Blasig I E, Mertsch K, Haseloff R F
Forschungsinstitut für Molekulare Pharmakologie, Delbrück-Zentrum für Molekulare Medizin, Robert-Rössle-Str.10, 13125 Berlin, Germany.
Neuropharmacology. 2002 Nov;43(6):1006-14. doi: 10.1016/s0028-3908(02)00180-6.
Nitronyl nitroxides (NN) effectively decompose free radicals (. As brain endothelium, forming the blood-brain barrier (BBB), is both the main source and the target of reactive species during cerebral oxidative stress, we studied the effect of NN on brain endothelial cells injured by the mediator of oxidative stress H(2)O(2) (. H(2)O(2) caused hydroxyl radical generation, lipid peroxidation, membrane dysfunction, membrane leak and cell death, concentration dependently. Due to 0.5 mM H(2)O(2), oxy-radical-induced membrane phospholipid peroxidation (malondialdehyde) increased to 0.61+/-0.04 nmol/mg protein vs control (0.32+/-0.03, p<0.05), cells lost cytosolic proteins into the medium and viability decreased to 28+/-2% of control (p<0.05). Permeability through the endothelial monolayer (measure for the tightness of the BBB) rose to 250+/-40% after 0.15 mM H(2)O(2) (p<0.001). Addition of 10 microM of the NN 5,5-dimethyl-2,4-diphenyl-4-methoxy-2-imidazoline-3-oxide-1-oxyl (NN-2), 1 mM phenylbutyl nitrone (PBN), or 10 microM of the lazaroid U83836E improved cell viability during incubation with 0.5 mM H(2)O(2) to 57+/-1%, 49+/-2%, and 42+/-3% (p<0.05, vs drug-free H(2)O(2) group). The permeability enhancement by 0.15 mM H(2)O(2) was reduced to 171+/-21%, 170+/-25%, and 118+/-32% (p<0.05 vs drug-free H(2)O(2) group). Generally, the assumption is supported that during cerebral oxidative stress the protection should also be directed to the cells of the BBB, which can be provided by antioxidative approaches. NN represent a new group of antioxdatively acting cytoprotectiva improving the survival and function of the endothelium against oxidative stress.
硝酰氮氧化物（NN）能有效分解自由基（·）。由于脑内皮细胞形成血脑屏障（BBB），在脑氧化应激期间既是活性物质的主要来源又是其作用靶点，我们研究了NN对受氧化应激介质过氧化氢（H₂O₂）损伤的脑内皮细胞的影响。H₂O₂会导致羟自由基生成、脂质过氧化、膜功能障碍、膜渗漏和细胞死亡，且呈浓度依赖性。由于0.5 mM H₂O₂，氧自由基诱导的膜磷脂过氧化（丙二醛）增加至0.61±0.04 nmol/mg蛋白质，而对照组为0.32±0.03（p<0.05），细胞将胞质蛋白释放到培养基中，活力降至对照组的28±2%（p<0.05）。0.15 mM H₂O₂作用后，内皮单层的通透性（血脑屏障紧密性的指标）升至250±40%（p<0.001）。添加10 μM的NN 5,5 - 二甲基 - 2,4 - 二苯基 - 4 - 甲氧基 - 2 - 咪唑啉 - 3 - 氧化物 - 1 - 氧基（NN - 2）、1 mM苯基丁基硝酮（PBN）或10 μM的拉扎罗类药物U83836E，可使与0.5 mM H₂O₂共同孵育期间的细胞活力分别提高至57±1%、49±2%和42±3%（p<0.05，与无药物的H₂O₂组相比）。0.15 mM H₂O₂引起的通透性增强分别降至171±21%、170±25%和118±32%（p<0.05，与无药物的H₂O₂组相比）。一般来说，这一假设得到支持，即在脑氧化应激期间，保护措施也应针对血脑屏障的细胞，这可通过抗氧化方法来实现。NN代表了一类新的具有抗氧化作用的细胞保护剂，可提高内皮细胞在氧化应激下的存活率和功能。
