism in astrocytes in a rapid and GDH2-dependent manner

“…Hepatic encephalopathy is a common complication occurring upon severe liver dysfunction. Albeit it is largely accepted that hyperammonemia-induced impairment of astrocyte function plays a major role in mediating neurological disturbances (Görg et al, 2018; Häussinger and Görg, 2010; Norenberg, 1987), the underlying molecular mechanisms are not well understood and numerous models were proposed (Cash et al, 2010; Cordoba, 2014; Ott and Vilstrup, 2014). One particular aspect that is quite controversially discussed is the role of altered brain energy metabolism caused by hyperammonemia.…”

“…An increase of free radicals can lead to mitochondrial dysfunction, energy failure as well as formation of the mitochondrial transition pore (Albrecht and Norenberg, 2006; Bai et al, 2001, 2001; Frank et al, 2012; Stewart et al, 2000) or RNA oxidation (Görg et al, 2008). Several studies demonstrated that hyperammonemia primarily disturbs astrocyte function resulting in subsequent neurological dysfunction (Görg et al, 2018; Häussinger and Görg, 2010; Norenberg, 1987). Astrocytes have an essential role to ensure neuronal function, such as provision with nutrients and recycling of the neurotransmitter glutamate (Sontheimer, 1995; Zalc, 1994).…”

Overview on Hepatic Encephalopathy

“…Oxidative stress results from inefficient removal of reactive oxygen species (ROS) and free radicals from astrocytes, leading to major damage of cells and finally cell death [22]. Oxidative stress is directly related to malfunction of astrocytes, which is responsible for deterioration in cognitive performance of patients with cirrhosis and HE [23].…”

Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy

“…In addition, blood-brain barrier (BBB) permeability/function, cerebrospinal fluid composition, glymphatic flow, cerebral energy metabolism, neurotransmission and cell-cell communication are all deranged, causing neurological impairment and providing potential therapeutic targets. [11][12][13][14][15][16][17] The AASLD-EASL clinical guidelines for HE, published in 2014, were an important initiative. 1 However, since this publication, there have been many advances in the classification of HE, as well as our understanding of its pathophysiology, diagnosis and treatment.…”