Brain Research Laboratory, Department of Emergency Medicine, 1365 B Clifton Rd NE, Suite 5100, Atlanta, GA 30322, USA.
Department of Pathology, Emory University Hospital Room H183, 1364 Clifton Rd NE, Atlanta, GA 30322, USA.
Horm Behav. 2017 Nov;96:21-30. doi: 10.1016/j.yhbeh.2017.08.004. Epub 2017 Sep 18.
Despite improved therapeutic methods, CNS toxicity resulting from cancer treatment remains a major cause of post-treatment morbidity. More than half of adult patients with cranial irradiation for brain cancer develop neurobehavioral/cognitive deficits that severely impact quality of life. We examined the neuroprotective effects of the neurosteroid progesterone (PROG) against ionizing radiation (IR)-induced neurobehavioral/cognitive deficits in mice. Male C57/BL mice were exposed to one of two fractionated dose regimens of IR (3Gy×3 or 3Gy×5). PROG (16mg/kg; 0.16mg/g) was given as a pre-, concurrent or post-IR treatment for 14days. Mice were tested for short- and long-term effects of IR and PROG on neurobehavioral/cognitive function on days 10 and 30 after IR treatment. We evaluated both hippocampus-dependent and -independent memory functions. Locomotor activity, elevated plus maze, novel object recognition and Morris water maze tests revealed behavioral deficits following IR. PROG treatment produced improvement in behavioral performance at both time points in the mice given IR. Western blot analysis of hippocampal and cortical tissue showed that IR at both doses induced astrocytic activation (glial fibrillary acidic protein), reactive macrophages/microglia (CD68) and apoptosis (cleaved caspase-3) and PROG treatment inhibited these markers of brain injury. There was no significant difference in the degree of deficit in any test between the two dose regimens of IR at either time point. These findings could be important in the context of patients with brain tumors who may undergo radiotherapy and eventually develop cognitive deficits.
尽管治疗方法有所改善，但癌症治疗引起的中枢神经系统毒性仍然是治疗后发病率的主要原因。超过一半的接受颅部放疗治疗脑癌的成年患者会出现神经行为/认知缺陷，严重影响生活质量。我们研究了神经甾体孕酮（PROG）对小鼠电离辐射（IR）诱导的神经行为/认知缺陷的神经保护作用。雄性 C57/BL 小鼠接受两种分次剂量方案的 IR（3Gy×3 或 3Gy×5）照射。PROG（16mg/kg；0.16mg/g）作为 IR 前、同期或后治疗，持续 14 天。在 IR 治疗后 10 天和 30 天，用小鼠检测 IR 和 PROG 对神经行为/认知功能的短期和长期影响。我们评估了海马依赖性和非依赖性记忆功能。在 IR 后，运动活动、高架十字迷宫、新物体识别和 Morris 水迷宫测试显示出行为缺陷。PROG 治疗在给予 IR 的小鼠的两个时间点均改善了行为表现。海马和皮质组织的 Western blot 分析表明，两种剂量的 IR 均诱导了星形胶质细胞激活（胶质纤维酸性蛋白）、反应性巨噬细胞/小胶质细胞（CD68）和细胞凋亡（裂解 caspase-3），而 PROG 治疗抑制了这些脑损伤标志物。在任何测试中，两种剂量方案的 IR 在两个时间点的缺陷程度都没有显著差异。这些发现对于可能接受放疗并最终出现认知缺陷的脑肿瘤患者可能具有重要意义。
