Joashi U C, Greenwood K, Taylor D L, Kozma M, Mazarakis N D, Edwards A D, Mehmet H
Weston Laboratory, Division of Paediatrics, Obstetrics and Gynaecology, Imperial College School of Medicine, Hammersmith Hospital, London, U.K.
Eur J Neurosci. 1999 Jan;11(1):91-100. doi: 10.1046/j.1460-9568.1999.00409.x.
Transient unilateral forebrain hypoxia-ischaemia (HI) in 14-day-old rats produces infarction and delayed neuronal death in the frontal cortex. Cell death can also be observed in regions distant from the primary injury, a phenomenon known as diaschisis. While apoptosis is involved in selective neuronal death, its role in infarction and diaschisis remains poorly understood. Here, we have investigated the proteolytic cleavage of poly(ADP ribose) polymerase (PARP) and the occurrence of apoptosis in the hippocampus and the cerebellum following either HI or traumatic brain injury. We demonstrate that: (i) in vitro, PARP is cleaved during apoptosis but not necrosis in cultured neuronal (N1E) cells and Swiss 3T3 fibroblasts; (ii) following HI, apoptotic cells can be detected by 4 h after injury in the hippocampus; (iii) in the ipsilateral hippocampus the appearance of cells with apoptotic morphology is preceded by a dramatic increase in PARP cleavage in the same region, starting immediately following HI and persisting for 24 h; (iv) HI also induces apoptosis in the cerebellum and, as in the hippocampus, the appearance of cells with apoptotic morphology is preceded by PARP cleavage that is greater on the side ipsilateral to forebrain injury; and (v) similarly, traumatic brain injury to the forebrain leads to PARP cleavage and apoptosis in the cerebellum. We conclude that HI injury or traumatic injury to the developing rat forebrain leads to PARP cleavage in directly affected areas and in sites distant from the primary injury that precedes the appearance of cells with apoptotic morphology. Our results are consistent with a role for apoptotic cell death in infarction and in diaschisis resulting from forebrain injury to the developing brain.
14日龄大鼠短暂性单侧前脑缺氧缺血（HI）会导致额叶皮质梗死和迟发性神经元死亡。在远离原发性损伤的区域也可观察到细胞死亡，这种现象称为交叉性小脑失联络。虽然凋亡参与了选择性神经元死亡，但其在梗死和交叉性小脑失联络中的作用仍知之甚少。在此，我们研究了聚（ADP核糖）聚合酶（PARP）的蛋白水解切割以及HI或创伤性脑损伤后海马体和小脑中凋亡的发生情况。我们证明：（i）在体外，PARP在培养的神经元（N1E）细胞和瑞士3T3成纤维细胞的凋亡过程中被切割，但在坏死过程中未被切割；（ii）HI后，海马体中损伤后4小时即可检测到凋亡细胞；（iii）在同侧海马体中，具有凋亡形态的细胞出现之前，同一区域的PARP切割会急剧增加，从HI后立即开始并持续24小时；（iv）HI还会诱导小脑中的凋亡，与海马体一样，具有凋亡形态的细胞出现之前，PARP切割会增加，且在前脑损伤同侧更为明显；（v）同样，前脑的创伤性脑损伤会导致小脑中PARP切割和凋亡。我们得出结论，发育中大鼠前脑的HI损伤或创伤性损伤会导致直接受影响区域和远离原发性损伤部位的PARP切割，这发生在具有凋亡形态的细胞出现之前。我们的结果与凋亡性细胞死亡在发育中脑的前脑损伤导致的梗死和交叉性小脑失联络中的作用一致。
