L-kynurenine/aryl hydrocarbon receptor pathway mediates brain damage after experimental stroke

MI Cuartero, I Ballesteros, J de la Parra, AL Harkin… - Circulation, 2014 - Am Heart Assoc
Circulation, 2014Am Heart Assoc
Background—Aryl hydrocarbon receptor (AhR) is a transcription factor that belongs to the
basic helix-loop-helix PAS (Per-Arnt-Sim homology domain) family known to mediate the
toxic and carcinogenic effects of xenobiotics. Interestingly, AhR is widely expressed in the
central nervous system, but its physiological and pathological roles are still unclear.
Methods and Results—To define the role of AhR in stroke, we used middle cerebral artery
occlusion in mice and oxygen-glucose deprivation in rat cortical neurons. The results …
Background
Aryl hydrocarbon receptor (AhR) is a transcription factor that belongs to the basic helix-loop-helix PAS (Per-Arnt-Sim homology domain) family known to mediate the toxic and carcinogenic effects of xenobiotics. Interestingly, AhR is widely expressed in the central nervous system, but its physiological and pathological roles are still unclear.
Methods and Results
To define the role of AhR in stroke, we used middle cerebral artery occlusion in mice and oxygen-glucose deprivation in rat cortical neurons. The results presented here show that the ischemic insult increases total and nuclear AhR levels and AhR transcriptional activity in neurons in vivo and in vitro. We also show that AhR has a causal role in acute ischemic damage because pharmacological or genetic loss-of-function approaches result in neuroprotection. Inhibition of cAMP response element-binding protein–dependent signaling may participate in the deleterious actions of AhR. Finally, we have also found that L-kynurenine, a tryptophan metabolite with AhR agonistic properties, is an endogenous ligand that mediates AhR activation in the brain after middle cerebral artery occlusion.
Conclusions
Our data demonstrate that an L-kynurenine/AhR pathway mediates acute brain damage after stroke and open new possibilities for the diagnosis and treatment of this pathology.
Am Heart Assoc