Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

Abstract

To explore the mechanism of agmatine's antidepressant action. Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period. The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically. For bromodeoxyuridine (BrdU; thymidine analog as a marker for dividing cells) labeling, the mice were injected with BrdU (100 mg/kg, ip, twice per d for 2 d), and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry. The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay. After the onset of chronic stress, the locomotor activity of the mice in the open field significantly decreased, while coadministration of agmatine 10 mg/kg (po) blocked it. Furthermore, the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons. In vitro treatment with agmatine 0.1-10 micromol/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner. We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice. This may be one of the important mechanisms involved in agmatine's antidepressant action.