| First Author | Zhu X | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 45 | Pages | 10998-11020 |
| PubMed ID | 28986464 | Mgi Jnum | J:254871 |
| Mgi Id | MGI:6101063 | Doi | 10.1523/JNEUROSCI.3874-16.2017 |
| Citation | Zhu X, et al. (2017) A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors. J Neurosci 37(45):10998-11020 |
| abstractText | Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5alpha-reduction leading to 5alpha-dihydroprogesterone (5alpha-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP). In the female mouse brain, levels of 5alpha-DHP and 3alpha,5alpha-THP are lower and levels of 20alpha-DHP are higher than in males. After MCAO, levels of progesterone and 5alpha-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5alpha-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes.SIGNIFICANCE STATEMENT The brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5alpha-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the female brain. An important role of endogenous progesterone in cerebroprotection was demonstrated by the conditional inactivation of its receptor in neural cells. These results show the importance of endogenous progesterone, its metabolites, and neural progesterone receptors in acute cerebroprotection after stroke. This new concept could be exploited therapeutically by taking into account the progesterone status of patients and by supplementing and reinforcing endogenous progesterone signaling for attaining its full cerebroprotective potential. |
