Neuroprotection and Behavior Regulation by Adrenomedullin and PAMP as Shown by Conditional Knockout Models

Abstract

The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system and several functions have been suggested for brain AM. Until recently, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. The recent development of Cre/loxP conditional knockouts for this gene has opened a door for detailed physiopathological studies in the absence of neural AM. These animals present a subtle but very informative phenotype. For instance, it has been shown that neural stem cells lacking adm have delayed growth and their differentiation pattern is different from the one observed in wild type stem cells, producing less neurons and astrocytes but more oligodendrocytes. When the behavior of these animals was studied, it was found that knockout mice were more active, had less motor coordination and were more anxious than the control animals. As it relates to pain sensing, a very complex scenario has emerged; if pure spinal reflexes are tested, then AM functions as a pronociceptive modulator peptide. On the other hand, if the test involves encephalic processing, AM has the opposite effect and acts as an analgesic. Another field where the AM knockouts have shed additional light is in the involvement of AM in neuroprotection. Animals lacking neural AM had larger infarcts when subjected to focal brain ischemia and had compromised survival when exposed to hypobaria. These studies highlight the many functions of AM in the physiopathology of the nervous system.