TY - JOUR
T1 - Anti–Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct–Ligated Mice
AU - Gee, Lucy M.V.
AU - Barron-Millar, Ben
AU - Leslie, Jack
AU - Richardson, Claire
AU - Zaki, Marco Y.W.
AU - Luli, Saimir
AU - Burgoyne, Rachel A.
AU - Cameron, Rainie I.T.
AU - Smith, Graham R.
AU - Brain, John G.
AU - Innes, Barbara
AU - Jopson, Laura
AU - Dyson, Jessica K.
AU - McKay, Katherine R.C.
AU - Pechlivanis, Alexandros
AU - Holmes, Elaine
AU - Berlinguer-Palmini, Rolando
AU - Victorelli, Stella
AU - Mells, George F.
AU - Sandford, Richard N.
AU - Palmer, Jeremy
AU - Kirby, John A.
AU - Kiourtis, Christos
AU - Mokochinski, Joao
AU - Hall, Zoe
AU - Bird, Thomas G.
AU - Borthwick, Lee A.
AU - Morris, Christopher M.
AU - Hanson, Peter S.
AU - Jurk, Diana
AU - Stoll, Elizabeth A.
AU - LeBeau, Fiona E.N.
AU - Jones, David E.J.
AU - Oakley, Fiona
N1 - Publisher Copyright:
© 2023 American Society for Investigative Pathology
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2022.09.005
DO - 10.1016/j.ajpath.2022.09.005
M3 - Article
C2 - 36243043
AN - SCOPUS:85144434047
SN - 0002-9440
VL - 193
SP - 11
EP - 26
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -