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

Overview

Journal Can J Gastroenterol Hepatol

Specialty Gastroenterology

Date 2022 Dec 16

PMID 36523650

Authors

Aaron Wetten

Laura Ogle

George Mells

Vinod S Hegade

Laura Jopson

Margaret Corrigan

Jeremy Palmer

Maja Johansson

Torbjorn Backstrom

Magnus Doverskog

David E J Jones

Jessica K Dyson

Affiliations

Soon will be listed here.

Abstract

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), = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients ( (120) = -0.53, < 0.001) but not healthy controls ( (39) = -0.21, = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition ( = 1034, = 0.02), emotional ( = 1374, = 0.004), and itch ( = 795, = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); = 423 = 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.

Citing Articles

Extra-Synaptic GABA Receptor Potentiation and Neurosteroid-Induced Learning Deficits Are Inhibited by GR3027, a GABA Modulating Steroid Antagonist.

Bengtsson S, Sjostedt J, Malinina E, Das R, Doverskog M, Johansson M Biomolecules. 2023; 13(10).

PMID: 37892178 PMC: 10604444. DOI: 10.3390/biom13101496.

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