Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

Çolak, Ahmet
Kaya, Mehmet
Karaoğlan, Alper
Sağmanlıgil, Ayhan
Akdemir, Osman
Şahan, Elife
Çelik, Özge
Journal Title
Journal ISSN
Volume Title
Soc Espanola Neurocirugia, C/O Dr Poza, Gran Via Salzillo 42, 30005 Murcia, Spain
Research Projects
Organizational Units
Journal Issue
Background. An increase in the level of intracellular calcium activates the calcium-dependent neutral protease calpain, which in turn leads to cellular dysfunction and cell death after an insult to the central nervous system. fit this study, we evaluated the effect of a calpain inhibitor, AK 295, on spinal cord structure, neurologic function, and apoptosis after spinal cord injury (SCI) in a murine model. Methods. Thirty albino Wistar rats were divided into 3 groups of 10 each: the sham-operated control group (group 1), the spinal cord trauma group (group 2), and the spinal cord trauma plus AK 295 treatment group (group 3). After having received a combination of ketamine 60 mg/kg and xylazine 9 mg/kg to induce anesthesia, the rats in groups 2 and 3 were subjected to thoracic trauma by the weight drop technique (40 g-cm). One hour after having been subjected to that trauma, the rats in groups 2 and 3 were treated with an intraperitoneal injection of either dimethyl sulfoxide 2 mg/kg or AK 295 2 mg/kg. The effects of the injury and the efficacy of AK 295 were determined by an assessment of the TUNEL technique and the results of examination with a light microscope. The neurologic performance of 5 rats from group 2 and 5 from group 3 was assessed by means of the inclined plane technique and the modified Tarlov's motor grading scale 1, 3, and 5 days after spinal cord trauma. Findings. Light-microscopic examination of spinal cord specimens from group 2 revealed hemorrhage, edema, necrosis, and vascular thrombi 24 : hours after trauma. Similar (but less prominent) features were seen in specimens obtained from group 3 rats. Twenty-four hours after injury, the mean apoptotie cell numbers in groups I and 2 were zero and 4.57 +/- 0.37 cells, respectively. In group 3, the mean apoptotic cell number was 2.30 +/- 0.34 cells, a value significantly lower than that in group 2 (P < .05). Five days after trauma, the injured rats in group 2 demonstrated significant motor dysfunction (P < .05). In comparison, the motor scores exhibited by group 3 rats were markedly better (P < .05). Conclusions. AK 295 inhibited apoptosis via calpain-dependent pathway's and provided neuroprotection and improved neurologic function in a rat model of SCI. To our knowledge, this is the first study to evaluate the use of AK 295, a calpain inhibitor, after SCI. Our data suggest that AK 295 might be a novel therapeutic compound for the neuroprotection of tissue and the recovery of function in patients with a SCI.
AK 295, apoptosis, calpain inhibitor, secondary damage, spinal cord trauma, activated neutral proteinase, crystal-structure, down-regulation, calcium, brain, calpastatin, expression, neuroprotection, degradation, mechanism, apoptoz, ikincil hasar, omurilik travması, aktive nötr proteinaz, kristal yapı, kalsiyum, beyin, nöro, mekanizma, bozulma