María I Cuartero1, Iván Ballesteros1, Juan de la Parra1, Andrew L Harkin1, Aine Abautret-Daly1, Eoin Sherwin1, Pedro Fernández-Salguero1, Angel L Corbí1, Ignacio Lizasoain1, María A Moro2. 1. From the Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain (M.I.C., I.B., J.d.l.P., I.L.); Trinity College, Dublin, Ireland (A.L.H., A.A.-D., E.S.); Departamento Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain (P.F.-S.); and Centro de Investigaciones Biológicas, CSIC, Madrid, Spain (A.L.C.). 2. From the Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain (M.I.C., I.B., J.d.l.P., I.L.); Trinity College, Dublin, Ireland (A.L.H., A.A.-D., E.S.); Departamento Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain (P.F.-S.); and Centro de Investigaciones Biológicas, CSIC, Madrid, Spain (A.L.C.). neurona@med.ucm.es maribel_cd@hotmail.com.
Abstract
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.
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.
Authors: María Isabel Cuartero; Juan de la Parra; Alicia García-Culebras; Iván Ballesteros; Ignacio Lizasoain; María Ángeles Moro Journal: Curr Pharm Des Date: 2016 Impact factor: 3.116
Authors: Kimberly E Hawkins; Kelly M DeMars; Jon C Alexander; Lauren G de Leon; Sean C Pacheco; Christina Graves; Changjun Yang; Austin O McCrea; Jan C Frankowski; Timothy J Garrett; Marcelo Febo; Eduardo Candelario-Jalil Journal: Brain Behav Date: 2017-04-12 Impact factor: 2.708