title: Adrenomedullin protects neurons against oxygen glucose deprivation stress in an autocrine and paracrine manner.
abstract: The understanding of mechanisms involved in ischaemic brain tolerance may provide new therapeutical targets for stroke. In vivo genomic studies revealed an up-regulation of adrenomedullin expression by hypoxic pre-conditioning. Furthermore, adrenomedullin reduced ischaemia-induced brain damage in rodents. However, whether adrenomedullin is involved in hypoxic pre-conditioning-induced tolerance and whether adrenomedullin protects directly neurons against ischaemia remain unknown. Using a neuronal model of hypoxic pre-conditioning and oxygen glucose deprivation (OGD), we showed that 0.1% or 0.5% of O2 pre-conditioning reduced the OGD-induced neuronal death, whereas 1% or 2% of O2 pre-treatment did not induce neuroprotection. Adrenomedullin expression increased following the hypoxic period, and following OGD only in pre-conditioned (0.1% or 0.5% of O2) neurons. Adrenomedullin pre-treatment and post-treatment reduced the OGD-induced neuronal death, partly through PI3kinase-dependent pathway. However, adrenomedullin antagonism during hypoxic pre-conditioning failed to inhibit the neuroprotection whereas adrenomedullin antagonism following OGD abolished the hypoxic pre-conditioning-induced neuroprotection. Finally, we showed that adrenomedullin is involved in neuroprotection induced by endothelial cells and microglia. In contrast, neuroprotection induced by astrocytes occurred through adrenomedullin-independent mechanisms. Altogether, our results suggest that adrenomedullin is an effector of the hypoxic pre-conditioning-induced neuronal tolerance and a potent autocrine and paracrine neuroprotective factor during cerebral ischaemia.
authors.affiliation: Centre d'Imagerie-Neurosciences et Applications aux Pathologies (CI-NAPS), UMR 6232, Université de Caen Basse-Normandie, Université Paris Descartes, CNRS, CEA, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tixier
authors.forename: Claire
authors.initials: C
authors.lastname: Leconte
authors.forename: Omar
authors.initials: O
authors.lastname: Touzani
authors.forename: Simon
authors.initials: S
authors.lastname: Roussel
authors.forename: Edwige
authors.initials: E
authors.lastname: Petit
authors.forename: Myriam
authors.initials: M
authors.lastname: Bernaudin
mesh_terms: D053607:Adrenomedullin / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D019898:Autocrine Communication / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D005947:Glucose / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen; D019899:Paracrine Communication / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D018696:Neuroprotective Agents; D053607:Adrenomedullin; D005947:Glucose; D010100:Oxygen