Thrombin has been implicated in playing a role in hydrocephalus development following intraventricular hemorrhage (IVH). However, the mechanisms underlying the sex differences to the detrimental effects of thrombin post-IVH remain elusive. Three-month old male and female Sprague-Dawley rats underwent unilateral intracerebroventricular (ICV) injections of 3U or 5U thrombin, or saline, to examine differences in thrombin-induced hydrocephalus and white matter injury. Mortality, and lateral ventricle volume and white matter injury were measured on magnetic resonance imaging evaluation at 24 h post-injection. In addition, male rats were pretreated with 17-β estradiol (E2, 5 mg/kg) or vehicle at 24 and 2 h prior to ICV injection of 3U thrombin. All rats were euthanized at 24 h post-injection for histology and immunohistochemistry. ICV injection of 5U thrombin caused 100 and 0% mortality in female and male rats, respectively. 3U of thrombin resulted in significant ventricular dilation and white matter damage at 24 h in both male and female rats, but both were worse in females (p < 0.05). Furthermore, neutrophil infiltration into choroid plexus and periventricular white matter was enhanced in female rats and may play a critical role in the sex difference in brain injury. Pre-treating male rats with E2, increased thrombin (3U)-induced hydrocephalus, periventricular white matter injury and neutrophil infiltration into the choroid plexus and white matter. ICV thrombin injection induced more severe ventricular dilation and white matter damage in female rats compared to males. Estrogen appears to contribute to this difference which may involve greater neutrophil infiltration in females. Understanding sex differences in thrombin-induced brain injury may shed light on future interventions for hemorrhagic stroke.

中文翻译：

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性别差异对凝血酶诱发的脑积水和白质损伤的影响：中性粒细胞的作用


凝血酶在脑室内出血（IVH）后脑积水的发展中发挥作用。然而，性别差异对 IVH 后凝血酶有害影响的机制仍然难以捉摸。三个月大的雄性和雌性 Sprague-Dawley 大鼠接受单侧脑室内 (ICV) 注射 3U 或 5U 凝血酶或生理盐水，以检查凝血酶诱导的脑积水和白质损伤的差异。注射后 24 小时通过磁共振成像评估测量死亡率、侧脑室体积和白质损伤。此外，在 ICV 注射 3U 凝血酶之前 24 小时和 2 小时，用 17-β 雌二醇（E2，5 mg/kg）或载体预处理雄性大鼠。所有大鼠在注射后24小时处死以进行组织学和免疫组织化学分析。 ICV 注射 5U 凝血酶分别导致雌性和雄性大鼠死亡 100% 和 0%。 3U 凝血酶在 24 小时内导致雄性和雌性大鼠显着的心室扩张和白质损伤，但雌性大鼠的情况更严重 (p < 0.05)。此外，雌性大鼠中中性粒细胞浸润脉络丛和脑室周围白质增强，可能在脑损伤的性别差异中发挥关键作用。用 E2 预处理雄性大鼠，增加凝血酶 (3U) 诱导的脑积水、脑室周围白质损伤以及中性粒细胞浸润脉络丛和白质。与雄性大鼠相比，ICV 凝血酶注射引起雌性大鼠更严重的心室扩张和白质损伤。雌激素似乎导致了这种差异，这可能涉及女性中性粒细胞浸润的增加。 了解凝血酶引起的脑损伤的性别差异可能有助于未来出血性中风的干预措施。