title: Anti-oxidative, anti-apoptotic, and pro-angiogenic effects mediate functional improvement by sonic hedgehog against focal cerebral ischemia in rats.
abstract: Sonic hedgehog (SHH) is a morphogen important for neural development during embryogenesis. Recently, beneficial actions of SHH in ischemic injury have been noted. To test whether epidural application of the biolgically active N-terminal fragment of SHH (SHH-N) may reduce the extent of ischemic brain injury, male Long-Evans rats were exposed to a 60-min episode of middle cerebral artery occlusion (MCAO) with topical application of SHH-N and/or its specific inhibitor, cyclopamine, in fibrin glue over the peri-infarct cortex. We found that epidural application of SHH-N substaintially reduced infarct volumes after 7 days of reperfusion, which was reversed by cyclopamine; SHH-N also improved behavioral outcomes as assessed by global neurological functions, rotarod test, and grasping power test. Furthermore, SHH-N attenuated the extents of protein oxidation, lipid peroxidation, and apoptosis induced by focal ischemia/reperfusion. Immunohistochemical staining coupled with bromodeoxyuridine (BrdU) incorporation revealed that SHH-N enhanced post-ischemic angiogenesis, stimulated the proliferation of nestin-positive (nestin(+)) neural progenitor cells (NPCs), and suppressed astrocytosis. Our results thus revealed multifaceted protective mechanisms of SHH-N against focal cerebral ischemia/reperfusion.
authors.affiliation: Department of Pharmacology and Institute of Medicine, College of Medicine, Chung Shan Medical University, Taiwan.
authors.forename: Shiang-Suo
authors.initials: SS
authors.lastname: Huang
authors.forename: Henrich
authors.initials: H
authors.lastname: Cheng
authors.forename: Ching-Min
authors.initials: CM
authors.lastname: Tang
authors.forename: Mao-Wei
authors.initials: MW
authors.lastname: Nien
authors.forename: Yuahn-Sieh
authors.initials: YS
authors.lastname: Huang
authors.forename: I-Huei
authors.initials: IH
authors.lastname: Lee
authors.forename: Jiu-Haw
authors.initials: JH
authors.lastname: Yin
authors.forename: Terry B J
authors.initials: TB
authors.lastname: Kuo
authors.forename: Cheryl C H
authors.initials: CC
authors.lastname: Yang
authors.forename: Shen-Kou
authors.initials: SK
authors.lastname: Tsai
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018737:Hand Strength / Q000502:physiology; D053823:Hedgehog Proteins / Q000737:chemistry / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control*; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects; D009460:Neurologic Examination; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D045442:Rotarod Performance Test; D014704:Veratrum Alkaloids / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D053823:Hedgehog Proteins; C577486:Nes protein, rat; D064231:Nestin; D014704:Veratrum Alkaloids; D001973:Bromodeoxyuridine; C000541:cyclopamine
keywords: Angiogenesis; Anti-apoptosis; Anti-oxidation; Focal ischemia; Middle cerebral artery occlusion