The peri-menopause or menopausal transition—the time period that surrounds the final years of a woman’s reproductive life—is associated with profound reproductive and hormonal changes in a woman’s body and exponentially increases a woman’s risk of cerebral ischemia and Alzheimer’s disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

Background: RT-qPCR analysis is a widely used method for the analysis of mRNA expression throughout the field of mesenchymal stromal cell (MSC) research. Comparison between MSC studies, both in vitro and in vivo, are challenging due to the varied methods of RT-qPCR data normalization and analysis. Therefore, this study focuses on putative housekeeping genes for the normalization of RT-qPCR data between heterogeneous commercially available human MSC, compared with more homogeneous populations of MSC such as MIAMI and RS-1 cells. Results: Eight genes including; ACTB, B2M, EF1α, GAPDH, RPL13a, YWHAZ, UBC and HPRT1 were tested as possible housekeeping genes based on their expression level and variability. EF1α and RPL13a were validated for RT-qPCR analysis of MIAMI cells during expansion in varied oxygen tensions, endothelial differentiation, neural precursor enrichment, and during the comparison with RS-1 cells and commercially available MSC. RPL13a and YWHAZ were validated as normalization genes for the cross-species analysis of MIAMI cells in an animal model of focal ischemia. GAPDH, which is one of the most common housekeeping genes used for the normalization of RT-qPCR data in the field of MSC research, was found to have the highest variability and deemed not suitable for normalization of RT-qPCR data. Conclusions: In order to make comparisons between heterogeneous MSC populations, as well as adult stem cell like MSC which are used in different laboratories throughout the world, it is important to have a standardized, reproducible set of housekeeping genes for RT-qPCR analysis. In this study we demonstrate that EF1α, RPL13a and YWHAZ are suitable genes for the RT-qPCR analysis and comparison of several sources of human MSC during in vitro characterization and differentiation as well as in an ex vivo animal model of global cerebral ischemia. This will allow for the comparative RT-qPCR analysis of multiple MSC populations with the goal of future use in animal models of disease as well as tissue repair.

Ischemic stroke kills more women compared with men thus emphasizing a significant sexual dimorphism in ischemic pathophysiological outcomes. However, the mechanisms behind this sexual dimorphism are yet to be fully understood. It is well established that cerebral ischemia activates a variety of inflammatory cascades and that microglia are the primary immune cells of the brain. After ischemic injury, microglia are activated and play a crucial role in progression and resolution of the neuroinflammatory response. In recent years, research has focused on the role that microglia play in this sexual dimorphism that exists in the response to central nervous system (CNS) injury. Evidence suggests that the molecular mechanisms leading to microglial activation and polarization of phenotypes may be influenced by sex, therefore causing a difference in the pro/anti‐inflammatory responses after CNS injury. Here, we review advances highlighting that sex differences in microglia are an important factor in the inflammatory responses that are seen after ischemic injury. We discuss the main differences between microglia in the healthy and diseased developing, adult, and aging brain. We also focus on the dimorphism that exists between males and females in microglial‐induced inflammation and energy metabolism after CNS injury. Finally, we describe how all of the current research and literature regarding sex differences in microglia contribute to the differences in poststroke responses between males and females.