Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia
Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia
复制标题
延迟、长期施用 Caspase 抑制剂 Q-VD-OPh 可减少新生儿缺氧缺血引起的脑损伤
DOI：
10.1159/000357939
复制
发表时间：
2014-01-01
影响因子：
2.9
通讯作者：
Blomgren, Klas
中科院分区：
文献类型：
--
作者：
Han, Wei;Sun, Yanyan;Blomgren, Klas
细胞凋亡在新生儿脑缺氧缺血(HI)后细胞死亡的形态和生化特征中起重要作用，使这种细胞死亡模式成为一个有前途的治疗靶点。我们之前的研究表明，在出生后第9天，在缺氧缺血开始时和缺氧缺血后即刻，给予caspase抑制剂Q-VD-Oph 10 mg/kg可以减少脑梗塞体积。在本研究中，延迟给予Q-VD-Oph后12和36h，HI诱导的caspase-3活性(DEVD裂解)降低了23%，促炎症趋化因子CCL2(MCP-1)和CCL3(MIP-1α)的水平分别降低了29.3%和29.1%，但抗炎细胞因子IL-4和IL-10的水平没有下降。长期应用Q-VD-Oph于HI后12h开始，每隔24小时持续给药2周，可使脑组织总损失量减少31.3%，从HI16周后赋形剂组的41.5±3.1mm3降至Q-VD-Oph组的28.5±3.0mm3(p=0.004)。Q-VD-Oph治疗还改善了HI后3周的感觉运动功能的丧失(Q-VD-Oph：30.8±4.3%对车辆：59.7±6.3%)，并减少了HI所致的多动，如伤后7周的旷场试验(Q-VD-Oph：4,062±198 cm对车辆：4,792±205 cm)。然而，在以后的时间点再次分析时，不再观察到功能保护。持续的形态保护和短暂的功能保护之间存在差异的机制仍有待阐明。
Apoptosis contributes greatly to the morphological and biochemical features of cell death after neonatal cerebral hypoxia-ischemia (HI), making this mode of cell death a promising therapeutic target. We previously showed that 10 mg/kg of the caspase inhibitor Q-VD-OPh at the onset of and immediately after HI on postnatal day 9 reduced brain infarct volume. In this study, delayed administration of Q-VD-OPh, 12 and 36 h after HI, decreased HI-induced caspase-3 activity (DEVD cleavage) by 23% and diminished the levels of the proinflammatory chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) by 29.3 and 29.1%, respectively, but not the levels of the anti-inflammatory cytokines IL-4 and IL-10. Long-term administration of Q-VD-OPh initiated at 12 h after HI, and continued at 24-hour intervals for 2 weeks, reduced total brain tissue loss by 31.3% from 41.5 ± 3.1 mm3 in the vehicle group to 28.5 ± 3.0 mm3 in the Q-VD-OPh group when evaluated 16 weeks after HI (p = 0.004). Q-VD-OPh treatment also ameliorated the loss of sensorimotor function, as evaluated by a cylinder rearing test (Q-VD-OPh: 30.8 ± 4.3% vs. vehicle: 59.7 ± 6.3% in nonimpaired forepaw preference) 3 weeks after HI, and reduced HI-induced hyperactivity, as measured in an open field test (Q-VD-OPh: 4,062 ± 198 cm vs. vehicle: 4,792 ± 205 cm in distance moved) 7 weeks after the insult. However, the functional protection was no longer observed when analyzed again at later time points. The mechanisms underlying the discrepancy between sustained morphological protection and transient functional protection remain to be elucidated.