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SummaryBackground. 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. In 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 apoptotic cell numbers in groups 1 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 calpaindependent pathways 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.KEY WORDS: AK 295. Apoptosis. Calpain inhibitor. Secondary damage. Spinal cord trauma.El inhibidor de la calpaina AK 295 inhibe la apoptosis inducida por calpaina y mejora la función neurológica tras traumatismo medular en ratas ResumenIntroducción. Una lesión en el sistema nervioso central origina un incremento en los niveles de calcio intracelular que activa la proteasa neutral calciodependiente calpaina, que a su vez conduce a la producción de disfunción y muerte celular. En este estudio evaluamos el efecto de un inhibidor de la calpaina, AK 295, so...

SummaryBackground. 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 Q-VD-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.Conclusion. 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.KEY WORDS: Caspase. Q-VD-OPh. TUNEL. SCI. Secondary damage. Spinal cord injury.Q-VD-OPh, un inhibidor de caspasas, reduce la apoptosis relacionada con el trauma y mejora la recuperación funcional en ratas tras lesión medular traumática ResumenIntroducción. En el desarrollo de daño secundario tras lesión medular están implicadas diversas caspasas. La terapia anti-caspasas ha utilizado como diana una sola caspasa que ha sido investigada en una gran variedad de estudios tanto in-vitro como in-vivo. Estos estudios han examinado el efecto neuroprotector del Q-VD-PPh, un inhibidor pan-caspasa, en un modelo de lesión medular en rata.Material y métodos. Se dividieron 30 ratas Wistar en tres grupos de 10 ratas cada uno: una lesión medular traumática (con un trauma de 40 g-cm) se realizó a nivel torácico grupo control (grupo 1), grupo trauma control (grupo 2) y el grupo de ratas tratadas con Q-VD-OPh (grupo 3) se realizó a nivel torácico (T8-T10) mediante la técnica de caída de peso. La respues...

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