Progesterone and allopregnanolone improves stroke outcome in male mice via distinct mechanisms but neither promotes neurogenesis.

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.

MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury.

The administration of pan histone deacetylase (HDAC) inhibitors reduces ischemic damage to the CNS, both in vitro and in animal models of stroke, via mechanisms which we are beginning to understand. The acetylation of p53 is regulated by Class I HDACs and, because p53 appears to play a role in ischemic pathology, the purpose of this study was to discover, using an in vitro white matter ischemia model and an in vivo cerebral ischemia model, if neuroprotection mediated by HDAC inhibition depended on p53 expression. Optic nerves were excised from wild-type and p53-deficient mice, and then subjected to oxygen-glucose deprivation in the presence and absence of a specific inhibitor of Class I HDACs (MS-275, entinostat) while compound action potentials were recorded. Furthermore, transient focal ischemia was imposed on wild-type and p53-deficient mice, which were subsequently treated with MS-275. Interestingly, and in both scenarios, the beneficial effects of MS-275 were most pronounced when p53 was absent. These results suggest that modulation of p53 activity is not responsible for MS-275-mediated neuroprotection, and further illustrate how HDAC inhibitors variably influence p53 and associated apoptotic pathways. Optic nerves from wild-type and p53-deficient mice, engineered to express cyan fluorescent protein (CFP) in neuronal mitochondria, were subjected to oxygen-glucose deprivation (OGD) in the presence and absence of a specific inhibitor of Class I histone deacetylases. The protective effect of MS-275 was evidenced by mitochondrial preservation, and this was most pronounced in the absence of p53.