Treatment with progesterone after focal cerebral ischemia suppresses proliferation of progenitor cells but enhances survival of newborn neurons in adult male mice

Abstract

Stroke stimulates cell proliferation in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG) in adult rodents and humans. However, most newborn cells will die within 1-2 weeks. We recently have revealed that progesterone (P4) promotes the survival of newborn neurons in the DG and improves the neurological dysfunction after cerebral ischemia. The aim of this study was to further explore the effects of P4 on the ischemia-induced neurogenesis in the DG, SVZ and striatum. Bromodeoxyuridine (BrdU) was used to label proliferating cells on day 3 after middle cerebral artery occlusion (MCAO). P4 (4 mg/kg) was injected for 3 consecutive days at BrdU-D(-1 to 1) (from one day before to one day after BrdU-injection) or BrdU-D(4-6) (4-6 days after BrdU-injection). The P4-treatment at BrdU-D(-1 to 1) attenuated the increase in the density of 24-h-old BrdU(+) cells in MCAO-DG and -SVZ, which was blocked by the 5alpha-reductase inhibitor finasteride. The P4-treatment at BrdU-D(4-6) significantly increased the density of 28-day-old BrdU(+) cells in MCAO-DG without changing the population ratios of BrdU(+)/NeuN(+) and BrdU(+)/GFAP(+) cells, which was sensitive to the blockade of P4 receptor and extracellular signal-regulated kinase (ERK). In addition, the P4-treatment at BrdU-D(4-6) produced approximately 2-fold increase in the density of 28-day-old BrdU(+) cells in MCAO-striatum. This study provides evidence that the P4-treatment after stroke suppresses ischemia-stimulated proliferation of progenitor cells but improves the poor survival of ischemia-induced newborn cells.