Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstrasse 200 a, 69118 Heidelberg, Germany.
Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Exp Neurol. 2018 Aug;306:250-259. doi: 10.1016/j.expneurol.2018.01.018. Epub 2018 Feb 2.
Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI.
脊髓损伤 (SCI) 后会形成一个生长抑制环境，由纤维瘢痕和抑制因子组成，进一步限制了受伤成年中枢神经系统 (CNS) 神经元已经很低的内在生长潜力。先前的研究表明，局部给予微管稳定剂紫杉醇或埃坡霉素 B (Epo B) 可减少纤维瘢痕形成和轴突退变，并在 SCI 后诱导轴突生长/发芽。同样，Epo B 的全身给药也促进了功能恢复。在这项研究中，我们研究了埃坡霉素 D (Epo D) 的作用，Epo D 是 Epo B 的类似物，可能具有更大的治疗指数，对 SCI 后纤维瘢痕形成、轴突发芽和功能恢复的影响。在雌性 Fischer 344 大鼠中度挫伤损伤 (150 kdyn) 后延迟全身给予 Epo D，会导致损伤后 4 周和 8 周时横梯跨越时的足点数减少。BBB 旷场运动评分和 Catwalk 步态分析评估的后肢运动功能没有明显改变。此外，在 Epo D 治疗后，损伤部位以下的层粘连蛋白阳性纤维瘢痕组织和 5-HT 阳性 5-羟色胺能纤维长度没有改变。这些发现重现了在大鼠挫伤 SCI 中全身给予微管稳定剂后的功能益处。
