Inhibition of X-Linked Inhibitor of Apoptosis with Embelin Differentially Affects Male versus Female Behavioral Outcome following Neonatal Hypoxia-Ischemia in Rats
Inhibition of X-Linked Inhibitor of Apoptosis with Embelin Differentially Affects Male versus Female Behavioral Outcome following Neonatal Hypoxia-Ischemia in Rats
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DOI：
10.1159/000331651
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发表时间：
2011-01-01
影响因子：
2.9
通讯作者：
Fitch, R. H.
中科院分区：
文献类型：
--
作者：
Hill, C. A.;Alexander, M. L.;Fitch, R. H.
缺氧缺血（HI；并发缺氧/缺血）和相关脑病是早产儿/低出生体重儿和患有出生并发症的足月儿神经损伤的常见原因。由此产生的行为障碍包括认知和/或感觉处理缺陷以及语言障碍，临床证据表明，与具有同等损伤的女性婴儿相比，患有 HI 的男性婴儿表现出更严重的认知缺陷。证据还表明，HI 事件后性别依赖性细胞凋亡途径被激活，男性优先激活不依赖 caspase 的细胞死亡级联，而女性在新生儿缺氧和/或缺血性损伤后优先激活 caspase 依赖性级联。基于这些综合数据，HI损伤后的“女性保护”可能反映了内源性X连锁细胞凋亡抑制剂（XIAP），它有效地结合效应器半胱天冬酶并停止效应器半胱天冬酶的下游裂解（从而减少细胞死亡）。为了检验这一理论，当前的研究在出生后第 7 天 (P7) 对有或没有诱发 HI 损伤的雄性和雌性大鼠进行了新生注射媒介物或 embelin（XIAP 的小分子抑制剂）。随后使用临床相关任务进行的行为测试表明，XIAP 的抑制加剧了 HI 引起的女性持续行为缺陷，而对 HI 男性没有影响。这些结果支持早期 HI 损伤后细胞死亡机制的性别差异，并表明开发用于治疗 HI 的性别特异性神经保护剂具有潜在的临床益处。版权所有 (C) 2011 S. Karger AG，巴塞尔
Hypoxia-ischemia (HI; concurrent oxygen/blood deficiency) and associated encephalopathy represent a common cause of neurological injury in premature/low-birth-weight infants and term infants with birth complications. Resulting behavioral impairments include cognitive and/or sensory processing deficits, as well as language disabilities, and clinical evidence shows that male infants with HI exhibit more severe cognitive deficits compared to females with equivalent injury. Evidence also demonstrates activation of sex-dependent apoptotic pathways following HI events, with males preferentially activating a caspase-independent cascade of cell death and females preferentially activating a caspase-dependent cascade following neonatal hypoxic and/or ischemic insults. Based on these combined data, the 'female protection' following HI injury may reflect the endogenous X-linked inhibitor of apoptosis (XIAP), which effectively binds effector caspases and halts downstream cleavage of effector caspases (thus reducing cell death). To test this theory, the current study utilized neonatal injections of vehicle or embelin (a small molecule inhibitor of XIAP) in male and female rats with or without induced HI injury on postnatal day 7 (P7). Subsequent behavioral testing using a clinically relevant task revealed that the inhibition of XIAP exacerbated HI-induced persistent behavioral deficits in females, with no effect on HI males. These results support sex differences in mechanisms of cell death following early HI injuries, and suggest a potential clinical benefit from the development of sex-specific neuroprotectants for the treatment of HI. Copyright (C) 2011 S. Karger AG, Basel