Mechanisms of cell death and neuroprotection by poloxamer 188 after mechanical trauma
Mechanisms of cell death and neuroprotection by poloxamer 188 after mechanical trauma
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DOI：
10.1096/fj.05-4024fje
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发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Barbee, Kenneth
中科院分区：
文献类型：
--
作者：
Serbest, Gulyeter;Horwitz, Joel;Barbee, Kenneth
创伤性脑损伤（TBI）后细胞死亡和神经组织进行性退化的机制已得到深入研究。然而，多种细胞类型中不断演变的病理学之间复杂的相互作用掩盖了细胞水平上机械创伤的初始影响与长期功能障碍和神经元死亡之间的因果关系。我们使用神经元损伤的体外模型来研究细胞响应明确的机械损伤而死亡的机制，发现大多数死亡细胞都是凋亡的。我们之前曾报道过，非离子表面活性剂泊洛沙姆 188 (P188) 能显着促进细胞膜修复，使细胞活力在损伤后 24 小时恢复至对照值。在这里，我们证明 P188 显着抑制细胞凋亡并防止坏死。我们还研究了丝裂原激活蛋白激酶（MAPK）在细胞死亡中的作用。机械损伤后，细胞外信号调节激酶、c-Jun N 末端激酶和 p38 出现快速、短暂的激活。其中，促凋亡 p38 的激活是最大的。 P188 治疗可抑制 p38 激活；然而，SB203580 直接抑制 p38（选择性抑制 p38 MAPK 的活性）仅部分抑制细胞凋亡，对坏死没有影响。这些数据表明多种信号通路可能参与神经元对机械损伤的长期反应。此外，P188 的膜重新密封作用提供了如此显着的保护，防止坏死和细胞凋亡，这表明创伤引起的急性膜损伤是一个关键的诱发事件，它是导致随后病理学的许多信号级联的上游。
The mechanisms of cell death and the progressive degeneration of neural tissue following traumatic brain injury (TBI) have come under intense investigation. However, the complex interactions among the evolving pathologies in multiple cell types obscure the causal relationships between the initial effects of the mechanical trauma at the cellular level and the long‐term dysfunction and neuronal death. We used an in vitro model of neuronal injury to study the mechanisms of cell death in response to a well‐defined mechanical insult and found that the majority of dead cells were apoptotic. We have previously reported that promotion of membrane repair acutely with the non‐ionic surfactant poloxamer 188 (P188) restored cell viability to control values at 24 h postinjury. Here, we showed that P188 significantly inhibits apoptosis and prevents necrosis. We also examined the role of mitogen‐activated protein kinases (MAPKs) in cell death. There was a rapid, transient activation of extracellular signal‐regulated kinases, c‐Jun N‐terminal kinase, and p38s after mechanical insult. Of these, activation of the proapoptotic p38 was the greatest. Treatment with P188 inhibited p38 activation; however, direct inhibition of p38 by SB203580, which selectively inhibits the activity of the p38 MAPK, provided only partial inhibition of apoptosis and had no effect on necrosis. These data suggest that multiple signaling pathways may be involved in the long‐term response of neurons to mechanical injury. Furthermore, that the membrane resealing action of P188 provides such significant protection from both necrosis and apoptosis suggests that acute membrane damage due to trauma is a critical precipitating event that is upstream of the many signaling cascades contributing to the subsequent pathology.