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Progesterone and allopregnanolone improves stroke outcome in male mice via distinct mechanisms but neither promotes neurogenesis
Author(s) -
Lee Rona J,
Kim Joon Kyung,
Chao Diana,
Kuo Lisa,
Mally Adheip,
McClean Megan E.,
Pemberton Heather E.,
Wilmington Andrew R.,
Wong Jennifer,
Murphy Sean P.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12990
Subject(s) - allopregnanolone , neurogenesis , doublecortin , subventricular zone , neun , striatum , endocrinology , medicine , biology , neuroactive steroid , neuroscience , receptor , hippocampus , dentate gyrus , dopamine , microbiology and biotechnology , gabaa receptor , neural stem cell , stem cell , immunohistochemistry
Based on the outcome of a number of experimental studies, progesterone (PROG) holds promise as a new therapy for stroke. To understand more about the mechanisms involved, we administered PROG (or the major metabolite, allopregnanolone, ALLO), intra‐peritoneally, for a period of 24 h after transient middle cerebral artery occlusion to male mice variably expressing intracellular progesterone receptors (iPR) A/B. Effects on infarct volume and neurogenesis were then assessed up to 1 month later. Predictably, infarct volume in wild‐type mice receiving either drug was significantly smaller. However, mice heterozygous for iPRs A/B showed protection by ALLO but not by PROG. There was robust amplification of cell division in the wall of the lateral ventricle on the injured side of the brain, these cells migrated into the striatum and lateral cortex, and a significant number survived for at least 3 weeks. However, very few doublecortin‐positive cells emerged from the subventricular zone and subsequent expression of NeuN in these newborn neurons was extremely rare. Neither PROG nor ALLO amplified the rate of neurogenesis, suggesting that the long‐term benefits of acute drug administration results from tissue preservation.Male mice derive long‐lasting benefit from progesterone and allopregnanolone after ischemic stroke. In mice heterozygous for iPRs, only allopregnanolone proved effective, suggesting distinct mechanisms. Abundant newborn cells were found in the wall of the lateral ventricle on the injured side (many doublecortin‐positive), some migrated into the striatum and lateral cortex, but very few survived as mature neurons. Neurosteroid administration did not amplify this process.