Abstract
BackgroundCerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia.ResultsFollowing exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition.ConclusionsSex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke.
Highlights
Cerebral ischemic stroke is a significant cause of morbidity and mortality
Following oxygen and glucose deprivation (OGD) there was a significant increase in the amount of cell death in both CA1 and dentate gyrus (DG) regions within the neonatal hippocampal slice cultures which was seen in both male (P < 0.001) and female-derived (P < 0.001) slices compared to normoxic controls
We determined whether the effect of the various vehicle treatments had any effect on the amount of cell death seen in the CA1 and DG regions (Fig. 2)
Summary
Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Cerebral ischemic stroke is a major cause of mortality and morbidity with limited effective treatments available [1] Multiple factors influence both the incidence and outcome of ischemic stroke including sex, age, race/ethnicity, hypertension, cardiac disease, diabetes mellitus, hypercholesterolemia, cigarette smoking and alcohol abuse [2]. Over the lifespan, women have a higher risk of stroke and increased rates of post-stroke mortality, Altaee and Gibson BMC Neurosci (2020) 21:5 disability, depression and dementia, compared to men [4] Such an increased risk and worsened post-stroke seen in women may be a consequence of women’s longer life expectancy due to age being the strongest independent risk factor for stroke [5] and a negative predictor for clinical outcome [6]. Sex differences may occur in response to treatment, such as steroid hormones, which has been reported previously for aspirin, warfarin and thrombolytic therapy following stroke [13,14,15]
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