(526.2) Acquisition of a Senescence-like Phenotype in Neurons Contributing to the Pathogenesis of Hepatic Encephalopathy Due to Chronic Liver Disease

Poster Board Number: D19
Introduction:

Zachary Kobs (St. Marys University), Elaina Williams (College of Pharmacy, The University of Texas at Austin), Christopher Chu (College of Pharmacy, The University of Texas at Austin), Anca Petrescu (College of Pharmacy, The University of Texas at Austin), Suyeon An (College of Pharmacy, The University of Texas at Austin), Juliet Venter (College of Pharmacy, The University of Texas at Austin), Sharon DeMorrow (College of Pharmacy, The University of Texas at Austin, Dell Medical School, The University of Texas at Austin, Central Texas Veterans Healthcare System)

Background: Hepatic encephalopathy resultant from chronic liver failure (Type C HE) is associated with neurological dysfunction and hyperammonemia. In HE, senescent markers have been found in astrocytes, but research into neuronal senescence has been limited. TGFb1 is one of the senescence-associated secretory phenotype (SASP) factors released from senescent cells, and has been shown to be upregulated in the brain in Type A HE, but its role in Type C HE is unknown. The aim of this study was to assess the role of a senescence-like phenotype in the pathogenesis of Type C HE.

Methods: SD rats underwent bile duct ligation (BDL) surgery and C57BL/6 mice were treated with CCl4 for 16 wks to induce chronic liver failure. CCl4-treated mice received a senolytic cocktail of Dasatinib and qercertin (D/Q via oral gavage) starting after 8 weeks of CCl4 injections. In parallel, human autopsy brain samples from patients with HE due to liver cirrhosis and age- and sex-matched controls were used. Neurobehavioral testing to assess cognitive and neuromuscular function was performed. Markers of senescence (p21, p16, b-galactosidase expression), SASPs (CCL2, TGFb1, and IL-6) and neuroinflammation were assayed in the cerebellum and hippocampus by qPCR and immunohistochemistry.

Results: In rodent models of HE and in human autopsy samples, markers of senescence and SASP were observed in neurons of the CA1 and dentate gyrus in the hippocampus and in the purkinje cell layer in the cerebellum, regions known for their involvement in learning and memory and motor control. Treatment with D/Q reduced the number of senescent neurons, and attenuated the cognitive deficits, the neuromuscular impairment, presence of ataxia and neuroinflammation observed in the mouse model of HE.

Conclusion: Taken together, these data suggest that the acquisition of a senescent-like phenotype in neurons in the hippocampus and cerebellum in models of Type C HE may contribute to the pathogenesis of Type C HE. Taken together our data suggests that targeting the senescence-like phenotype in HE may be a viable option for the development of novel therapeutic strategies.

This study was funded by NIH R01 awards (DK082435 and DK112803) to Dr. DeMorrow and a ASIP SROPP to Mr. Kobs. This work was completed with support from the Veterans Health Administration and with resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas.