Progesterone treatment in rats after severe global cerebral ischemia promotes hippocampal dentate gyrus neurogenesis and functional recovery.

Objective: Rats treated with progesterone (P4) after ischemia show an adequate functional performance despite a significant loss of hippocampal pyramidal neurons, suggesting that P4 could favour a permissive microenvironment for cerebral plasticity mechanisms. The possibility of P4 treatment promoting the survival of newly generated hippocampal neurons, in relation to the performance of ischemic rats in a spatial learning task, was assessed in this study. Methods: Adult male rats were subjected to a severe global cerebral ischemia episode (30 min) and treated with P4 or its vehicle at 15 min, 2, 6, 24, 48 and 72 h of reperfusion. From day 4 to 8 post-ischemia 5-bromo-2-deoxyuridine (BrdU) was administered to label proliferating cells. Twenty-one days post-ischemia, the rats were exposed to the Morris water maze to assess behavioral parameters of spatial learning and memory. Subsequently, the brain was perfusion-fixed and immunofluorescence procedures were performed to quantify the number of new mature neurons (BrdU(+)/NeuN(+)) in the dentate gyrus (DG) of the hippocampus. Results: Rats subjected to severe global cerebral ischemia and treated with P4 had a significantly better performance in spatial learning-memory tests, than those treated with vehicle, and a significantly higher number of new mature neurons (BrdU(+)/NeuN(+)) in the DG. Conclusion: These findings show that post-ischemia P4 treatment, following an episode of severe global cerebral ischemia, promotes the survival of newly generated hippocampal neurons in the DG, which may be one of the mechanisms of cerebral plasticity induced by the hormone, that underlie a successful functional performance in learning and memory tests.