Chen Nan-Fu, Huang Shi-Ying, Lu Ching-Hsiang, Chen Chun-Lin, Feng Chien-Wei, Chen Chun-Hong, Hung Han-Chun, Lin Yen-You, Sung Ping-Jyun, Sung Chun-Sung, Yang San-Nan, Wang Hui-Min David, Chang Yu-Chia, Sheu Jyh-Horng, Chen Wu-Fu, Wen Zhi-Hong
Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
Mar Drugs. 2014 Jun 27;12(7):3792-817. doi: 10.3390/md12073792.
Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI) model of neuropathic pain. First, we found that a single intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-μg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-β1 (TGF-β1) at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-β type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-β1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide.
慢性神经炎症在神经性疼痛的发生和维持中起重要作用。可从养殖软珊瑚中获得的化合物柔扁枝石松内酯，在大鼠角叉菜胶外周炎症模型中具有抗炎和镇痛作用。在本研究中，我们研究了柔扁枝石松内酯在大鼠神经性疼痛慢性压迫损伤（CCI）模型中的镇痛特性。首先，我们发现单次鞘内注射柔扁枝石松内酯可显著减轻术后14天CCI诱导的热痛觉过敏。其次，每天两次鞘内注射10μg柔扁枝石松内酯能够预防CCI大鼠热痛觉过敏和负重缺陷的发展。第三，鞘内注射柔扁枝石松内酯可显著抑制CCI诱导的同侧脊髓背角小胶质细胞和星形胶质细胞的激活，以及促炎酶诱导型一氧化氮合酶的上调。此外，柔扁枝石松内酯可减轻术后14天CCI诱导的脊髓转化生长因子-β1（TGF-β1）的下调。最后，TGF-βI型受体的选择性抑制剂鞘内注射SB431542可阻断柔扁枝石松内酯对CCI大鼠的镇痛作用。我们的结果表明，柔扁枝石松内酯可能作为一种治疗神经性疼痛的药物。此外，脊髓TGF-β1可能参与柔扁枝石松内酯的抗神经炎症和镇痛作用。
