Department of Neuroscience, Psychology & Behaviour, University of Leicester, Leicester, LE1 9HN, UK.
Department of Physiology and Pharmacology, University of Karbala, Karbala, Iraq.
BMC Neurosci. 2020 Jan 29;21(1):5. doi: 10.1186/s12868-020-0553-1.
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. 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.
Following 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.
Sex 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.
脑缺血性中风是发病率、症状、预后和某些治疗反应方面存在性别差异的重要原因。重要的是，缺血后损伤的分子机制在性别之间可能不同，如果是这样，至少部分解释了治疗反应中观察到的性别差异。在这里，我们旨在使用单性别器官型海马切片培养物确定，一种潜在治疗选择（即性激素）的有效性是否表现出任何性别二态性，以及性别是否影响缺血后激活的细胞凋亡机制。
在暴露于缺血后，雄性组织比雌性组织表现出更高水平的细胞死亡。各种性激素，如孕酮、别孕烯醇酮和雌二醇，在减少雄性和雌性组织的细胞死亡量方面具有保护作用，而醋酸甲地孕酮（MPA）仅在雌性组织中具有保护作用。在存在 5α-还原酶抑制剂非那雄胺的情况下，孕酮的保护作用被消除，这表明它主要通过转化为别孕烯醇酮介导。为了测试缺血后激活的细胞凋亡途径的特定元素的激活存在性别差异的假设，我们给予 Q-VD-OPH，一种半胱天冬酶抑制剂，或 PJ34，一种多聚（ADP 核糖）聚合酶（PARP）抑制剂。只有在雌性组织中，半胱天冬酶抑制才有效，降低细胞死亡，而只有在雄性组织中，PARP 抑制才具有保护作用。然而，在两性中，孕酮和雌二醇的保护作用在存在半胱天冬酶或 PARP 抑制的情况下都没有观察到。
在缺血性损伤后产生的细胞死亡量和激活的细胞死亡途径的元素方面存在性别差异。在性激素提供缺血性损伤后神经保护的有效性方面也存在一些性别差异，即 MPA 仅在雌性组织中具有保护作用。这进一步支持了这样一种观点，即性别是研究中枢神经系统疾病（如缺血性中风）未来药物靶点时需要考虑的一个重要因素。
