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. 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.

Q-VD-OPh, a pancaspase inhibitor, reduces trauma-induced apoptosis and improvesthe recovery of hind-limb function in rats after spinal cord injury

Background. Various caspases have been implicatedin the development of secondary damage after spinalcord injury (SCI). Anticaspase therapy that targets onlyone caspase has been investigated in a variety of in vitroand in vivo studies. This study examined the neuroprotectiveeffects of Q-VD-OPh, a pan-caspase inhibitor, ina rat model of SCI.Methods. Thirty Wistar albino rats were divided into3 groups of 10 each: the sham-operated controls (group1), the trauma-created controls (group 2), and the QVD-OPh–treated rats (group 3). An SCI (a trauma of40 g-cm) was produced at the thoracic level (T8-T10) bythe weight-drop technique. The response to injury andthe neuroprotective effects of Q-VD-OPh were investigatedby histopathologic examination and terminaldeoxynucleotidyl transferase dUTP nick-end labeling(TUNEL) 24 hours and 5 days after trauma. The inclinedplane technique of Rivlin and Tator and a modifiedversion of Tarlov’s grading scale were used to assess thefunctional status of the rats 24 hours, 3 days, and 5 daysafter injury.Results. Twenty-four hours after trauma, lightmicroscopic examination of a specimen taken fromgroup 2 rats revealed hemorrhage, necrosis, vascularthrombi, and edema. Group 3 tissue samples showedsimilar features at that time. Twenty-four hours aftertrauma, the mean apoptotic cell number was 4.47 ± 0.35cells in group 2 and 1.58 ± 0.33 in group 3. Five daysafter injury, the mean apoptotic cell count was 4.35 ±0.47 in group 2 and 1.25 ± 0.34 in group 3. Thus thenumber of TUNEL-positive cells in an injured spinalcord was greatly reduced by treatment with Q-VDOPh.The neurologic function scores (both the inclinedplane performance and motor grading scores) were significantlybetter in the Q-VD-OPh–treated (AU)

Introducción. 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 delQ-VD-PPh, un inhibidor pan-caspasa, en un modelo delesión medular en rata. Material y métodos. Se dividieron 30 ratas Wistar entres grupos de 10 ratas cada uno: una lesión medulartraumática (con un trauma de 40 g-cm) se realizó anivel torácico grupo control (grupo 1), grupo traumacontrol (grupo 2) y el grupo de ratas tratadas con QVD-OPh (grupo 3) se realizó a nivel torácico (T8-T10) mediante la técnica de caída de peso. La respuesta a la lesión y los efectos neuroprotectores de Q-VD-OPh se valoraron mediante el examen histopatológico y la técnica de TUNEL 24 horas y 5 días tras el traumatismo. Se usó la prueba del plano inclinado de Rivlin y Tatory una versión modificada de la escala de Tarlov paravalorar el resultado funcional de las ratas 24 horas, 3 días y 5 días tras la lesión. Resultado. Veinticuatro horas tras la lesión, el estudio histopatológico de las secciones obtenidas del grupo 2 revelaron hemorragia, necrosis, trombos vasculares y edema. Las secciones obtenidos del grupo 3 mostraron hallazgos similares en ese momento. 24 horas tras lalesión el número de células apoptóticas fue 4.47 ± 0.35en el grupo 2 y 1.58 ± 0.33 en el grupo 3. Cinco días trasla lesión el número medio de células apoptóticas fue de4.35 ± 0.47 en el grupo 2 y de 1.25 ± 0.34 en el grupo 3. De esta forma el número de células TUNEL positivas enla médula dañada se redujo de forma considerable conel tratamiento con Q-VD-OPh (AU)