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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. [ABSTRACT FROM AUTHOR]

Despite the large number of molecules reported as being over-expressed after ischaemia, little is known regarding their regulation. mi RNAs are potent post-transcriptional regulators of gene expression, and reports have shown differentially mi RNA expression in response to focal cerebral ischaemia. The present study analysed mi RNA expression from acute to late phases of ischaemia to identify specific ischaemia-related mi RNAs, elucidate their role, and identify potential targets involved in stroke pathophysiology. Of 112 mi RNAs, 32 showed significant changes and different expression profiles. In addition to the previously reported differentially expressed mi RNAs, new ischaemia-regulated mi RNAs have been found, including miR-347. Forty-seven genes involved in brain functions or related to ischaemia are predicted to be potential targets of the differentially expressed mi RNAs after middle cerebral artery occlusion. Analysis of four of these targets (Acsl4, Arf3, Btg2 and Dpysl5) showed them to be differentially regulated by ischaemia at the transcriptional or post-transcriptional level. Acsl4, Bnip3l and Phyhip, potential targets of miR-347, were up-regulated after miR-347 over-expression, inducing neuronal apoptotic death. Our findings suggest that miR-347 plays an important role in regulating neuronal cell death, identify Acsl4 as a new protein requiring study in ischaemia, and provide an important resource for future functional studies of mi RNAs after ischaemia. [ABSTRACT FROM AUTHOR]