title: AR-A014418 as a glycogen synthase kinase-3 inhibitor: anti-apoptotic and therapeutic potential in experimental spinal cord injury.
abstract: OBJECTIVE
  We aimed to investigate the effects of AR-A014418, a strong inhibitor specific to GSK-3beta, on neuronal apoptosis and neuroprotection in the traumatic SCI model.
  
  
  METHODS
  In this study, three groups were generated from 36 Wistar rats; (1) control, (2) spinal cord trauma group created by clip compression technique after laminectomy, and (3) AR-A014418 (4mg/kg, i.p., DMSO) treatment group after laminectomy and spinal cord trauma. The TUNEL assay for apoptosis detection, immunohistochemical staining for bax and TGF-beta were applied in spinal cord tissues. For light microscopic examination, necrotic, and apoptotic cells were counted, and PMNL counting was applied to detect inflammation. Functional recovery was tested by field locomotor test in the 3rd and 7th days following surgery.
  
  
  RESULTS
  In the trauma group, diffuse hemorrhage, cavitation, necrosis and edematous regions, degeneration in motor neurons and leukocyte infiltration were observed in gray matter. In the AR-A014418-treated groups, healthy cells were observed in more places compared to the trauma groups, however, cavitation, hemorrhagic, and edematous areas were seen in gray matter. In the AR-A014418-treatment groups, the number of apoptotic cells in the 3rd and 7th days (respectively; p<0.05, p<0.01), were significantly decreased compared to the trauma groups, as were the levels of bax (p<0.01) and TGF-beta 1 immunoreactivity. Results of the locomotor test were significantly increased in the treatment group (p<0.001) as compared to the trauma group.
  
  
  CONCLUSIONS
  In this experimental spinal cord trauma model study neural apoptosis was significantly triggered in secondary damage developed after trauma, however, neurological healing was expedited by preventing mitochondrial apoptosis and reducing the inflammation by the potent inhibitor AR-A014418, which is GSK-3beta selective.
authors.affiliation: Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Matem
authors.initials: M
authors.lastname: Tunçdemir
authors.forename: Aziz
authors.initials: A
authors.lastname: Yıldırım
authors.forename: Alper
authors.initials: A
authors.lastname: Karaoğlan
authors.forename: Osman
authors.initials: O
authors.lastname: Akdemir
authors.forename: Melek
authors.initials: M
authors.lastname: Oztürk
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007794:Lameness, Animal / Q000209:etiology / Q000517:prevention & control; D007796:Laminectomy; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000032:analysis; D010264:Paraplegia / Q000209:etiology / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000737:chemistry / Q000473:pathology; D013117:Spinal Cord Compression / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D000893:Anti-Inflammatory Agents; C494828:Bax protein, rat; D009419:Nerve Tissue Proteins; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D038362:Glycogen Synthase Kinase 3