VALPROATE REDUCES CHOP LEVELS AND PRESERVES OLIGODENDROCYTES AND AXONS AFTER SPINAL CORD INJURY
VALPROATE REDUCES CHOP LEVELS AND PRESERVES OLIGODENDROCYTES AND AXONS AFTER SPINAL CORD INJURY
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DOI：
10.1016/j.neuroscience.2011.01.012
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发表时间：
2011-03-31
期刊：
影响因子：
3.3
通讯作者：
Casas, C.
中科院分区：
文献类型：
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作者：
Penas, C.;Verdu, E.;Casas, C.
脊髓损伤(SCI)是致残的主要原因，目前尚无有效的治疗方法。我们先前报道，脊髓损伤后发生的少突胶质细胞和神经元的变性与内质网应激的发展和促凋亡因子CHOP的进行性积累有关。由于在内质网应激之后，支持生存的伴侣蛋白Bip和CHOP之间的平衡决定了细胞的命运，我们的目标是找到有利于前者的药物来调节这一比例。我们发现丙戊酸盐(VPA)可显著降低内质网应激后脊髓组织器官培养中CHOP的水平。然后，我们给脊髓挫伤后的大鼠注射不同剂量的VPA，发现这种治疗导致损伤后早期CHOP水平显著降低。此外，VPA可部分阻止脊髓组织、髓鞘和轴突的丢失，并显著增加受损脊髓中存活的少突胶质细胞的相对数量。此外，VPA治疗组大鼠脊髓损伤后运动功能恢复明显好于车辆组大鼠。由于VPA是一种已经在临床上使用的药物，这些结果为其在脊髓损伤和脱髓鞘疾病中的治疗开辟了道路。(C)2011年IBRO。爱思唯尔有限公司出版。保留所有权利。
Spinal cord injury (SCI) is a major cause of disability to which there are not yet effective treatments. We previously reported that degeneration of oligodendrocytes and neurons that occurs after SCI is associated with the development of endoplasmic reticulum (ER) stress and the progressive accumulation of the pro-apoptotic factor CHOP. Since following ER stress, the balance between the pro-survival chaperone BiP and CHOP drives the cell destiny, we aimed to find drugs that modulate this ratio in favour of the former. We found that valproate (VPA) induced a significant reduction of CHOP levels after ER stress in an organotypic-based culture of spinal cord in vitro. We then administered different doses of VPA to rats following spinal cord contusion, and found that the treatment caused a marked reduction of CHOP levels early after the lesion. In addition, VPA administration partially prevented cord tissue, myelin and axonal loss, and significantly increased the relative number of surviving oligodendrocytes in the damaged spinal cord. Besides, VPA-treated rats showed better recovery of the locomotor activity than vehicle-treated rats after SCI. Since VPA is a drug already in clinical use, these results open the avenue for its therapeutical use in SCI as well as in demyelinating disorders. (c) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.