title: Intranasal delivery of HMGB1 siRNA confers target gene knockdown and robust neuroprotection in the postischemic brain.
abstract: Noninvasive intranasal drug administration has been noted to allow direct delivery of drugs to the brain. In the present study, the therapeutic efficacy of intranasal small interfering RNA (siRNA) delivery was investigated in the postischemic rat brain. Fluorescein isothiocyanate (FITC)-labeled control siRNA was delivered intranasally in normal adult rats using e-PAM-R, a biodegradable PAMAM dendrimer, as gene carrier. Florescence-tagged siRNA was found in the cytoplasm and processes of neurons and of glial cells in many brain regions, including the hypothalamus, amygdala, cerebral cortex, and striatum, in 1 hour after infusion, and the FITC-fluorescence was continuously detected for at least 12 hours. When siRNA for high mobility group box 1 (HMGB1), which functions as an endogenous danger molecule and aggravates inflammation, was delivered intranasally, the target gene was significantly depleted in many brain regions, including the prefrontal cortex and striatum. More importantly, intranasal delivery of HMGB1 siRNA markedly suppressed infarct volume in the postischemic rat brain (maximal reduction to 42.8 ± 5.6% at 48 hours after 60 minutes middle cerebral artery occlusion (MCAO)) and this protective effect was manifested by recoveries from neurological and behavioral deficits. These results indicate that the intranasal delivery of HMGB1 siRNA offers an efficient means of gene knockdown-mediated therapy in the ischemic brain.
authors.affiliation: Department of Anatomy and Center for Advanced Medical Education (BK21 project), Inha University School of Medicine, Inchon, Korea.
authors.forename: Il-Doo
authors.initials: ID
authors.lastname: Kim
authors.forename: Joo-Hyun
authors.initials: JH
authors.lastname: Shin
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Sunghyun
authors.initials: S
authors.lastname: Choi
authors.forename: Junseong
authors.initials: J
authors.lastname: Ahn
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
authors.forename: Jong-Sang
authors.initials: JS
authors.lastname: Park
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D024243:HMGB1 Protein; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering