Increased Synthesis of Spermidine as a Result of Upregulation of Arginase I Promotes Axonal Regeneration in Culture and In Vivo
Increased Synthesis of Spermidine as a Result of Upregulation of Arginase I Promotes Axonal Regeneration in Culture and In Vivo
复制标题
DOI：
10.1523/jneurosci.1175-09.2009
复制
发表时间：
2009-07-29
影响因子：
5.3
通讯作者：
Filbin, Marie T.
中科院分区：
文献类型：
--
作者：
Deng, Kangwen;He, Huifang;Filbin, Marie T.
成年脊髓轴突在损伤后不能自发再生。然而，如果背根神经节神经元的外周分支在损伤背柱中相同神经元的中央分支之前被损伤，则这些中央轴突将再生，并且如果被培养，则不被髓鞘相关再生抑制剂（例如髓鞘相关糖蛋白（MAG））抑制延伸神经突。这种效应可以通过升高cAMP来模拟，并且是转录依赖性的。cAMP克服MAG在培养物中的抑制的能力涉及酶促生长酶I（Arg I）的上调和随后的多胺如腐胺合成的增加。现在，我们发现，外周病变也诱导增加精氨酸I的表达和多胺的合成。我们还表明，在克服抑制MAG的条件损伤效应最初是依赖于正在进行的多胺合成，但随着时间的损伤后，成为独立的正在进行的合成。然而，如果在体内阻断多胺的合成，则在条件损伤后的良好生长的早期阶段被完全阻断，并且当在培养期间不需要进行多胺合成时，生长的后期阶段被减弱。我们还表明，腐胺必须转化为亚精胺，在文化和在体内克服抑制MAG和亚精胺可以促进视神经再生在体内。这些结果表明，亚精胺可能是一个有用的工具，在促进中枢神经系统轴突损伤后再生。
Adult spinal axons do not spontaneously regenerate after injury. However, if the peripheral branch of dorsal root ganglion neurons is lesioned before lesioning the central branch of the same neurons in the dorsal column, these central axons will regenerate and, if cultured, are not inhibited from extending neurites by myelin-associated inhibitors of regeneration such as myelin-associated glycoprotein (MAG). This effect can be mimicked by elevating cAMP and is transcription dependent. The ability of cAMP to overcome inhibition by MAG in culture involves the upregulation of the enzyme arginase I (Arg I) and subsequent increase in synthesis of polyamines such as putrescine. Now we show that a peripheral lesion also induces an increase in Arg I expression and synthesis of polyamines. We also show that the conditioning lesion effect in overcoming inhibition by MAG is initially dependent on ongoing polyamine synthesis but, with time after lesion, becomes independent of ongoing synthesis. However, if synthesis of polyamines is blocked in vivo the early phase of good growth after a conditioning lesion is completely blocked and the later phase of growth, when ongoing polyamine synthesis is not required during culture, is attenuated. We also show that putrescine must be converted to spermidine both in culture and in vivo to overcome inhibition by MAG and that spermidine can promote optic nerve regeneration in vivo. These results suggest that spermidine could be a useful tool in promoting CNS axon regeneration after injury.