Intranasal Administration of Interleukin-1 Receptor Antagonist in a Transient Focal Cerebral Ischemia Rat Model

  • Lee, Jae Hoon (Department of Anesthesiology and Pain Medicine, Severance Hospital) ;
  • Kam, Eun Hee (Anesthesia and Pain Research Institute, Yonsei University College of Medicine) ;
  • Kim, Jeong Min (Department of Anesthesiology and Pain Medicine, Severance Hospital) ;
  • Kim, So Yeon (Department of Anesthesiology and Pain Medicine, Severance Hospital) ;
  • Kim, Eun Jeong (Department of Anesthesiology and Pain Medicine, Severance Hospital) ;
  • Cheon, So Yeong (Anesthesia and Pain Research Institute, Yonsei University College of Medicine) ;
  • Koo, Bon-Nyeo (Department of Anesthesiology and Pain Medicine, Severance Hospital)
  • Received : 2016.02.29
  • Accepted : 2016.05.24
  • Published : 2017.03.01


The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of $interleukin-1{\beta}$ and tumor necrosis $factor-{\alpha}$ at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia.



Supported by : Yonsei University College of Medicine, National Research Foundation of Korea (NRF)


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