Campana W Marie, Myers Robert R
Department of Anesthesiology, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0629, USA.
Eur J Neurosci. 2003 Sep;18(6):1497-506. doi: 10.1046/j.1460-9568.2003.02875.x.
Erythropoietin (Epo) has been shown to have potent anti-apoptotic activity in central nervous system neurons in animal models of ischaemic injury. Recently, Epo and its receptor (EpoR) have been identified in the peripheral nervous system [Campana & Myers (2001), FASEB J., 15, 1804-1806]. Herein, we demonstrate that in painful neuropathy caused by L5 spinal nerve crush (SNC), therapy with recombinant human Epo (rhEpo) reduced dorsal root ganglion (DRG) apoptosis and pain behaviours. Quantification of both DRG neurons and satellite cells revealed that vehicle-treated, crush-injured DRGs had 35.5 +/- 8.3% apoptotic neurons and 23.5 +/- 2.36% satellite cells compared with 7.5 +/- 6.3% apoptotic neurons and 6.4 +/- 3.94% satellite cells in rhEpo-treated, crush-injured DRGs (P < 0.05). While rhEpo-treated animals were not initially protected from mechanical allodynia associated with L5 SNC, rhEpo did significantly improve recovery rates compared to vehicle-treated animals (P < 0.01). Systemic rhEpo therapy increased JAK2 phosphorylation, a key anti-apoptotic signalling molecule for Epo-induced neuroprotection, in DRGs after crush. Dual immunofluorescence demonstrated Epo-induced JAK2-p was associated with both neuronal and glial cells. JAK2-p was associated with NF200-positive large neurons and with smaller neurons. This population of small neurons did not colocalize with IB4, a marker of nonpeptidergic, glial derived growth factor-responsive neurons. The findings link anti-apoptosis activities of Epo/EpoR/JAK2 in DRG neurons capable of inducing protracted pain states with reductions in pain behaviours, and therefore support a role for Epo therapy in the treatment of neuropathic pain.
在缺血性损伤动物模型中，促红细胞生成素（Epo）已被证明在中枢神经系统神经元中具有强大的抗凋亡活性。最近，在外周神经系统中发现了Epo及其受体（EpoR）[坎帕纳和迈尔斯（2001年），《美国实验生物学会联合会杂志》，第15卷，第1804 - 1806页]。在此，我们证明在由L5脊神经挤压（SNC）引起的疼痛性神经病变中，重组人促红细胞生成素（rhEpo）治疗可减少背根神经节（DRG）凋亡和疼痛行为。对DRG神经元和卫星细胞的定量分析显示，与rhEpo治疗的挤压损伤DRG中7.5±6.3%的凋亡神经元和6.4±3.94%的卫星细胞相比，载体处理的挤压损伤DRG中有35.5±8.3%的凋亡神经元和23.5±2.36%的卫星细胞（P<0.05）。虽然rhEpo治疗的动物最初并未免受与L5 SNC相关的机械性异常性疼痛的影响，但与载体处理的动物相比，rhEpo确实显著提高了恢复率（P<0.01）。全身rhEpo治疗增加了挤压后DRG中JAK2的磷酸化，JAK2是Epo诱导神经保护的关键抗凋亡信号分子。双重免疫荧光显示Epo诱导的JAK2-p与神经元和神经胶质细胞均有关联。JAK2-p与NF200阳性的大神经元以及较小的神经元有关。这群小神经元与IB4不共定位，IB4是非肽能、胶质细胞源性生长因子反应性神经元的标志物。这些发现将Epo/EpoR/JAK2在能够诱导持续性疼痛状态的DRG神经元中的抗凋亡活性与疼痛行为的减轻联系起来，因此支持Epo治疗在神经性疼痛治疗中的作用。
