Mi Ruifa, Chen Weiran, Höke Ahmet
Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4664-9. doi: 10.1073/pnas.0603243104. Epub 2007 Mar 5.
Regeneration in the peripheral nervous system is poor after chronic denervation. Denervated Schwann cells act as a "transient target" by secreting growth factors to promote regeneration of axons but lose this ability with chronic denervation. We discovered that the mRNA for pleiotrophin (PTN) was highly up-regulated in acutely denervated distal sciatic nerves, but high levels of PTN mRNA were not maintained in chronically denervated nerves. PTN protected spinal motor neurons against chronic excitotoxic injury and caused increased outgrowth of motor axons out of the spinal cord explants and formation of "miniventral rootlets." In neonatal mice, PTN protected the facial motor neurons against cell death induced by deprivation from target-derived growth factors. Similarly, PTN significantly enhanced regeneration of myelinated axons across a graft in the transected sciatic nerve of adult rats. Our findings suggest a neurotrophic role for PTN that may lead to previously unrecognized treatment options for motor neuron disease and motor axonal regeneration.
慢性去神经支配后，周围神经系统的再生能力较差。去神经支配的施万细胞通过分泌生长因子促进轴突再生，从而充当“短暂靶点”，但在慢性去神经支配后会失去这种能力。我们发现，在急性去神经支配的坐骨神经远端，多效生长因子（PTN）的mRNA高度上调，但在慢性去神经支配的神经中，PTN mRNA的高水平无法维持。PTN保护脊髓运动神经元免受慢性兴奋性毒性损伤，并导致脊髓外植体中运动轴突的生长增加以及“微小腹侧神经根”的形成。在新生小鼠中，PTN保护面神经运动神经元免受因靶源性生长因子剥夺所致的细胞死亡。同样，PTN显著增强了成年大鼠横断坐骨神经移植物中髓鞘轴突的再生。我们的研究结果表明PTN具有神经营养作用，这可能为运动神经元疾病和运动轴突再生带来此前未被认识到的治疗选择。
