Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
J Cell Mol Med. 2012 Apr;16(4):708-21. doi: 10.1111/j.1582-4934.2011.01350.x.
Progranulin haploinsufficiency is associated with frontotemporal dementia in humans. Deficiency of progranulin led to exaggerated inflammation and premature aging in mice. The role of progranulin in adaptations to nerve injury and neuropathic pain are still unknown. Here we found that progranulin is up-regulated after injury of the sciatic nerve in the mouse ipsilateral dorsal root ganglia and spinal cord, most prominently in the microglia surrounding injured motor neurons. Progranulin knockdown by continuous intrathecal spinal delivery of small interfering RNA after sciatic nerve injury intensified neuropathic pain-like behaviour and delayed the recovery of motor functions. Compared to wild-type mice, progranulin-deficient mice developed more intense nociceptive hypersensitivity after nerve injury. The differences escalated with aging. Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal. Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth. A deficiency in this mechanism may increase the risk for injury-associated chronic pain.
颗粒蛋白前体基因单倍体不足与人类额颞叶痴呆有关。颗粒蛋白前体的缺乏导致小鼠炎症反应过度和早衰。颗粒蛋白前体在神经损伤和神经病理性疼痛适应中的作用尚不清楚。本研究发现，颗粒蛋白前体在小鼠坐骨神经损伤后同侧背根神经节和脊髓中上调，在损伤运动神经元周围的小胶质细胞中上调最为明显。坐骨神经损伤后持续鞘内脊髓递送小干扰 RNA 下调颗粒蛋白前体，可加重神经病理性疼痛样行为，并延迟运动功能的恢复。与野生型小鼠相比，颗粒蛋白前体缺陷型小鼠在神经损伤后表现出更强的痛觉过敏。这种差异随着年龄的增长而加剧。颗粒蛋白前体的下调减少了分离的原代神经元的存活和突起生长，而重组颗粒蛋白前体的添加可挽救神经生长因子撤出诱导的原代背根神经节神经元死亡。因此，神经元损伤后颗粒蛋白前体的上调可能通过促进损伤神经元的存活和支持再生，减轻神经病理性疼痛并有助于运动功能的恢复，至少部分如此。这种机制的缺乏可能会增加与损伤相关的慢性疼痛的风险。
