Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.
Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.
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DOI：
10.1159/000441024
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发表时间：
2016
影响因子：
2.9
通讯作者：
Robinson S
中科院分区：
文献类型：
--
作者：
Jantzie LL;Winer JL;Corbett CJ;Robinson S
早产儿中枢神经系统（CNS）因缺氧缺血和炎症而受损，称为早产儿脑病。成熟CNS损伤激活半胱天冬酶和钙蛋白酶。促红细胞生成素（EPO）限制活化的半胱天冬酶介导的细胞凋亡，但其在调节钙蛋白酶激活的作用尚未得到广泛的研究后，损伤的发展中的中枢神经系统。我们假设，过量的钙蛋白酶激活降解发育调节的分子，中枢神经系统回路的形成，髓鞘和轴突的完整性，包括神经元钾-氯共转运蛋白（KCC 2），髓鞘碱性蛋白（MBP），磷酸化神经丝（pNF），分别必不可少的。此外，我们预测，损伤后EPO治疗可以减轻CNS钙蛋白酶介导的降解。使用大鼠产前短暂性全身性缺氧缺血（TSHI）模拟极端早产引起的CNS损伤，并使用临床相关给药方案进行出生后EPO治疗，我们发现产前TSHI后持续的出生后过量皮质钙蛋白酶激活，如α II-血影蛋白裂解为145 kDa α II-血影蛋白降解产物（α II-SDS）和p35裂解为p25所示。出生后内源性钙蛋白酶抑制剂钙蛋白酶抑制素的表达也减少了产前TSHI。钙蛋白酶底物表达TSHI后，包括皮质KCC 2，MBP和NF，调制出生后EPO治疗。钙蛋白酶激活反映在αII-SDPs和KCC 2片段的血清水平中，值得注意的是，EPO治疗也调节了KCC 2片段水平。总之，这些数据表明钙蛋白酶活性过多有助于早产儿脑病的发病机制。钙蛋白酶激活的血清生物标志物可以检测正在进行的脑损伤，以及对EPO或类似神经保护策略的反应性。
Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation, termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally-regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP), and phosphorylated-neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically-relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by cleavage of αII-spectrin into 145kDa αII-spectrin-degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury, and responsiveness to EPO or similar neuroprotective strategies.