Post-stroke Intranasal (+)-Naloxone Delivery Reduces Microglial Activation and Improves Behavioral Recovery from Ischemic Injury.
Post-stroke Intranasal (+)-Naloxone Delivery Reduces Microglial Activation and Improves Behavioral Recovery from Ischemic Injury.
复制标题
DOI：
10.1523/eneuro.0395-17.2018
复制
发表时间：
2018-03
期刊：
影响因子：
3.4
通讯作者：
Airavaara M
中科院分区：
文献类型：
--
作者：
Anttila JE;Albert K;Wires ES;Mätlik K;Loram LC;Watkins LR;Rice KC;Wang Y;Harvey BK;Airavaara M
缺血性中风是致残的主要原因，需要有效的治疗策略来促进完全康复。神经炎症在中风病理生理中起着重要作用，对其如何影响康复的理解有限。本研究的目的是表征小胶质细胞激活的时空表达谱，以及中风后抑制小胶质细胞/巨噬细胞激活是否有助于恢复。为了抑制小胶质细胞/巨噬细胞的激活，我们选择了鼻内给药纳洛酮，这是一种已经用于阿片类药物过量的药物，已知可以减少小胶质细胞/巨噬细胞的激活。我们描述了大鼠皮层缺血性损伤后小胶质细胞/巨噬细胞激活的时间进展，发现脑卒中后7 d皮层激活达到峰值。出乎意料的是，吞噬细胞在丘脑的慢性表达与神经元丢失有关。（+）-纳洛酮是一种降低小胶质细胞激活而不拮抗阿片受体的对构象，在中风后第1天开始鼻内给药，持续7天。(+)-纳洛酮治疗降低纹状体和丘脑中的小胶质细胞/巨噬细胞激活，促进14天监测期间的行为恢复，减少受损皮层和同侧丘脑的神经元死亡。我们的研究结果首次表明，脑卒中后鼻内(+)-纳洛酮可促进短期功能恢复，并减少小胶质细胞/巨噬细胞的激活。因此，(+)-纳洛酮是一种治疗缺血性脑卒中的有前景的药物，值得进一步研究。
Ischemic stroke is the leading cause of disability, and effective therapeutic strategies are needed to promote complete recovery. Neuroinflammation plays a significant role in stroke pathophysiology, and there is limited understanding of how it affects recovery. The aim of this study was to characterize the spatiotemporal expression profile of microglial activation and whether dampening microglial/macrophage activation post-stroke facilitates the recovery. For dampening microglial/macrophage activation, we chose intranasal administration of naloxone, a drug that is already in clinical use for opioid overdose and is known to decrease microglia/macrophage activation. We characterized the temporal progression of microglia/macrophage activation following cortical ischemic injury in rat and found the peak activation in cortex 7 d post-stroke. Unexpectedly, there was a chronic expression of phagocytic cells in the thalamus associated with neuronal loss. (+)-Naloxone, an enantiomer that reduces microglial activation without antagonizing opioid receptors, was administered intranasally starting 1 d post-stroke and continuing for 7 d. (+)-Naloxone treatment decreased microglia/macrophage activation in the striatum and thalamus, promoted behavioral recovery during the 14-d monitoring period, and reduced neuronal death in the lesioned cortex and ipsilateral thalamus. Our results are the first to show that post-stroke intranasal (+)-naloxone administration promotes short-term functional recovery and reduces microglia/macrophage activation. Therefore, (+)-naloxone is a promising drug for the treatment of ischemic stroke, and further studies should be conducted.