Biomol Ther (Seoul)  
Intranasal Administration of Interleukin-1 Receptor Antagonist in a Transient Focal Cerebral Ischemia Rat Model
Jae Hoon Lee1,2, Eun Hee Kam2, Jeong Min Kim1,2, So Yeon Kim1,2, Eun Jeong Kim1,2, So Yeong Cheon2 and Bon-Nyeo Koo1,2,*
1Department of Anesthesiology and Pain Medicine, Severance Hospital,
2Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
E-mail: koobn@yuhs.ac, Tel: +82-2-2228-2420, Fax: +82-2-312-7185
Received: February 29, 2016; Revised: May 6, 2016; Accepted: May 24, 2016; Published online: August 19, 2016.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
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-1β and tumor necrosis factor-α 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.
Keywords: Cerebral ischemia, Interleukin-1 receptor antagonist, Intranasal administration, Neuroinflammation


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