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

半胱天酶被认为在大鼠脑缺氧缺血（HI）损伤后的延迟神经元细胞死亡中起关键作用。Caspase抑制剂作为抗凋亡药物已被开发。HI损伤后的海马损伤与组织温度密切相关，临床已引入全身低温来保护大脑。在这项研究中，我们检测了半胱天冬酶抑制剂和全身低温对发育中的大鼠大脑神经元保护的影响。取出生后第7天的大鼠幼仔进行1 h的Rice缺氧模型，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-天冬氨酸-(OMe)-氟甲基酮（BAF）注射到脑室。对同侧海马进行caspase检测和组织学评估。37℃下HI组（HI-37℃）的caspase-3活性在16 h后达到峰值。在BAF或低温（HI-29℃组）存在时，该活性显著降低。p<0.05)或HI-29℃+BAF联合作用（与HI-37℃相比p<0.01）。HI-37℃组同侧海马CA1区神经元细胞数量明显减少（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%）神经元细胞数量保持不变（与HI-37℃相比p<0.05）。全身低温和BAF的结合对发育中的大鼠大脑中的神经元损伤产生了很强的保护作用，同时也降低了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.