title: Axonal outgrowth and dendritic plasticity in the cortical peri-infarct area after experimental stroke.
abstract: OBJECTIVE
  Axonal remodeling is critical to brain repair after stroke. The present study investigated axonal outgrowth after stroke and the signaling pathways mediating axonal outgrowth in cortical neurons.
  
  
  METHODS
  Using a rodent model of middle cerebral artery occlusion, we examined high-molecular weight neurofilament (NFH) immunoreactive axons and myelin basic protein-positive oligodendrocytes in the peri-infarct area. In vitro, using cultured cortical neurons in a microfluidic chamber challenged by oxygen-glucose deprivation (OGD), we investigated mechanisms selectively regulating axonal outgrowth after OGD.
  
  
  RESULTS
  NFH(+) axons and MBP(+) oligodendrocytes substantially increased in the peri-infarct area during stroke recovery, concomitantly with an increase in dendrites and spines identified by Golgi-Cox staining. In vitro, cortical neurons subjected to OGD exhibited significant increases in axonal outgrowth and in phosphorylated NFH protein levels, concurrently with downregulation of phosphatase tensin homolog deleted on chromosome 10, activation of Akt, and inactivation of glycogen synthase kinase-3β in regenerated axons. Blockage of phosphoinositide 3-kinase with pharmacological inhibitors suppressed Akt activation and attenuated phosphorylation of glycogen synthase kinase-3β, which resulted in suppression of phosphorylated NFH and axonal outgrowth after OGD; whereas GSK-3 inhibitors augmented axonal regeneration and elevated phosphorylated NFH levels after OGD.
  
  
  CONCLUSIONS
  Stroke induces axonal outgrowth and myelination in rodent ischemic brain during stroke recovery, and the phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β signaling pathway mediates axonal regeneration of cortical neurons after OGD.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ueno
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Buller
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Liu
authors.forename: Norman L
authors.initials: NL
authors.lastname: Lehman
authors.forename: Xian Shuang
authors.initials: XS
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology*; D018920:Coculture Techniques; D003712:Dendrites / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000473:pathology; D008297:Male; D009186:Myelin Sheath / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009836:Oligodendroglia / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000473:pathology*
chemical_list: D016900:Neurofilament Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3