title: Involvement of the glycogen synthase kinase-3 signaling pathway in TBI pathology and neurocognitive outcome.
abstract: BACKGROUND
  Traumatic brain injury (TBI) sets in motion cascades of biochemical changes that result in delayed cell death and altered neuronal architecture. Studies have demonstrated that inhibition of glycogen synthase kinase-3 (GSK-3) effectively reduces apoptosis following a number of stimuli. The Wnt family of proteins, and growth factors are two major factors that regulate GSK-3 activity. In the absence of stimuli, GSK-3 is constitutively active and is complexed with Axin, adenomatous polyposis coli (APC), and casein kinase Iα (CK1α) and phosphorylates ß-Catenin leading to its degradation. Binding of Wnt to Frizzled receptors causes the translocation of GSK-3 to the plasma membrane, where it phosphorylates and inactivates the Frizzled co-receptor lipoprotein-related protein 6 (LRP6). Furthermore, the translocation of GSK-3 reduces ß-Catenin phosphorylation and degradation, leading to ß-Catenin accumulation and gene expression. Growth factors activate Akt, which in turn inhibits GSK-3 activity by direct phosphorylation, leading to a reduction in apoptosis.
  
  
  RESULTS
  Using a rodent model, we found that TBI caused a rapid, but transient, increase in LRP6 phosphorylation that is followed by a modest decrease in ß-Catenin phosphorylation. Phospho-GSK-3β immunoreactivity was found to increase three days post injury, a time point at which increased Akt activity following TBI has been observed. Lithium influences several neurochemical cascades, including inhibiting GSK-3. When the efficacy of daily lithium was assessed, reduced hippocampal neuronal cell loss and learning and memory improvements were observed. These influences were partially mimicked by administration of the GSK-3-selective inhibitor SB-216763, as this drug resulted in improved motor function, but only a modest improvement in memory retention and no overt neuroprotection.
  
  
  CONCLUSIONS
  Taken together, our findings suggest that selective inhibition of GSK-3 may offer partial cognitive improvement. As a broad spectrum inhibitor of GSK-3, lithium offers neuroprotection and robust cognitive improvement, supporting its clinical testing as a treatment for TBI.
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America. P.Dash@uth.tmc.edu
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
authors.forename: Daniel
authors.initials: D
authors.lastname: Johnson
authors.forename: Jordan
authors.initials: J
authors.lastname: Clark
authors.forename: Sara A
authors.initials: SA
authors.lastname: Orsi
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Grill
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Moore
authors.forename: Shibani
authors.initials: S
authors.lastname: Pati
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007211:Indoles / Q000627:therapeutic use; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007211:Indoles; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555477:Lrp6 protein, rat; D008301:Maleimides; C417521:SB 216763; D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3