Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?
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-amino...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2022-01-01
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| Series: | Canadian Journal of Gastroenterology and Hepatology |
| Online Access: | http://dx.doi.org/10.1155/2022/3618090 |
| _version_ | 1797980293933563904 |
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| author | Aaron Wetten Laura Ogle George Mells Vinod S. Hegade Laura Jopson Margaret Corrigan Jeremy Palmer Maja Johansson Torbjörn Bäckström Magnus Doverskog David E. J. Jones Jessica K. Dyson |
| author_facet | Aaron Wetten Laura Ogle George Mells Vinod S. Hegade Laura Jopson Margaret Corrigan Jeremy Palmer Maja Johansson Torbjörn Bäckström Magnus Doverskog David E. J. Jones Jessica K. Dyson |
| author_sort | Aaron Wetten |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:52:26Z |
| format | Article |
| id | doaj.art-9fcfa82491ac470e963dd7cf21e73f2a |
| institution | Directory Open Access Journal |
| issn | 2291-2797 |
| language | English |
| last_indexed | 2024-04-11T05:52:26Z |
| publishDate | 2022-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Canadian Journal of Gastroenterology and Hepatology |
| spelling | doaj.art-9fcfa82491ac470e963dd7cf21e73f2a2022-12-22T04:42:01ZengHindawi LimitedCanadian Journal of Gastroenterology and Hepatology2291-27972022-01-01202210.1155/2022/3618090Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?Aaron Wetten0Laura Ogle1George Mells2Vinod S. Hegade3Laura Jopson4Margaret Corrigan5Jeremy Palmer6Maja Johansson7Torbjörn Bäckström8Magnus Doverskog9David E. J. Jones10Jessica K. Dyson11Translational and Clinical Research InstituteTranslational and Clinical Research InstituteDepartment of Human GeneticsLeeds Liver UnitTranslational and Clinical Research InstituteLiverpool University Hospitals NHS Foundation TrustTranslational and Clinical Research InstituteUmecrine Cognition ABUmecrine Cognition ABUmecrine Cognition ABTranslational and Clinical Research InstituteTranslational and Clinical Research InstituteBackground 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.http://dx.doi.org/10.1155/2022/3618090 |
| spellingShingle | Aaron Wetten Laura Ogle George Mells Vinod S. Hegade Laura Jopson Margaret Corrigan Jeremy Palmer Maja Johansson Torbjörn Bäckström Magnus Doverskog David E. J. Jones Jessica K. Dyson Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis? Canadian Journal of Gastroenterology and Hepatology |
| title | Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis? |
| title_full | Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis? |
| title_fullStr | Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis? |
| title_full_unstemmed | Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis? |
| title_short | Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis? |
| title_sort | neurosteroid activation of gaba a receptors a potential treatment target for symptoms in primary biliary cholangitis |
| url | http://dx.doi.org/10.1155/2022/3618090 |
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