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- W4311441345 abstract "Abstract Background Bile acids (BAs), which act in the liver-brain axis, are liver-derived signaling molecules found in the brain. However, how they modulate neurological function remains largely unknown. Methods To assess the role of BAs in the brain, we generated mice with absent 12α-hydroxylase ( Cyp8b1 ), a BA synthesis enzyme, and determined if brain BA levels were altered in these mice, and if and how this may modulate neuronal function. Results The absence of CYP8B1 increased brain levels of the primary BA chenodeoxycholic acid (CDCA), and decreased ischemic stroke infarct area. Furthermore, CDCA administration reduced ischemic stroke lesion area in wild-type mice. Excitotoxicity due to elevated extra-cellular glutamate contributes to neuronal death in ischemic stroke. Neurons from Cyp8b1 -/- mice showed reduced susceptibility to glutamate-induced toxicity, and exogenous CDCA reduced glutamate-induced toxicity in neurons from wild-type mice. These data suggest that CDCA-mediated decreases in excitotoxic neuronal death contributes to the reduced stroke lesion area in Cyp8b1 -/- mice. Aberrant N-methyl-D-aspartate receptor (NMDAR) over-activation contributes to excitotoxicity. CDCA decreased NMDAR-mediated excitatory post-synaptic currents (EPSCs) in wild-type brain slices, by reducing over-activation of the NMDAR subunit GluN2B. In line with this, synaptic NMDAR activity was also decreased in Cyp8b1 -/- brain slices. Expression level and synaptic distribution of GluN2B were unaltered in Cyp8b1 -/- mice, suggesting that CDCA may directly antagonize GluN2B-containing NMDARs. Conclusions Our data suggests that CDCA acts in the liver-brain axis and decreases the aberrant over-activation of neuronal GluN2B-containing NMDARs, contributing to neuroprotection." @default.
- W4311441345 created "2022-12-26" @default.
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- W4311441345 date "2022-12-14" @default.
- W4311441345 modified "2023-10-15" @default.
- W4311441345 title "Absence of the bile acid enzyme CYP8B1 increases brain chenodeoxycholic acid and reduces neuronal excitotoxicity in mice" @default.
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- W4311441345 doi "https://doi.org/10.1101/2022.12.11.520005" @default.
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