The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABAA receptors
Abstract
The bile steroids (BS) cholic acid and chenodeoxycholic acid are produced in hepatocytes and in the brain. Nothing is known about neuronal actions of BS. Deficiency in a 27-hydroxylase enzyme coincides with reduced production of chenodeoxycholic acid (CDCA) and a relative increase in cholic acid in an inherited lipid storage disease, cerebrotendinous xanthomatosis, characterized by neurological dysfunctions, which can be treated by dietary CDCA. We have examined the modulation of hypothalamic network activity by nine common BS. Cholate and CDCA significantly reduced the firing of hypothalamic neurons and synchronized network activity with CDCA being nearly 10 times more potent. The synthetic BS dehydrocholate synchronized the activity without affecting the firing rate. Gabazine, a GABA(A) receptor antagonist, occluded synchronization by BS. Whole-cell patch clamp recordings revealed a block of NMDA- and GABA(A)-receptors by BS. Potencies of nine common BS differed between NMDA and GABA(A) receptors, however in both cases they correlated with BS affinities for albumin but not with their lipophilicity, supporting a direct action at ligand gated ion channels. GABAergic synaptic currents displayed a faster decay under BS. Our data provide new insight into extrahepatic functions of BS revealing their neuroactive potential.
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Bile acids may substantially affect cognitive function through their affinity to muscarinic, GABA, and NMDA receptors.
“BAs may substantially affect cognitive function by their affinity to muscarinic receptors, as well as GABA and NMDA receptors (325).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [325]
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“Consistent with this idea, freely circulating BAs have been implicated in the modulation of CNS proteins such as NMDA, GABAA and M3 muscarinic receptors (Raufman et al., 2002; Schubring et al., 2012), the activation of neuronal ion channels (Wiemuth et al.”
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- Authors
- Schubring, S. R., Fleischer, W., Lin, J. S., Haas, H. L., & Sergeeva, O. A.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Inserm (FR)
- Corresponding author
- Sergeeva, O.A.
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 506
- Issue
- 2
- Pages
- 322-326
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W1991971927
- Cited by
- 81
- References
- 21
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 11 · 2021: 10 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DFG SE 1767, SFB 575/3 and 8)
- INSERM (U628)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- chenodeoxycholic acid, cholic acid, NMDA receptor antagonism, GABA-A receptor antagonism, hypothalamic neurons, neuronal network synchronization, cerebrotendinous xanthomatosis, dehydrocholic acid, albumin binding
- MeSH terms
- Animals, Animals, Newborn, Chenodeoxycholic Acid, Hypothalamus, Neurons, Receptors, GABA-A, Receptors, N-Methyl-D-Aspartate, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Mice, GABA-A Receptor Antagonists
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