Neuroprotective effects of GYKI 52466 on experimental spinal cord injury in rats.
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.
Colak
Ahmet
A
Neurosurgery and Pathology Clinics, Taksim Education and Research Hospital, Istanbul, Turkey. drahmetcolak@yahoo.com
Soy
Osman
O
Uzun
Hafize
H
Aslan
Ozcan
O
Barut
Seref
S
Belce
Ahmet
A
Akyildiz
Ayşenur
A
Taşyürekli
Mustafa
M
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
D014151:Anti-Anxiety Agents; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines; D000255:Adenosine Triphosphate