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Adrenomedullin protects neurons against oxygen glucose deprivation stress in an autocrine and paracrine manner
Author(s) -
Tixier Emmanuelle,
Leconte Claire,
Touzani Omar,
Roussel Simon,
Petit Edwige,
Bernaudin Myriam
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05494.x
Subject(s) - adrenomedullin , neuroprotection , medicine , endocrinology , pharmacology , neuroscience , ischemia , biology , receptor
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 O 2 pre‐conditioning reduced the OGD‐induced neuronal death, whereas 1% or 2% of O 2 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 O 2 ) 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.