Q-VD-OPh, a pancaspase inhibitor, reduces trauma-induced apoptosis and improves the recovery of hind-limb function in rats after spinal cord injury.
BACKGROUND
Various caspases have been implicated in the development of secondary damage after spinal cord injury (SCI). Anticaspase therapy that targets only one caspase has been investigated in a variety of in vitro and in vivo studies. This study examined the neuroprotective effects of Q-VD-OPh, a pan-caspase inhibitor, in a rat model of SCI.


METHODS
Thirty Wistar albino rats were divided into 3 groups of 10 each: the sham-operated controls (group 1), the trauma-created controls (group 2), and the QVD- OPh-treated rats (group 3). An SCI (a trauma of 40 g-cm) was produced at the thoracic level (T8-T10) by the weight-drop technique. The response to injury and the neuroprotective effects of Q-VD-OPh were investigated by histopathologic examination and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) 24 hours and 5 days after trauma. The inclined plane technique of Rivlin and Tator and a modified version of Tarlov's grading scale were used to assess the functional status of the rats 24 hours, 3 days, and 5 days after injury.


RESULTS
Twenty-four hours after trauma, light microscopic examination of a specimen taken from group 2 rats revealed hemorrhage, necrosis, vascular thrombi, and edema. Group 3 tissue samples showed similar features at that time. Twenty-four hours after trauma, the mean apoptotic cell number was 4.47 +/- 0.35 cells in group 2 and 1.58 +/- 0.33 in group 3. Five days after injury, the mean apoptotic cell count was 4.35 +/- 0.47 in group 2 and 1.25 +/- 0.34 in group 3. Thus the number of TUNEL-positive cells in an injured spinal cord was greatly reduced by treatment with Q-VDOPh. The neurologic function scores (both the inclined plane performance and motor grading scores) were significantly better in the Q-VD-OPh-treated group than in the trauma-created control group.


CONCLUSIONS
The marked antiapoptotic properties of Q-VD-OPh due to the inhibition of all caspases render it a promising novel agent. A therapeutic strategy using Q-VD-OPh may eventually lead to the effective treatment of SCI in humans.
Colak
A
A
Department of Neurosurgery, Maltepe University, School of Medicine, Istanbul, Turkey. drahmetcolak@yahoo.com
Antar
V
V
Karaoğlan
A
A
Akdemir
O
O
Sahan
E
E
Celik
O
O
Sağmanligil
A
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D006614:Hindlimb / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH