Females have been understudied in pre-clinical and clinical traumatic brain injury (TBI), despite distinct biology and worse clinical outcomes versus males. Sulfonylurea receptor 1 (SUR1) inhibition has shown promising results in predominantly male TBI. A phase II trial is ongoing. We investigated whether SUR1 inhibition effects on contusional TBI differ by sex given that this may inform clinical trial design and/or interpretation. We studied the moderating effects of sex on post-injury brain tissue loss in 142 male and female ATP-binding cassette transporter subfamily C member 8 (Abcc8) wild-type, heterozygote, and knockout mice (12–15 weeks). Monkey fibroblast-like cells and mouse brain endothelium-derived cells were used for in vitro studies. Mice were injured with controlled cortical impact and euthanized 21 days post-injury to assess contusion, brain, and hemisphere volumes (vs. genotype- and sex-matched naïves). Abcc8 knockout mice had smaller contusion volumes (p = 0.012) and larger normalized contralateral (right) hemisphere volumes (nRHV; p = 0.03) after injury versus wild type. This was moderated by sex: Contusions were smaller (p = 0.020), nRHV was higher (p = 0.001), and there was less global atrophy (p = 0.003) in male, but not female, knockout versus wild-type mice after TBI. Less atrophy occurred in males for each copy of Abcc8 lost (p = 0.023–0.002, all outcomes). In vitro, sex-determining region Y (SRY) stimulated Abcc8 promoter activity and increased Abcc8 expression. Loss of Abcc8 strongly protected against post-traumatic cerebral atrophy in male, but not female, mice. This may partly be mediated by SRY on the Y-chromosome. Sex differences may have important implications for ongoing and future trials of SUR1 blockade.

中文翻译：

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Abcc8（磺酰脲受体-1）对脑外伤后脑萎缩的影响因性别而异


尽管与男性相比，女性具有不同的生物学特性和更差的临床结果，但女性在临床前和临床创伤性脑损伤 (TBI) 方面的研究还不够。磺酰脲受体 1 (SUR1) 抑制在以男性为主的 TBI 中显示出有希望的结果。二期试验正在进行中。我们研究了 SUR1 抑制对挫伤性 TBI 的影响是否因性别而异，因为这可能为临床试验设计和/或解释提供信息。我们在 142 只雄性和雌性 ATP 结合盒转运蛋白亚家族 C 成员 8 ( Abcc8 ) 野生型、杂合子和基因敲除小鼠（12-15 周）中研究了性别对损伤后脑组织损失的调节作用。猴成纤维细胞样细胞和小鼠脑内皮衍生细胞用于体外研究。通过受控的皮质撞击使小鼠受伤，并在受伤后 21 天对其实施安乐死，以评估挫伤、大脑和半球体积（与基因型和性别匹配的幼鼠相比）。与野生型相比， Abcc8敲除小鼠受伤后挫伤体积更小 ( p = 0.012)，而标准化对侧（右）半球体积 (nRHV； p = 0.03) 更大。这种情况受到性别的调节：与野生型 TBI 后的野生型小鼠相比，雄性（而非雌性）基因敲除小鼠的挫伤更小（ p = 0.020），nRHV 更高（ p = 0.001），并且整体萎缩更少（ p = 0.003） 。每丢失一个Abcc8拷贝，雄性中发生的萎缩就会减少（ p = 0.023–0.002，所有结果）。在体外，性别决定区 Y (SRY) 刺激Abcc8启动子活性并增加Abcc8表达。 Abcc8的缺失对雄性小鼠（而非雌性小鼠）的创伤后脑萎缩有很强的保护作用。这可能部分是由 Y 染色体上的 SRY 介导的。性别差异可能对正在进行和未来的 SUR1 阻断试验产生重要影响。