Anti–Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct–Ligated Mice

Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition...

Full description

Saved in:

Bibliographic Details
Published in:	The American journal of pathology Vol. 193; no. 1; pp. 11 - 26
Main Authors:	Gee, Lucy M.V., Barron-Millar, Ben, Leslie, Jack, Richardson, Claire, Zaki, Marco Y.W., Luli, Saimir, Burgoyne, Rachel A., Cameron, Rainie I.T., Smith, Graham R., Brain, John G., Innes, Barbara, Jopson, Laura, Dyson, Jessica K., McKay, Katherine R.C., Pechlivanis, Alexandros, Holmes, Elaine, Berlinguer-Palmini, Rolando, Victorelli, Stella, Mells, George F., Sandford, Richard N., Palmer, Jeremy, Kirby, John A., Kiourtis, Christos, Mokochinski, Joao, Hall, Zoe, Bird, Thomas G., Borthwick, Lee A., Morris, Christopher M., Hanson, Peter S., Jurk, Diana, Stoll, Elizabeth A., LeBeau, Fiona E.N., Jones, David E.J., Oakley, Fiona
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-01-2023
Subjects:	Animals Bile Ducts - surgery Chenodeoxycholic Acid - pharmacology Cholestasis - drug therapy Humans Ligation Liver Memory, Short-Term Mice
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence. [Display omitted]
ISSN:	0002-9440 1525-2191
DOI:	10.1016/j.ajpath.2022.09.005