Department of Emergency and Critical Care Medicine, School of Medicine, Fukuoka University, Fukuoka, Japan.
Transl Res. 2010 Nov;156(5):292-301. doi: 10.1016/j.trsl.2010.08.002. Epub 2010 Sep 8.
Calcitonin gene-related peptide (CGRP) released from sensory neurons increases the production of a neuroprotective substance insulin-like growth factor I (IGF-I), and sensory neuron stimulation contributes to a reduction of spinal cord injury (SCI) by inhibiting inflammatory responses in rats. Because receptors for prostaglandin E₂ (EP receptors) are present on sensory neurons, it is possible that prostaglandin E₁ analog limaprost reduces SCI by increasing IGF-I production through sensory neuron stimulation. We examined this possibility in rats subjected to compression-trauma-induced SCI. Limaprost increased the CGRP release from dorsal root ganglion (DRG) neurons isolated from rats, and this increase was reversed by pretreatment with the EP4 receptor antagonist ONO-AE3-208. Spinal cord tissue levels of CGRP and IGF-I were increased after the induction of SCI, peaking at 2 h postinduction. The intravenous administration of limaprost enhanced increases of spinal cord tissue levels of CGRP, IGF-I, and IGF-I mRNA at 2 h after the induction of SCI. Increases of spinal cord tissue levels of tumor necrosis factor, caspase-3, myeloperoxidase, and the number of apoptotic nerve cells were inhibited by the administration of limaprost. Motor disturbances of hind legs in animals subjected to the compression-trauma-induced SCI were reduced by the administration of limaprost. These effects of limaprost were reversed completely by pretreatment with a specific transient receptor potential vanilloid 1 inhibitor SB366791 and by sensory denervation. These observations strongly suggest that limaprost may increase the IGF-I production by stimulating sensory neurons in the spinal cord, thereby ameliorating compression-trauma-induced SCI through attenuation of inflammatory responses.
降钙素基因相关肽（CGRP）从感觉神经元释放出来会增加神经营养因子胰岛素样生长因子 I（IGF-I）的产生，而感觉神经元的刺激通过抑制大鼠脊髓损伤（SCI）中的炎症反应有助于减少 SCI。因为前列腺素 E₂（EP 受体）的受体存在于感觉神经元上，因此前列腺素 E₁类似物 limaprost 有可能通过刺激感觉神经元来增加 IGF-I 的产生，从而减少 SCI。我们在经受压迫性创伤诱导的 SCI 的大鼠中检查了这种可能性。Limaprost 增加了从大鼠背根神经节（DRG）神经元分离出的 CGRP 释放，并且这种增加可通过 EP4 受体拮抗剂 ONO-AE3-208 预处理而逆转。在 SCI 诱导后，脊髓组织中 CGRP 和 IGF-I 的水平增加，在诱导后 2 小时达到峰值。在 SCI 诱导后 2 小时，静脉内给予 limaprost 增强了脊髓组织中 CGRP、IGF-I 和 IGF-I mRNA 的水平增加。Limaprost 的给予抑制了脊髓组织中肿瘤坏死因子、半胱天冬酶-3、髓过氧化物酶和凋亡神经细胞数量的增加。在经受压迫性创伤诱导的 SCI 的动物中，后腿的运动障碍通过给予 limaprost 而减轻。这种 limaprost 的作用可通过预先给予特定的瞬时受体电位香草素 1 抑制剂 SB366791 和感觉神经切断术完全逆转。这些观察结果强烈表明，limaprost 通过刺激脊髓中的感觉神经元，可能会增加 IGF-I 的产生，从而通过减轻炎症反应来改善压迫性创伤诱导的 SCI。
