Sex differences in neuroinflammation and neuroprotection in ischemic stroke

Abstract

Stroke is not only a leading cause of mortality and morbidity worldwide it also disproportionally affects women. There are currently over 500,000 more women stroke survivors in the US than men, and elderly women bear the brunt of stroke-related disability. Stroke has dropped to the fifth leading cause of death in men, but remains the third in women. This review discusses sex differences in common stroke risk factors, the efficacy of stroke prevention therapies, acute treatment responses, and post-stroke recovery in clinical populations. Women have an increased lifetime risk of stroke compared to men, largely due to a steep increase in stroke incidence in older postmenopausal women, yet most basic science studies continue to only evaluate young male animals. Women also have an increased lifetime prevalence of many common stroke risk factors, including hypertension and atrial fibrillation, as well as abdominal obesity and metabolic syndrome. None of these age-related risk factors have been well modeled in the laboratory. Evidence from the bench has implicated genetic and epigenetic factors, differential activation of cell-death programs, cell-cell signaling pathways, and systemic immune responses as contributors to sex differences in ischemic stroke. The most recent basic scientific findings have been summarized in this review, with an emphasis on factors that differ between males and females that are pertinent to stroke outcomes. Identification and understanding of the underlying biological factors that contribute to sex differences will be critical to the development of translational targets to improve the treatment of women after stroke.

Sexual dimorphisms in adult human neural, mesoderm‐derived, and neural crest‐derived stem cells

“…In this line, sex and gender differences were reported with a men to women ratio of approximately 2 : 1 in Parkinson 0 s disease [53]. Accordingly, sex differences were observed in other neurodegenerative diseases such as Alzheimer's disease [6], but also in ischemic stroke [54] and neurodegeneration [7]. Since this matter is directly associated with mechanisms of stem cell-mediated neuroprotection, we will focus on this issue in the following.…”

“…While female embryonic neurons were found to be more sensitive to etoposide-and staurosporine-induced apoptosis, male embryonic neurons showed an incapacity to maintain intracellular levels of reduced glutathione [52]. Accordingly, sex differences were observed in other neurodegenerative diseases such as Alzheimer's disease [6], but also in ischemic stroke [54] and neurodegeneration [7]. During dopaminergic differentiation of human adult NC-derived nasal stem cells [inferior turbinate stem cells (ITSCs)], we discovered a significant higher maturation of female dopaminergic neurons in comparison to their male counterparts.…”

“…On genetic level, deletion of PTEN, which germline mutations are found in a subset of children suffering from autism spectrum disorder, was further described to result in an initial increase of self-renewal of NSCs in the dentate gyrus followed by a shift from neuronal to astrocytic differentiation [103,104]. As we reviewed in chapter 3, mechanisms of stem cell-mediated neuroprotection are also dependent on the sex of the individual with direct implication for sex differences reported in Parkinson 0 s disease [53], Alzheimer's disease [6], ischemic stroke [54], and neurodegeneration [7].…”

Age and neuroinflammation are important components of the mechanism of cognitive and neurobehavioral deficits in sickle cell disease

“…14 There was also a significantly higher levels of neuroinflammation (evidenced by a higher density of activated microglia and bone marrowderived proinflammatory mononuclear cells) as well as abnormal neuroplasticity (evidenced by lower dendrite and dendritic spine density and a higher proportion of immature dendritc spine) in aged sickle cell mice compared to age matched controls. We also noted that these neuroimmune and neuronal abnormalities track with the presence and severity of cognitive and neurobehavioral function and that treatment with minocycline (a drug which has been shown to reverse these changes 19,20,42,57 ), restored cognitive and neurobehavioral function as well as led to a decrease in evidence of neuroinflammation and abnormal neuroplasticity.…”

Sex as a biological variable in the pathology and pharmacology of neurodegenerative and neurovascular diseases

“…Activation of ERα after oestrogen treatment significantly inhibits the inflammatory response of microglia, induced by LPS, as measured by mRNA levels of MMP‐9 (Vegeto et al, ). Sex differences in the immunological response to ischaemic injury (Spychala, Honarpisheh, & McCullough, ) are increasingly recognized and will be an area of considerable interest in the future. Sex differences in astrocytes have been recently reviewed elsewhere (Chowen, Argente‐Arizón, Freire‐Regatillo, & Argente, ).…”