The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery
The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery
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DOI：
10.1073/pnas.0402595101
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发表时间：
2004-06-08
影响因子：
11.1
通讯作者：
Filbin, MT
中科院分区：
文献类型：
--
作者：
Nikulina, E;Tidwell, JL;Filbin, MT
虽然哺乳动物脊髓轴突在损伤后不能自发再生，但在切断脊髓轴突之前，如果神经元胞体内cAMP升高，则可以诱导它们生长。然而，预防性注射cAMP对脊柱损伤的治疗无效。我们现在证明，磷酸二酯酶4(PDE4)抑制剂罗利普兰(很容易穿过血脑屏障)在培养中克服了髓鞘再生的抑制剂，并促进了体内的再生。在C3/4半切损伤后两周，胚胎脊髓组织立即植入损伤部位，10天的Rolipram交付导致大量轴突重新生长到移植体内，并显著改善运动功能。令人惊讶的是，在接受罗利普兰治疗的动物中，反应性胶质细胞增多症也有所减弱。因此，由于罗利普兰促进轴突再生，减少胶质瘢痕的形成，并显著促进功能恢复，而且由于它在SC注射时以及损伤后有效，因此它是脊髓损伤后有效的治疗方法。
Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3/4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.