The role of neurotrophic factors in nerve regeneration.
The role of neurotrophic factors in nerve regeneration.
复制标题
DOI：
10.3171/foc.2009.26.2.e3
复制
发表时间：
2009-02-01
影响因子：
4.1
通讯作者：
Gordon, Tessa
中科院分区：
文献类型：
--
作者：
Gordon, Tessa
本文综述了周围神经系统（PNS）中神经营养因子的两个来源，即失神经远端残端的神经元和非神经元细胞，以及它们在轴突再生中的作用。神经损伤和修复后，外源性生长因子的管理再生成功的形态学评估表明，在远端神经残端的雪旺细胞的内源性神经营养因子的作用。然而，轴突数量的增加可能反映了更多的神经元再生其轴突和/或相同数量的神经元的轴突芽的数量增加。使用荧光染料计数神经元再生的轴突穿过缝合部位，并进入远端神经残端，脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）被发现不增加神经元再生后立即神经修复轴突的数量。然而，这些因素确实逆转了延迟神经修复的有害影响，表明再生到远端神经残端的轴突通常可以获得足够水平的内源性神经营养因子以维持其再生，而无法获得这些因子的神经元需要外源性因子来维持轴突再生。轴突切断后神经元上调神经营养因子。上调通常是缓慢的，在7天后开始，并与轴突再生的延长期相关，其中轴突在啮齿动物中从近端神经残端穿过缝合部位长出1个月。这种跨越缝合部位的交错轴突再生通过1小时的低频电刺激来加速，该低频电刺激同时加速神经元中BDNF及其trkB受体的表达。2天后，BDNF水平升高至未刺激神经元中发现的3倍以上，伴随着cAMP水平的升高，随后是生长相关基因、微管蛋白、肌动蛋白和GAP-43的加速上调以及神经丝蛋白的下调。通过咯利普兰抑制磷酸二酯酶4的cAMP水平的升高模仿了低频电刺激的效果。总之，电刺激轴突切断的神经元中神经营养因子的增强上调加速轴突长入远端神经残端，其中雪旺细胞中生长因子的内源性来源支持轴突朝向去神经靶的再生。这些发现为轴突切断的神经元和失神经支配的雪旺细胞的内源性神经营养因子在支持PNS轴突再生中发挥关键作用提供了强有力的支持。
This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effect of delayed nerve repair, indicating that the axons that regenerate into the distal nerve stump normally have access to sufficient levels of endogenous neurotrophic factors to sustain their regeneration, while neurons that do not have access to these factors require exogenous factors to sustain axon regeneration. Neurons upregulate neurotrophic factors after axotomy. The upregulation is normally slow, beginning after 7 days and occurring in association with a protracted period of axonal regeneration in which axons grow out from the proximal nerve stump across a suture site over a period of 1 month in rodents. This staggered axon regeneration across the suture site is accelerated by a 1-hour period of low-frequency electrical stimulation that simultaneously accelerates the expression of BDNF and its trkB receptor in the neurons. Elevation of the level of BDNF after 2 days to > 3 times that found in unstimulated neurons was accompanied by elevation of the level of cAMP and followed by accelerated upregulation of growth-associated genes, tubulin, actin, and GAP-43 and downregulation of neurofilament protein. Elevation of cAMP levels via rolipram inhibition of phosphodiesterase 4 mimicked the effect of the low-frequency electrical stimulation. In conclusion, the enhanced upregulation of neurotrophic factors in the electrically stimulated axotomized neurons accelerates axon outgrowth into the distal nerve stumps where endogenous sources of growth factors in the Schwann cells support the regeneration of the axons toward the denervated targets. The findings provide strong support for endogenous neurotrophic factors of axotomized neurons and of denervated Schwann cells playing a critical role in supporting axon regeneration in the PNS.