Biomol Ther.  2017 Mar;25(2):149-157. 10.4062/biomolther.2016.050.

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

• Lee JH
• Kam EH
• Kim JM
• Kim SY
• Kim EJ
• Cheon SY
• Koo BN

• KMID: 2375034
• DOI: http://doi.org/10.4062/biomolther.2016.050

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.

Keyword

Cerebral ischemia; Interleukin-1 receptor antagonist; Intranasal administration; Neuroinflammation

MeSH Terms

Administration, Intranasal*
Animals
Blood-Brain Barrier
Brain
Brain Ischemia*
Cytokines
Humans
Infarction, Middle Cerebral Artery
Interleukin 1 Receptor Antagonist Protein
Interleukin-1*
Ischemic Attack, Transient
Male
Methods
Microglia
Models, Animal*
Necrosis
Neurons
Neuroprotection
Rats*
Rats, Sprague-Dawley
Stroke
Cytokines
Interleukin 1 Receptor Antagonist Protein
Interleukin-1