| Autor: |
Vera F. Monteiro-Cardoso, Xin Yi Yeo, Han-Gyu Bae, David Castano Mayan, Mariam Wehbe, Sejin Lee, Kumar Krishna-K, Seung Hyun Baek, Leon F. Palomera, Sangeetha Shanmugam, Kai Ping Sem, Matthew P. Parsons, Michael R. Hayden, Elisa A. Liehn, Sreedharan Sajikumar, Svend Davanger, Dong-Gyu Jo, Sangyong Jung, Roshni R. Singaraja |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.11.520005 |
| Popis: |
BackgroundBile 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.MethodsTo 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.ResultsThe 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 inwild-typemice. Excitotoxicity due to elevated extra-cellular glutamate contributes to neuronal death in ischemic stroke. Neurons fromCyp8b1-/-mice showed reduced susceptibility to glutamate-induced toxicity, and exogenous CDCA reduced glutamate-induced toxicity in neurons fromwild-typemice. These data suggest that CDCA-mediated decreases in excitotoxic neuronal death contributes to the reduced stroke lesion area inCyp8b1-/-mice. Aberrant N-methyl-D-aspartate receptor (NMDAR) over-activation contributes to excitotoxicity. CDCA decreased NMDAR-mediated excitatory post-synaptic currents (EPSCs) inwild-typebrain slices, by reducing over-activation of the NMDAR subunit GluN2B. In line with this, synaptic NMDAR activity was also decreased inCyp8b1-/-brain slices. Expression level and synaptic distribution of GluN2B were unaltered inCyp8b1-/-mice, suggesting that CDCA may directly antagonize GluN2B-containing NMDARs.ConclusionsOur data suggests that CDCA acts in the liver-brain axis and decreases the aberrant over-activation of neuronal GluN2B-containing NMDARs, contributing to neuroprotection. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
