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

Gee, Lucy; 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; Innes, Barbara A.; Jopson, Laura; Dyson, Jessica; McKay, Katherine .R.C.; Pechlivanis, Alexandros; Holmes, Elaine; Berlinguer‐Palmini, Rolando; Victorelli, Stella; Mells, George; Sandford, Richard; Palmer, Jeremy M.; Kirby, John A.; Kiourtis, Christos; Mokochinski, João Benhur; Hall, Zoe; Bird, Tom; Borthwick, Lee A.; Morris, Christopher M.; Hanson, Peter S.; Jurk, Diana; Stoll, Elizabeth A.; LeBeau, Fiona E. N.; Jones, David; Oakley, Fiona

doi:10.1016/j.ajpath.2022.09.005

Cited by 9 publications

(1 citation statement)

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“…A potential mechanism resulting in neuro-inflammation in liver disease patients with central fatigue has previously been proposed [ 62 ]. Recent data using bile duct ligation (BDL) in rodents (an established model of cholestasis) supports these postulated mechanisms, with BDL rodents developing cognitive symptoms early in the disease process, which was associated with disruption of the blood-brain-barrier and hippocampal dysfunction [ 63 ]. This might suggest a mechanistic explanation for the increased allopregnanolone levels seen in this study and is an area that warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Wetten

Ogle

Mells

et al. 2022

Canadian Journal of Gastroenterology and Hepatology

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Background and Aims. A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method. Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results. There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42 ). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = −0.53, p < 0.001 ) but not healthy controls (r (39) = −0.21, p = 0.21 ). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p = 0.02 ), emotional (u = 1374, p = 0.004 ), and itch (u = 795, p = 0.03 ). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p = 0.001 ). Conclusion. Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.

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Section: Discussionmentioning

confidence: 99%