title: Neuroprotective effects of GYKI 52466 on experimental spinal cord injury in rats.
abstract: OBJECTIVE
  The toxic effects of glutamate in the central nervous system are well known. This neurotoxicity occurs through metabotropic and ionotropic receptors, the latter group composed of N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), and kainate receptors. The authors investigated the neuroprotective effects of GYKI 52466, a 2,3-benzodiazepine that is a selective and potent AMPA receptor antagonist, in a rat spinal cord trauma model.
  
  
  METHODS
  Sixty Wistar albino rats were studied in three groups of 20 animals each: sham-operated controls (Group 1); spinal cord-injured rats (Group 2); and spinal cord-injured plus GYKI 52466-treated rats (Group 3). In Groups 2 and 3, spinal cord injury (SCI) was induced at the thoracic level by applying an aneurysm clip to the cord for 1 minute. One minute after the clip was removed, the rats in Group 3 received an intraperitoneal injection of 15 mg/kg GYKI 52466. Responses to injury and treatment were evaluated based on biochemical parameters (lipid peroxidation and adenosine 5'-triphosphate [ATP] levels in tissue), and on light and transmission electron microscopy findings in cord tissue collected at different times post-SCI. Five rats from each group underwent assessment of functional recovery at 1, 3, and 5 days after SCI; evaluation was performed using the inclined-plane technique and Tarlov motor grading scale. The mean lipid peroxidation levels in Groups 1 and 2 were 21.73 +/- 4.35 and 35.53 +/- 2.99 nmol/g of wet tissue, respectively. The level in Group 3 was 27.98 +/- 3.93 nmol/g of wet tissue, which was significantly lower than that in Group 2 (p < 0.01). The mean ATP levels in Groups 1 and 2 were 166.21 +/- 25.57 and 41.72 +/- 12.28 nmol/g of wet tissue, respectively. The ATP level in Group 3 was 85.82 +/- 13.92 nmol/g of wet tissue, which was significantly higher than that in Group 2 (p < 0.01). Light microscopic examination of Group 2 tissues showed hemorrhage, necrosis, polymorphonuclear leukocyte infiltration, and vascular thrombi. In contrast, the examination of Group 3 tissues showed limited hemorrhage and no necrosis or vascular thrombi. The most prominent findings in Group 2 were hemorrhage and necrosis, whereas the most prominent findings in Group 3 were focal hemorrhage and leukocyte infiltration. Electron microscopy demonstrated that GYKI 52466 protected the neurons, myelin, axons, and intracellular organelles. The mean inclined-plane angles in Groups 1, 2, and 3 were 65 degrees, 40 to 45 degrees, and 55 degrees, respectively. Motor scale results in all groups showed a similar trend.
  
  
  CONCLUSIONS
  The findings in this rat model suggest that GYKI 52466 may provide significant therapeutic protection from secondary damage after acute SCI. This agent may be a viable alternative treatment for SCI.
authors.affiliation: Neurosurgery and Pathology Clinics, Taksim Education and Research Hospital, Istanbul, Turkey. drahmetcolak@yahoo.com
authors.forename: Ahmet
authors.initials: A
authors.lastname: Colak
authors.forename: Osman
authors.initials: O
authors.lastname: Soy
authors.forename: Hafize
authors.initials: H
authors.lastname: Uzun
authors.forename: Ozcan
authors.initials: O
authors.lastname: Aslan
authors.forename: Seref
authors.initials: S
authors.lastname: Barut
authors.forename: Ahmet
authors.initials: A
authors.lastname: Belce
authors.forename: Ayşenur
authors.initials: A
authors.lastname: Akyildiz
authors.forename: Mustafa
authors.initials: M
authors.lastname: Taşyürekli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001569:Benzodiazepines; D016022:Case-Control Studies; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D014151:Anti-Anxiety Agents; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines; D000255:Adenosine Triphosphate