title: Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.
abstract: Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China. blsun88@163.com.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China. blsun88@163.com.
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Sun
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Taishan Hospital, Taian, Shandong, 271000, China.
authors.forename: Mei-Qing
authors.initials: MQ
authors.lastname: He
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Emergency, Jining People's Hospital, Jining, Shandong, 272000, China.
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Han
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|College of Basic Medicine, Taishan Medical University, Taian, Shandong, 271016, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Sun
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Cun-Dong
authors.initials: CD
authors.lastname: Fan
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Mao
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Li
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Zong-Yong
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.|Library, Taishan Medical University, Taian, Shandong, 271016, China.
authors.forename: Cheng-Bi
authors.initials: CB
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, 45701, USA.
authors.forename: Yang V
authors.initials: YV
authors.lastname: Li
authors.affiliation: Department of Neurology and Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
authors.forename: R Anne
authors.initials: RA
authors.lastname: Stetler
authors.affiliation: Department of Neurology and Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China. zhanfx2@upmc.edu.|Department of Neurology and Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA, USA. zhanfx2@upmc.edu.|Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA. zhanfx2@upmc.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D014404:Tubulin; D016179:Granulocyte Colony-Stimulating Factor; D051547:Heme Oxygenase-1; D002118:Calcium
keywords: BBB; Brain ischemia; G-CSF; HO-1