期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 34, 页码 12581-12586出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803174105
关键词
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资金
- Spanish Ministry of Science and Education [BFU2004-02838, SAF2007-60010]
- Instituto de Salud Carlos III [RD06/0026/1001]
- Intramural Research Program of the National Institutes of Health
- National Cancer Institute
- Center for Cancer
The adrenomedullin (AM) gene, adm, is widely expressed in the central nervous system (CNS) and several functions have been suggested for brain AM. Until now, a formal confirmation of these actions using genetic models has been elusive since the systemic adm knockout results in embryo lethality. We have built a conditional knockout mouse model using the Cre/loxP approach. When crossed with transgenic mice expressing the Cre recombinase under the tubulin T alpha-1 promoter, we obtained animals with no AM expression in the CNS but normal levels in other organs. These animals lead normal lives and do not present any gross morphological defect. Specific areas of the brain of animals lacking CNS AM contain hyperpolymerized tubulin, a consequence of AM down-regulation. Behavioral analysis shows that mice with no AM in their brain have impaired motor coordination and are hyperactive and overanxious when compared to their wild-type littermates. Treatment with methylphenidate, haloperidol, and diazepam did not show differences between genotypes. Circulating levels of adrenocorticotropic hormone and corticosterone were similar in knockout and wild-type mice. Animals with no brain AM were less resistant to hypobaric hypoxia than wild-type mice, demonstrating the neuroprotective function of AM in the CNS. In conclusion, AM exerts a beneficial action in the brain by maintaining homeostasis both under normal and stress conditions.
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