Ischemic stroke initiates a cascade of changes that lead to cell death and also coordinates endogenous processes that counteract the nocuous consequences of ischemia. Understanding these processes is very important for the development of potential neuroprotectants which can be just boosters of endogenous processes. Treatment with exogenous progesterone is neuroprotective after middle cerebral artery occlusion (MCAO). However, the male and female brains contain significant amounts of endogenous progesterone.The aim of our work was to study: 1) the effects of MCAO on the endogenous levels of steroids and the role of neural progesterone receptors (PR) at the acute phase after stoke in young and aging mice of both sexes; 2) the cellular basis of the neuroprotection by progesterone following stroke and the role of neural PR. We used an in vivo model of MCAO; a transgenic mice line (PRNesCre) selectively lacking the expression of PR in neural cells; gas chromatography-tandem mass spectrometry (GC-MS/MS); and histological, behavioral, and immunofluorescence analyses.In the first part of the study, we showed that in the male mouse brain, progesterone is mainly converted to 5a-dihydroprogesterone (5a-DHP), which is a natural PR agonist ligand. After MCAO, brain levels of progesterone and 5a-DHP are rapidly upregulated in males but not in females. In contrast, females may use the interconversion of 20a-dihydroprogesterone and progesterone for regulating the availability of PR-active pregnanes. Moreover, young and aging male and female PRNesCre mice exhibited increased infarcts, severe sensorimotor deficits, and decreased densities of neurons and microglia comparatively to age-matched control mice PRloxP/loxP. In addition, our results revealed sex differences in stroke outcomes in young but not in aging mice. In the second part of the study, we showed that, in male PRloxP/loxP mice, progesterone improved sensorimotor outcomes and reduced infarct volumes. In the peri-infarct, progesterone increased the densities of neurons, oligodendrocytes and their precursors, decreased the densities of activated astrocytes and microglia, and the expression of the aquaporin 4. These beneficial effects of progesterone were not observed in PRNesCre mice.Our findings 1) uncover the importance of endogenous pregnanes and neural PR for the cerebroprotection at the early acute phase after stroke; 2) show that progesterone treatment in male mice has neuro-protectant, pro-myelinating and anti-inflammatory effects after MCAO and that neural PR is required for the mediation of these effects. These data strongly suggest that ligands of PR or agents targeting their downstream signaling could be developed for neuroprotection after stroke.