AN L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke
Background—AhR (Aryl hydrocarbon receptor) is a transcription factor that belongs to the basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim homology domain) family known to mediate the toxic and carcinogenic effects of xenobiotics. Interestingly, AhR is widely expressed in the CNS 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 (MCAO) in mice and oxygen-glucose deprivation (OGD) in rat cortical neurons. The results presented herein show that the ischemic insult increases total and nuclear AhR levels as well as AhR transcriptional activity in neurons in vivo and in vitro. We also show that AhR has a causal role in acute ischemic damage since pharmacological or genetic loss-of-function approaches result in neuroprotection. Inhibition of CREB-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 MCAO.
Conclusions—Our data demonstrate that an L-kynurenine-AhR pathway mediates acute brain damage after stroke and open new possibilities for diagnosis and treatment of this pathology.
- Received May 28, 2014.
- Revision received September 11, 2014.
- Accepted September 26, 2014.