title: A Smoothened receptor agonist is neuroprotective and promotes regeneration after ischemic brain injury.
abstract: Ischemic stroke occurs as a result of blood supply interruption to the brain causing tissue degeneration, patient disabilities or death. Currently, treatment of ischemic stroke is limited to thrombolytic therapy with a narrow time window of administration. The sonic hedgehog (Shh) signaling pathway has a fundamental role in the central nervous system development, but its impact on neural cell survival and tissue regeneration/repair after ischemic stroke has not been well investigated. Here we report the neuroprotective properties of a small-molecule agonist of the Shh co-receptor Smoothened, purmorphamine (PUR), in the middle cerebral artery occlusion model of ischemic stroke. We found that intravenous administration of PUR at 6 h after injury was neuroprotective and restored neurological deficit after stroke. PUR promoted a transient upregulation of tissue-type plasminogen activator in injured neurons, which was associated with a reduction of apoptotic cell death in the ischemic cortex. We also observed a decrease in blood-brain barrier permeability after PUR treatment. At 14 d postinjury, attenuation of inflammation and reactive astrogliosis was found in PUR-treated animals. PUR increased the number of newly generated neurons in the peri-infarct and infarct area and promoted neovascularization in the ischemic zone. Notably, PUR treatment did not significantly alter the ischemia-induced level of Gli1, a Shh target gene of tumorigenic potential. Thus our study reports a novel pharmacological approach for postischemic treatment using a small-molecule Shh agonist, providing new insights into hedgehog signaling-mediated mechanisms of neuroprotection and regeneration after stroke.
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA.
authors.forename: O V
authors.initials: OV
authors.lastname: Chechneva
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, 2425 Stockton Boulevard, Sacramento, CA 95817, USA.
authors.forename: F
authors.initials: F
authors.lastname: Mayrhofer
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Daugherty
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Krishnamurty
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, 2425 Stockton Boulevard, Sacramento, CA 95817, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bannerman
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA [2] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, 2425 Stockton Boulevard, Sacramento, CA 95817, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Pleasure
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA [2] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, 2425 Stockton Boulevard, Sacramento, CA 95817, USA [3] Medical College, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China.
authors.forename: W
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use*; D009416:Nerve Regeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D020521:Stroke / Q000150:complications / Q000503:physiopathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053823:Hedgehog Proteins; D009025:Morpholines; D018696:Neuroprotective Agents; D011687:Purines; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D010959:Tissue Plasminogen Activator; C470893:purmorphamine