The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice.

Bile acids (BAs) are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a BA synthesis enzyme. In these Cyp8b1^-/-, and in wild-type mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) over-activation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1^-/- and CDCA-treated wild-type mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in wild-type brains. Synaptic NMDAR activity was also decreased in Cyp8b1^-/- brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1^-/- mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR over-activation, contributing to neuroprotection in stroke.