Males and females possess distinct biological differences that manifest in diverse risk profiles for acute and chronic diseases. A well-documented example of this is ischemic stroke. It has been demonstrated that older females have greater prevalence of, and worse outcome after, ischemic stroke than do males and younger females. Loss of estrogen after menopause is heavily implicated as a contributing factor for this phenomenon; however, there is mounting evidence to suggest that certain risk factors tend to occur more often in older females, such as hypertension and atrial fibrillation, while others more adversely affect females than they do males, such as diabetes and smoking. Sex-specific risk factors, such as oral contraceptive use and menopause, could also contribute to the discrepancy in stroke prevalence and outcome. Additionally, there is evidence to suggest that females tend to present with more nontraditional symptoms of acute stroke than do males, making it more difficult for clinicians to correctly identify the occurrence of a stroke, which may delay the administration of thrombolytic intervention. Finally, certain sociodemographic factors, such as the fact that females were more likely to live alone prior to stroke, may contribute to poorer recovery in females. This review will explore the various co-morbidities and sociodemographic factors that contribute to the greater prevalence of and poorer outcome after stroke in older females and will highlight the critical need for considering sex as a predisposing biological variable in stroke studies.

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MicroRNAs have gained popularity as a potential treatment for many diseases, including stroke. This study identifies and characterizes a specific member of the miR-17–92 cluster, miR-20a-3p, as a possible stroke therapeutic. A comprehensive microRNA screening showed that miR-20a-3p was significantly upregulated in astrocytes of adult female rats, which typically have better stroke outcomes, while it was profoundly downregulated in astrocytes of middle-aged females and adult and middle-aged males, groups that typically have more severe stroke outcomes. Assays using primary human astrocytes and neurons show that miR-20a-3p treatment alters mitochondrial dynamics in both cell types. To assess whether stroke outcomes could be improved by elevating astrocytic miR-20a-3p, we created a tetracycline (Tet)-induced recombinant adeno-associated virus (rAAV) construct where miR-20a-3p was located downstream a glial fibrillary acidic protein promoter. Treatment with doxycycline induced miR-20-3p expression in astrocytes, reducing mortality and modestly improving sensory motor behavior. A second Tet-induced rAAV construct was created in which miR-20a-3p was located downstream of a neuron-specific enolase (NSE) promoter. These experiments demonstrate that neuronal expression of miR-20a-3p is vastly more neuroprotective than astrocytic expression, with animals receiving the miR-20a-3p vector showing reduced infarction and sensory motor improvement. Intravenous injections, which are a therapeutically tractable treatment route, with miR-20a-3p mimic 4 h after middle cerebral artery occlusion (MCAo) significantly improved stroke outcomes including infarct volume and sensory motor performance. Improvement was not observed when miR-20a-3p was given immediately or 24 h after MCAo, identifying a unique delayed therapeutic window. Overall, this study identifies a novel neuroprotective microRNA and characterizes several key pathways by which it can improve stroke outcomes.

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