对神经保护的转化失效的潜在昼夜影响
Elga Esposito1, Wenlu Li1, Emiri T Mandeville1
1Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Nature
|June 5, 2020
概括
循环节律对中风神经保护有影响. 在动物模型中有效的治疗在人类中失败了,因为动物和人类的中风阶段不同,影响了治疗效率和脑损伤.
科学领域:
- 神经科学
- 时间生物学
- 脑卒中研究
背景情况:
- 在动物中风模型中成功的神经保护策略在人类临床试验中经常失败.
- 夜行动物和白天活动的人类之间对立的昼夜周期可能解释了这种转化差距.
- 大多数人脑中风发生在白天活动阶段,与夜间动物活动周期形成鲜明对比.
研究的目的:
- 研究昼夜阶段在中风神经保护策略的有效性中的作用.
- 确定动物和人类之间不同昼夜周期是否有助于临床转化中风治疗的失败.
- 在实验中风模型中评估昼夜节律对大脑组织脆弱性和治疗反应的影响.
主要方法:
- 在动物焦点脑缺血模型中测试了三种神经保护药物 (normobaric hyperoxia,α-phenyl-butyl-tert-nitrone (αPBN),MK801).
- 在白天 (无活性阶段) 与夜间 (活性阶段) 动物中风模型中的治疗疗效比较.
- 使用激光光斑成像来评估脑缺血半阴影和细胞死亡的道染色.
- 在昼夜类似周期下的小鼠初级神经元中研究了分子机制,评估了谷氨酸和反应性氧物种的释放,以及亡/亡介质的激活.
主要成果:
- 所有经过测试的神经保护疗法在非活性阶段的动物中风模型中降低了心脏病发作,但在活性阶段的模型中没有降低.
- 活动阶段的动物中风模型显示出更窄的缺血半阴影和减少的心脏病增长.
- 在活性阶段的神经元显示较少的谷氨酸和反应性氧物种释放,在氧气-葡萄糖缺乏下较低的亡/亡信号.
- αPBN和MK801只能在非活性阶段的神经元中降低神经元死亡.
结论:
- 在实验中,循环节律显著影响神经保护疗法的有效性.
- 动物和人类之间不同昼夜阶段是中风治疗转化失败的关键因素.
- 未来对中风和其他中枢神经系统疾病的转化研究必须考虑昼夜节律对治疗结果的影响.
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