Intranasal Delivery of HMGB1 siRNA Confers Target Gene Knockdown and Robust Neuroprotection in the Postischemic Brain
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 cont...
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| Veröffentlicht in: | Molecular therapy 2012-04, Vol.20 (4), p.829-839 |
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| creator | Kim, Il-Doo Shin, Joo-Hyun Kim, Seung-Woo Choi, Sunghyun Ahn, Junseong Han, Pyung-Lim Park, Jong-Sang Lee, Ja-Kyeong |
| description | 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. |
| doi_str_mv | 10.1038/mt.2011.291 |
| format | Article |
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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.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2011.291</identifier><identifier>PMID: 22252450</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Administration, Intranasal ; Alzheimer's disease ; Animals ; Blood-brain barrier ; Brain cancer ; Brain Ischemia - drug therapy ; Brain Ischemia - metabolism ; Brain Ischemia - prevention & control ; Cytoplasm ; Drugs ; Efficiency ; Growth factors ; HMGB1 Protein - antagonists & inhibitors ; HMGB1 Protein - genetics ; Hypothalamus ; Immunoblotting ; Immunohistochemistry ; Insulin ; Male ; Nervous system ; Neuroprotective Agents - administration & dosage ; Neuroprotective Agents - therapeutic use ; Original ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - therapeutic use</subject><ispartof>Molecular therapy, 2012-04, Vol.20 (4), p.829-839</ispartof><rights>2012 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Apr 2012</rights><rights>Copyright © 2012 The American Society of Gene & Cell Therapy 2012 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-21d9ba2430ce4c1bdafb0c1d8d2ea3b18883c5af3a4a14bb48854dc727a0407b3</citedby><cites>FETCH-LOGICAL-c553t-21d9ba2430ce4c1bdafb0c1d8d2ea3b18883c5af3a4a14bb48854dc727a0407b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321593/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1792073265?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771,64361,64363,64365,72215</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22252450$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Il-Doo</creatorcontrib><creatorcontrib>Shin, Joo-Hyun</creatorcontrib><creatorcontrib>Kim, Seung-Woo</creatorcontrib><creatorcontrib>Choi, Sunghyun</creatorcontrib><creatorcontrib>Ahn, Junseong</creatorcontrib><creatorcontrib>Han, Pyung-Lim</creatorcontrib><creatorcontrib>Park, Jong-Sang</creatorcontrib><creatorcontrib>Lee, Ja-Kyeong</creatorcontrib><title>Intranasal Delivery of HMGB1 siRNA Confers Target Gene Knockdown and Robust Neuroprotection in the Postischemic Brain</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>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.</description><subject>Administration, Intranasal</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Blood-brain barrier</subject><subject>Brain cancer</subject><subject>Brain Ischemia - drug therapy</subject><subject>Brain Ischemia - metabolism</subject><subject>Brain Ischemia - prevention & control</subject><subject>Cytoplasm</subject><subject>Drugs</subject><subject>Efficiency</subject><subject>Growth factors</subject><subject>HMGB1 Protein - antagonists & inhibitors</subject><subject>HMGB1 Protein - genetics</subject><subject>Hypothalamus</subject><subject>Immunoblotting</subject><subject>Immunohistochemistry</subject><subject>Insulin</subject><subject>Male</subject><subject>Nervous system</subject><subject>Neuroprotective Agents - administration & dosage</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Original</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>RNA, Small Interfering - 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drug therapy</topic><topic>Brain Ischemia - metabolism</topic><topic>Brain Ischemia - prevention & control</topic><topic>Cytoplasm</topic><topic>Drugs</topic><topic>Efficiency</topic><topic>Growth factors</topic><topic>HMGB1 Protein - antagonists & inhibitors</topic><topic>HMGB1 Protein - genetics</topic><topic>Hypothalamus</topic><topic>Immunoblotting</topic><topic>Immunohistochemistry</topic><topic>Insulin</topic><topic>Male</topic><topic>Nervous system</topic><topic>Neuroprotective Agents - administration & dosage</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Original</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>RNA, Small Interfering - administration & dosage</topic><topic>RNA, Small Interfering - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Il-Doo</creatorcontrib><creatorcontrib>Shin, Joo-Hyun</creatorcontrib><creatorcontrib>Kim, Seung-Woo</creatorcontrib><creatorcontrib>Choi, Sunghyun</creatorcontrib><creatorcontrib>Ahn, Junseong</creatorcontrib><creatorcontrib>Han, Pyung-Lim</creatorcontrib><creatorcontrib>Park, Jong-Sang</creatorcontrib><creatorcontrib>Lee, Ja-Kyeong</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Il-Doo</au><au>Shin, Joo-Hyun</au><au>Kim, Seung-Woo</au><au>Choi, Sunghyun</au><au>Ahn, Junseong</au><au>Han, Pyung-Lim</au><au>Park, Jong-Sang</au><au>Lee, Ja-Kyeong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intranasal Delivery of HMGB1 siRNA Confers Target Gene Knockdown and Robust Neuroprotection in the Postischemic Brain</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2012-04-01</date><risdate>2012</risdate><volume>20</volume><issue>4</issue><spage>829</spage><epage>839</epage><pages>829-839</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22252450</pmid><doi>10.1038/mt.2011.291</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular therapy, 2012-04, Vol.20 (4), p.829-839 |
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| subjects | Administration, Intranasal Alzheimer's disease Animals Blood-brain barrier Brain cancer Brain Ischemia - drug therapy Brain Ischemia - metabolism Brain Ischemia - prevention & control Cytoplasm Drugs Efficiency Growth factors HMGB1 Protein - antagonists & inhibitors HMGB1 Protein - genetics Hypothalamus Immunoblotting Immunohistochemistry Insulin Male Nervous system Neuroprotective Agents - administration & dosage Neuroprotective Agents - therapeutic use Original Rats Rats, Sprague-Dawley Real-Time Polymerase Chain Reaction RNA, Small Interfering - administration & dosage RNA, Small Interfering - therapeutic use |
| title | Intranasal Delivery of HMGB1 siRNA Confers Target Gene Knockdown and Robust Neuroprotection in the Postischemic Brain |
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