A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors.

Abstract : 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 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower while levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are rapidly upregulated to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we selectively inactivated PR in the central nervous system. 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 STATEMENTThe 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 5α-dihydroprogesterone are rapidly upregulated 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 therapeutically exploited by taking into account the progesterone status of patients and by supplementing and reinforcing endogenous progesterone signaling for attaining its full cerebroprotective potential.
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Journal of Neuroscience, Society for Neuroscience, 2017, epub ahead of print. 〈10.1523/JNEUROSCI.3874-16.2017〉
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Xiaoyan Zhu, Magalie Frechou, Philippe Liere, Shaodong Zhang, Antoine Pianos, et al.. A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors.. Journal of Neuroscience, Society for Neuroscience, 2017, epub ahead of print. 〈10.1523/JNEUROSCI.3874-16.2017〉. 〈inserm-01623387〉

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