Effects of Caspase Inhibitor Administration against Hypoxic-Ischemic Brain Damage in Neonatal Rats.

Caspase被认为在缺氧缺血（HI）损伤后大鼠脑中观察到的迟发性神经元细胞死亡中起关键作用。半胱天冬酶抑制剂已被开发为抗凋亡剂。HI损伤后的海马损伤与组织温度密切相关，临床上已引入全身性低温用于脑保护。在这项研究中，我们研究了半胱天冬酶抑制剂和全身低温对发育中的大鼠脑神经元保护的影响。出生后第7天的大鼠幼仔经受缺氧1小时的Rice模型。用29℃水浴诱导全身低温。在HI损伤之前，将泛半胱天冬酶抑制剂boc-乙酰基-（OMe）-氟甲基-酮（BAF）注射到脑室中。对同侧海马进行半胱天冬酶测定和组织学评估。HI-37 ℃组caspase-3活性在伤后16 h达高峰。在BAF或低温（HI-29℃组）存在下，该活性显著降低。p<0.05）或HI-29℃+BAF组合（p<0.01 vs HI-37℃）。HI-37℃组同侧海马CA 1区神经元细胞数显著减少（与对照组相比减少62.9%）。HI-37℃ + BAF组（82.7%）、HI-29℃组（78.7%）和联合组（95.2%）的神经元细胞数量保持不变（p<0.05 vs HI-37℃）。全身低温和BAF的组合产生了强大的保护作用，对神经元损伤的发育中的大鼠大脑，沿着减少caspase-3的活性。

Caspases are believed to play a key role in the delayed neuronal cell death observed in the rat brain following hypoxic-ischemic (HI) insult. Caspase inhibitors have been developed as anti-apoptotic agents. Hippocampal damage after HI insult is strongly related to tissue temperature, and systemic hypothermia has been introduced clinically for brain protection. In this study, we examined the effects of a caspase inhibitor and systemic hypothermia on neuronal protection in the developing rat brain. Postnatal day 7 rat pups were subjected to the Rice model of hypoxia for 1 h. Systemic hypothermia was induced with a water bath at 29℃. Prior to HI insult, a pan-caspase inhibitor, boc-aspartyl-(OMe)-fluoromethyl-ketone (BAF), was injected into the cerebral ventricle. The ipsilateral hippocampus was subjected to caspase assays and histologic assessment. The HI group at 37℃ (HI-37℃) showed a peak of caspase-3 activity 16 h after insult. This activity was significantly reduced in the presence of BAF or hypothermia (HI-29℃ group. p<0.05) or by the combination of HI-29℃+BAF (p<0.01 versus HI-37℃). The number of neuronal cells in the ipsilateral hippocampal CA1 region in the HI-37℃ group was significantly decreased (62.9% versus control). The number of neuronal cells was maintained in the HI-37℃ + BAF group (82.7%), the HI-29℃ group (78.7%), and the combination group (95.2%) (p<0.05 versus HI-37℃). A combination of systemic hypothermia and BAF produced a strong protective effect against neuronal damage in the developing rat brain, along with a reduction in caspase-3 activity.