title: Sonic hedgehog signaling pathway mediates cerebrolysin-improved neurological function after stroke.
abstract: OBJECTIVE
  Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis and improves neurological outcome in experimental neurodegenerative diseases and stroke. The Sonic hedgehog (Shh) signaling pathway stimulates neurogenesis after stroke. The present study tests whether the Shh pathway mediates cerebrolysin-induced neurogenesis and improves neurological outcome after stroke.
  
  
  METHODS
  Rats subjected to embolic stroke were treated with cerebrolysin with or without cyclopamine.
  
  
  RESULTS
  Using neural progenitor cells derived from the subventricular zone of the lateral ventricle of adult rats, we found that cerebrolysin significantly increased neural progenitor cells proliferation and their differentiation into neurons and myelinating oligodendrocytes, which were associated with upregulation of Shh and its receptors patched and smoothened. Blockage of the Shh signaling pathway with a pharmacological smoothened inhibitor, cyclopamine, abolished cerebrolysin-induced in vitro neurogenesis and oligodendrogenesis. In the ischemic rats, treatment with cerebrolysin starting 24 hours after stroke significantly increased neural progenitor cell proliferation in the subventricular zone and enhanced neurogenesis, oligodendrogenesis, and axonal remodeling in the peri-infarct area. Moreover, profound neurological function improvements were observed in rats treated with cerebrolysin from week 3 to week 5 after stroke onset compared with vehicle-treated rats. However, in vivo inhibition of the Shh pathway with cyclopamine completely reversed the effects of cerebrolysin on neurorestoration and functional recovery.
  
  
  CONCLUSIONS
  These results demonstrate that the Shh pathway mediates cerebrolysin-enhanced neurogenesis and white matter remodeling and improves functional recovery in rats after stroke.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Dieter H
authors.initials: DH
authors.lastname: Meier
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Alexandra
authors.initials: A
authors.lastname: Szalad
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000072079:Patched Receptors; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000596:Amino Acids; D000959:Antihypertensive Agents; D053823:Hedgehog Proteins; D018696:Neuroprotective Agents; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C546888:Shh protein, rat; C006952:cerebrolysin
keywords: neurogenesis; recovery; stroke