Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition
Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition
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DOI：
10.1523/jneurosci.4353-06.2007
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发表时间：
2007-04-11
影响因子：
5.3
通讯作者：
Li, Shuxin
中科院分区：
文献类型：
--
作者：
Fu, Qiao;Hue, Jeongsim;Li, Shuxin
成年哺乳动物中枢神经系统损伤后，由于自身生长能力降低和不允许轴突伸长的环境，轴突再生非常有限。中枢神经系统髓磷脂和星形胶质细胞硫酸软骨素蛋白聚糖的生长抑制部分解释了中枢神经系统缺乏修复。在这里，我们发现非甾体抗炎药（NSAIDs）布洛芬和吲哚美辛，这些在临床上广泛用作止痛药的药物，可以通过有效抑制髓磷脂和蛋白多糖的下游通路RhoA信号来克服轴突生长的限制。与Rho和Rock抑制剂C3转移酶或Y27632 [(R)-(+)反式- N-（4-吡啶基）-4-（1-氨基乙基）-环己anecarboxamide]类似，这两种非甾体抗炎药都能刺激暴露于抑制底物的培养背根神经节神经元的显著神经突生长。通过Rho-GTP结合试验，对脊髓损伤的啮齿动物全身给予布洛芬可以逆转损伤区域周围的RhoA信号。通过微型泵皮下注射布洛芬给胸段脊髓断裂或挫伤大鼠，可导致脊髓尾部大量皮质脊髓和血清素能轴突萌发，促进运动功能恢复，甚至可延迟创伤后1周的治疗。相反，非rhoa抑制非甾体抗炎药萘普生对培养或损伤神经元没有轴突生长促进作用。这些研究表明，抑制rhoa的非甾体抗炎药在治疗以轴突断开为特征的中枢神经系统损伤（包括脊髓损伤）方面具有治疗潜力。
After a CNS injury in the adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Here, we show that the nonsteroidal antiinflammatory drugs ( NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal. Similar to Rho and Rock inhibitors C3 transferase or Y27632 [( R)-(+)trans- N-(4-pyridyl)-4-(1-aminoethyl)- cyclohexanecarboxamide], both NSAID drugs stimulate a significant neurite growth in the cultured dorsal root ganglion neurons exposed to the inhibitory substrates. Systemic administration of ibuprofen to spinal cord-lesioned rodents reverses the active RhoA signal around injury area measured via Rho-GTP binding assay. Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma. In contrast, the non-RhoA-inhibiting NSAID naproxen does not have the axon growth-promoting effects on cultured or lesioned neurons. These studies demonstrate the therapeutic potential of RhoA-inhibiting NSAIDs in treating CNS injuries characterized by axonal disconnection including spinal cord injury.