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.

Effects of GYKI 52466 on early vasospasm in rats.

OBJECTIVE: The pathogenesis and treatment of cerebral vasospasm (CV) after subarachnoid hemorrhage (SAH) remains a matter of discussion. The authors investigated the efficacy of GYKI 52466, a 2,3-benzodiazepine that is a selective and potent alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist, in a rat femoral artery vasospasm model. METHODS: Twenty-seven Wistar albino rats were used in this study. The animals were divided into 3 groups of 9 animals each: sham-operated control (group 1), vasospasm group (group 2), and vasospasm-plus-treatment group (group 3). In groups 2 and 3, autologous blood (0.1 mL) was applied to a 1-cm segment of the femoral artery, which was then wrapped with a silicone cuff. One minute after blood application, the rats in group 3 received an intraperitoneal injection of 15 mg/kg GYKI 52466 every 12 h for 24 h. Responses to blood application and treatment were evaluated with light and electron microscopy examinations of femoral artery specimens at 72 h. RESULTS: On light microscope examination, the mean diameters of the arterial lumens in groups 1, 2, and 3 were 514.47+/-15.3, 317.63+/-12.1, and 503.91+/-9.6 microm, respectively. At 24 h, the mean arterial wall thickness in group 1 was 77.69+/-4.2 microm. This mean thickness in group 2 increased to 164.82+/-9.1 microm. After GYKI treatment in group 3, the mean arterial wall thickness measured 95.37+/-5.3 microm. In group 2 rats, electron microscopy demonstrated various changes including marked luminal narrowing and increased wall thickness in the femoral arterial wall. The most striking finding were the degenerative changes in the endothelium, which presented as a corrugated appearance of the internal elastic lamina. Rats in group 3 had endothelia that were slightly constricted and smooth muscle cells that were relaxed; changes in the vessel wall and internal elastic lamina were less prominent in these rats than in the rats of group 2. CONCLUSIONS: The results of the present study suggest that GYKI 52466 inhibited AMPA receptors and induced relaxation of smooth muscle cells in the wall of the femoral artery in a rat model. This substance may be a protective and therapeutic agent in the treatment of cerebral vasospasm.

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

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. 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.

Beck Depression Inventory II: evaluation of the psychometric properties and cut-off points in a Turkish adult population.

Numerous studies have been previously conducted to assess the Beck Depression Inventory-II's [BDI II; Beck et al., 1996] psychometric properties. However, none of these studies has examined whether the original cut-off scores were applicable to other cultures. Thus, in addition to evaluating its psychometric properties, we also determined the cut-off scores of the BDI II for the Turkish population. Data from nonclinical (n = 362) and clinical psychiatric outpatients diagnosed as depressive disorder according to DSM-IV criteria (n = 176) were gathered. Analyses for internal consistency and test-retest reliabilities and for convergent and discriminant validities were computed. Two confirmatory factor analyses, one derived from the present exploratory factor analyses and the other proposed in the original study were conducted for both groups. A receiver operating characteristics curve was utilized to determine the cut-off scores for the Turkish population revealing 0-12 for minimal, 13-18 for mild, 19-28 for moderate and 29-63 for severe depression. The internal consistency for the nonclinical and clinical groups were .90 and .89, respectively; test-retest stability was also high (r = .94). Convergent and discriminant validity results were satisfactory. Findings confirmed the present model for the clinical group and equally confirmed both models for the nonclinical group. Furthermore, the cut-off scores to classify minimal, mild, moderate, and severe depression were quite akin to the cut-off points previously suggested for the American population. Taken as a whole our findings revealed that BDI II has sound psychometric properties and comparable cut-off scores for the Turkish population.