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

Autor: Wetten, Aaron, Ogle, Laura, Mells, George, Hegade, Vinod S, Jopson, Laura, Corrigan, Margaret, Palmer, Jeremy, Johansson, Maja, Bäckström, Torbjörn, Doverskog, Magnus, Jones, David EJ, Dyson, Jessica K
Přispěvatelé: Wetten, Aaron [0000-0003-4989-9726], Apollo - University of Cambridge Repository
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Canadian Journal of Gastroenterology and Hepatology.
ISSN: 2291-2789
DOI: 10.1155/2022/3618090
Popis: Funder: Umecrine Cognition AB
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.
Databáze: OpenAIRE
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