UCF-101, a novel Omi/HtrA2 inhibitor, protects against cerebral ischemia/reperfusion injury in rats.
The aim of this study was to investigate the therapeutic efficacy and neuroprotective mechanisms of UCF-101, a novel Omi/HtrA2 inhibitor, following ischemia/reperfusion brain injury. Male Wistar rats were subjected to 2 hr of middle cerebral artery occlusion followed by reperfusion. Animals were divided into 3 groups: sham, vehicle-treated ischemia/reperfusion, and UCF-101 treatment. In the UCF-101 treatment group, rats were intraperitoneally administered UCF-101 (1.5 micromol/kg) 10 min prior to reperfusion. The rats were evaluated for neurological deficits, and brain infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride. TUNEL staining was utilized to evaluate the amount of apoptosis. In addition, expressions of protein caspase-8, caspase-3, FasL, and FLIP were examined by Western blot analysis. Results demonstrated that UCF-101 treatment significantly decreased cerebral infarct size by about 16.27% (P < 0.05) and also improved neurological behavior. TUNEL staining revealed that UCF-101 treatment significantly reduced TUNEL-positive cells in the cerebral cortex. Furthermore, the upregulation in the expression of FasL and the cleavage products of active caspase-8 and caspase-3 induced by ischemia was attenuated in mice treated with UCF-101, whereas upregulation of FLIP levels was increased. The present results demonstrated that UCF-101 protects against cerebral ischemia/reperfusion injury in mice. UCF-101 provided neuroprotection in vivo, and this was correlated with regulation of Fas-mediated apoptotic proteins. Taken together, the use of UCF-101 is a potent, neuroprotective factor for the treatment of focal cerebral ischemia.
Su
Danying
D
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
Su
Zhiqiang
Z
Wang
Jiaye
J
Yang
Shanshan
S
Ma
Jing
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002545:Brain Ischemia / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002544:Cerebral Infarction / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000517:prevention & control*; D008297:Male; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D012697:Serine Endopeptidases; D000068103:Serine-Arginine Splicing Factors; D013871:Thiones / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011744:Pyrimidinones; D016601:RNA-Binding Proteins; D013871:Thiones; C490770:Tra2b protein, rat; C501517:UCF 101; D000068103:Serine-Arginine Splicing Factors; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D053148:Caspase 3; D053181:Caspase 8