The Effects of Difumarate Salt S-15176 after Spinal Cord Injury in Rats

Abstract

ObjectiveIn the present study we analyzed neuroprotective and antiapoptotic effect of the difumarate salt S-15176, as an anti-ischemic, an antioxidant and a stabilizer of mitochondrial membrane in secondary damage following spinal cord injury (SCI) in a rat model.MethodsThree groups were performed with 30 Wistar rats; control (1), trauma (2), and a trauma+S-15176 (10 mg/kg i.p., dimethyl sulfoxide) treatment (3). SCI was performed at the thoracic level using the weight-drop technique. Spinal cord tissues were collected following intracardiac perfusion in 3rd and 7th days of posttrauma. Hematoxylin and eosin staining for histopatology, terminal deoxynucleotidyl transferase dUTP nick end labeling assay for apoptotic cells and immunohistochemistry for proapoptotic cytochrome-c, Bax and caspase 9 were performed to all groups. Functional recovery test were applied to each group in 3rd and 7th days following SCI.ResultsIn trauma group, edematous regions, diffuse hemorrhage, necrosis, leukocyte infiltration and severe degeneration in motor neurons were observed prominently in gray matter. The number of apoptotic cells was significantly higher (p<0.05) than control group. In the S-15176-treated groups, apoptotic cell number in 3rd and 7th days (p<0.001), also cytochrome-c (p<0.001), Bax (p<0.001) and caspase 9 immunoreactive cells (p<0.001) were significantly decreased in number compared to trauma groups. Hemorrhage and edema in the focal areas were also noticed in gray matter of treatment groups. Results of the locomotor test were significantly increased in treatment group (p<0.05) when compared to trauma groups.ConclusionWe suggest that difumarate salt S-15176 prevents mitochondrial pathways of apoptosis and protects spinal cord from secondary injury and helps to preserve motor function following SCI in rats.

The Effect of S-15176 Difumarate Salt on Ultrastructure and Functions of Liver Mitochondria of C57BL/6 Mice with Streptozotocin/High-Fat Diet-Induced Type 2 Diabetes

“…Recent reports implicate that S-15176 difumarate salt exerts a number of effects on mitochondria. As shown by in vivo and in vitro studies, the drug can suppress the activity of mitochondrial CPT-1, the opening of the MPT pore, and overproduction of ROS by mitochondria [ 19 , 20 , 21 , 22 , 23 ]. So, the next objective of our work was to examine how this compound would affect the structural alterations in liver mitochondria of mice with T2DM.…”

“…It is well established that mitochondria of the liver are one of the main intracellular targets in the course of the development of T2DM [ 3 , 4 ]. The trimetazidine derivative S-15176 was reported to have diverse effects on mitochondria: the compound inhibits CPT-1, exhibits uncoupling and antioxidant properties, and suppresses the MPT pore opening [ 19 , 20 , 21 , 22 , 23 ]. Based on the above, we hypothesized that this compound would affect the mitochondrial function during the development of type 2 diabetes.…”

“…The drug is a derivative of the effective anti-ischemic agent trimetazidine and possesses a broad spectrum of action. A possible therapeutic effect of S-15176 can be related with its ability to inhibit CPT-1, to cause mild mitochondrial uncoupling, to decrease the excessive production of ROS (antioxidant effect), and to suppress the opening of the MPT pore in mitochondria [ 20 , 21 , 22 , 23 , 24 ]. Taking together, these effects of S-15176 difumarate salt may prevent mitochondrial injury occurring in T2DM.…”

The antioxidant and antiapoptotic effect of boric acid on hepatoxicity in chronic alcohol-fed rats

“…For negative control, TdT was omitted from the reaction mixture. Marked apoptotic cells were counted under high-powerfields (×400) with a light microscope (Leica DM2500, Wetzlar) (Erdogan et al 2015). All TUNEL positive cells in 15 different unit areas were counted on the crosssections by a blinded researcher.…”

Investigation of lipid peroxidation and antiapoptotic effects of zinc aganist liver damage in diabetic rats

“…Immunohistochemical analysis was performed as previously described. 21 Immunoperoxidase staining was performed using Ultra Vision Antibody Detection System (LabVision Corporation, Fremont, California, USA) kits, including mouse monoclonal MT antibody (Abcam; ab12228, 1:100 dilution). Immunostaining procedures were carried out following the manufacturer's instructions.…”