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

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Pedro Montesa* , Rosa María Vigueras-Villaseñorb , Julio César Rojas-Castañedab , Tomas Monfila , Miguel Cervantesc & Gabriela Moralí*a a Unidad de Investigación Médica en Farmacología, CMN Siglo XXI, IMSS, México, Méxicob Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, México, Méxicoc Facultad de Ciencias Médicas y Biológicas “Dr. Ignacio Chávez”, UMSNH, Morelia, MéxicoPedro Montes is a researcher interested in elucidating the mechanisms of cerebral plasticity that underlie functional recovery after ischemia and treatment with steroid hormones.Rosa María Vigueras-Villaseñor is the head researcher in her laboratory. Her studies on factors affecting reproductive tissues and the brain include molecular, histological, and immunohistochemical approaches.Julio César Rojas-Castañeda, researcher. His studies on factors affecting circadian rhythmicity include molecular, histological, and immunohistochemical procedures in brain tissue.Tomas Monfil is currently a PhD student. For his previous degrees, he participated in projects on the neuroprotective effects of progesterone on global cerebral ischemia.Miguel Cervantes is the head researcher in his laboratory and has extensive experience in neuroprotection studies. His studies focus on the search for neuroprotective agents of endogenous nature against neurological disorders such as cerebral ischemia.Gabriela Moralí is chief researcher with extensive experience in neuroprotection studies. She has focused mainly on the analysis of the neuroprotective effects of progesterone on global cerebral ischemia, as well as the associated mechanisms of cerebral plasticity.CONTACT Gabriela Moralí gmorali@hotmail.com Unidad de Investigación Médica en Farmacología, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, Mexico City 06720, Mexico* Present address: Laboratorio de Neurotoxicología, Instituto Nacional de Neurología y Neurocirugía ’Manuel Velasco Suárez’, SS, México, DF, MéxicoABSTRACTObjective: 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.