4.5 Article

Post-stroke Intranasal (+)-Naloxone Delivery Reduces Microglial Activation and Improves Behavioral Recovery from Ischemic Injury

期刊

ENEURO
卷 5, 期 2, 页码 -

出版社

SOC NEUROSCIENCE
DOI: 10.1523/ENEURO.0395-17.2018

关键词

Microglia; middle cerebral artery occlusion; naloxone; NF-kappa B; secondary injury; stroke

资金

  1. Academy of Finland [250275, 256398, 281394, 309489]
  2. Biocentrum Helsinki
  3. Sigrid Juselius Foundation
  4. EU FP7 GLORIA [602919]
  5. 3iRegeneration - Tekes
  6. National Institute on Drug Abuse, Intramural Research Program at the National Institutes of Health
  7. National Institute on Alcohol Abuse and Alcoholism
  8. Ella and Georg Ehrnrooth Foundation
  9. Paivikki and Sakari Sohlberg Foundation
  10. Alfred Kordelin Foundation
  11. Orion Research Foundation
  12. Academy of Finland (AKA) [309489, 309489] Funding Source: Academy of Finland (AKA)

向作者/读者索取更多资源

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.

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