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Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?
Wetten, Aaron; Ogle, Laura; Mells, George; Hegade, Vinod S; Jopson, Laura; Corrigan, Margaret; Palmer, Jeremy; Johansson, Maja; Bäckström, Torbjörn; Doverskog, Magnus; Jones, David E J; Dyson, Jessica K.
Afiliación
  • Wetten A; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.
  • Ogle L; Freeman Hospital, Newcastle-upon-Tyne, UK.
  • Mells G; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.
  • Hegade VS; Freeman Hospital, Newcastle-upon-Tyne, UK.
  • Jopson L; Department of Human Genetics, University of Cambridge, Cambridge, UK.
  • Corrigan M; Leeds Liver Unit, St James' University Hospital, Leeds, UK.
  • Palmer J; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.
  • Johansson M; Freeman Hospital, Newcastle-upon-Tyne, UK.
  • Bäckström T; Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
  • Doverskog M; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.
  • Jones DEJ; Umecrine Cognition AB, Solna, Sweden.
  • Dyson JK; Umecrine Cognition AB, Solna, Sweden.
Can J Gastroenterol Hepatol ; 2022: 3618090, 2022.
Article en En | MEDLINE | ID: mdl-36523650
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores de GABA-A / Neuroesteroides / Cirrosis Hepática Biliar Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Can J Gastroenterol Hepatol Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores de GABA-A / Neuroesteroides / Cirrosis Hepática Biliar Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Can J Gastroenterol Hepatol Año: 2022 Tipo del documento: Article