ICORD-International Collaboration On Repair Discoveries, Blusson Spinal Cord Centre, Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
J Neurosci Res. 2010 Oct;88(13):2833-46. doi: 10.1002/jnr.22440.
The failure of CNS axons to regenerate following traumatic injury is due in part to a growth-inhibitory environment in CNS as well as a weak intrinsic neuronal growth response. Olfactory ensheathing cell (OECs) transplants have been reported to create a favorable environment promoting axonal regeneration, remyelination, and functional recovery after spinal cord injury. However, in our previous experiments, OEC transplants failed to promote regeneration of rubrospinal axons through and beyond the site of a dorsolateral funiculus crush in rats. Rubrospinal neurons undergo massive cell atrophy and limited expression of regeneration-associated genes after axotomy. Using the same injury model, we tested the hypothesis that treatment of the red nucleus with cAMP, known to stimulate the intrinsic growth response in other neurons, will promote rubrospinal regeneration in combination with OEC transplants. In addition, we assessed a systemic increase of cAMP using the phosphodiesterase inhibitor rolipram. OECs prevented cavity formation, attenuated astrocytic hypertrophy and the retraction of the axotomized rubrospinal axons, and tended to reduce the overall lesion size. OEC transplantation lowered the thresholds for thermal sensitivity of both forepaws. None of our treatments, alone or in combination, promoted rubrospinal regeneration through the lesion site. However, the systemic elevation of cAMP with rolipram resulted in greater numbers of OECs and axonal density within the graft and improved motor performance in a cylinder test in conjunction with enhanced rubrospinal branching and attenuated astrocytic hypertrophy.
中枢神经系统轴突在外伤后不能再生的部分原因是中枢神经系统中存在生长抑制环境以及神经元内在生长反应较弱。嗅鞘细胞（OEC）移植已被报道可创造有利环境，促进脊髓损伤后的轴突再生、髓鞘再生和功能恢复。然而，在我们之前的实验中，OEC 移植未能促进红核脊髓束轴突通过并超越大鼠背外侧束挤压部位的再生。红核脊髓神经元在轴突切断后会发生大量细胞萎缩和有限的再生相关基因表达。使用相同的损伤模型，我们测试了以下假设：用 cAMP 处理红核，已知 cAMP 可刺激其他神经元的内在生长反应，与 OEC 移植结合将促进红核脊髓的再生。此外，我们还评估了使用磷酸二酯酶抑制剂 rolipram 引起的全身性 cAMP 增加。OEC 可防止空洞形成，减轻星形胶质细胞肥大和轴突的回缩，并倾向于减少整体损伤大小。OEC 移植降低了前爪热敏感性的阈值。我们的任何单一治疗或联合治疗都不能促进损伤部位的红核脊髓再生。然而，用 rolipram 系统地提高 cAMP 水平会导致移植体内 OEC 和轴突密度增加，并结合增强的红核脊髓分支和减轻的星形胶质细胞肥大，在圆筒测试中改善运动表现。
