Sex differences in stroke therapies

Abstract

Stroke is the 5th leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these were found to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few therapeutics, both preclinically and clinically, take into account possible sex differences in treatment. Reanalysis of data from the only currently FDA-approved stroke therapy, tPA, has shown to not only improve stroke outcomes for both sexes, but to also show sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti-inflammatory drugs (minocycline), stimulators of cell survival (IGF-1), and inhibitors of cell death pathways (pharmacological inhibition of PARP-1, NO production, and caspase activation), as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analyses in clinical trials, as well as in preclinical studies, must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systemized/structured way to translate promising therapies to both sexes and increase stroke recovery.

Sexually dimorphic microglia and ischemic stroke

“…It has been determined that early responses with tPA are more effective in women . Research shows that males are more likely to receive tPA as a therapeutic option, whereas women may be excluded owing to outside risk factors (ie, hypertension) . Furthermore, certain experimental anti‐inflammatory treatments, such as minocycline, which inhibits the PARP‐1 pathway, are more effective in males in both preclinical and clinical studies .…”

“…108 Research shows that males are more likely to receive tPA as a therapeutic option, whereas women may be excluded owing to outside risk factors (ie, hypertension). 109 Furthermore, certain experimental anti-inflammatory treatments, such as minocycline, which inhibits the PARP-1 pathway, are more effective in males in both preclinical and clinical studies. 109,110 Lastly, IGF-1, which can be microglial-regulated, has shown promise as treatment in estrogen-deficient middle-aged females by reducing stroke-induced damage and motor impairment in the aging brain.…”

“…109 Furthermore, certain experimental anti-inflammatory treatments, such as minocycline, which inhibits the PARP-1 pathway, are more effective in males in both preclinical and clinical studies. 109,110 Lastly, IGF-1, which can be microglial-regulated, has shown promise as treatment in estrogen-deficient middle-aged females by reducing stroke-induced damage and motor impairment in the aging brain. 34 It is possible that the sexual dimorphism in microglial function may contribute to the differences that are seen in treatment effectiveness between the two sexes.…”

Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy?

“…In contrast, stroke patients were often middle-aged (40-60 years old, 54.8%) or elderly (>60 years old, 45.2%), consisting of both males and females, and were always enrolled in clinical trials without selection (see Fig 7E, F). 32 Moreover, there is experimental evidence that cell donors' and recipients' ages can influence cell treatment efficacy, particularly in commonly applied MNC populations. However, this kind of influence cannot be excluded simply due to the very limited number of studies assessing female and aged individuals.…”

Sex/gender influences on the nervous system: Basic steps toward clinical progress

“…In previous investigations, Louise McCullough has reported neuronal utilization of distinct cell death pathways in a mouse model of ischemic cell death (McCullough, 2005). In this issue, Sex differences in stroke therapies (Sohrabji et al, 2017) explores the basis for altering stroke treatment algorithms.…”