Enhanced survival of dopaminergic neuronal transplants in hemiparkinsonian rats by the p53 inactivator PFT-α.
Enhanced survival of dopaminergic neuronal transplants in hemiparkinsonian rats by the p53 inactivator PFT-α.
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DOI：
10.3727/096368910x557173
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发表时间：
2011
影响因子：
3.3
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Chou J;Greig NH;Reiner D;Hoffer BJ;Wang Y
影响帕金森病细胞移植成功的一个关键限制因素是移植细胞的存活，而移植细胞的存活时间通常很短。本研究的重点是研究一种新策略，通过 p53 抑制剂 Pifithrin-α (PFT-α) 治疗来优化外源性胎儿腹中脑 (VM) 移植物的存活，从而改善帕金森病动物的生物学结果。将 6-羟基多巴胺注入成年雄性 Sprague-Dawley 大鼠的左内侧前脑束以诱导半帕金森状态。损伤后 7 周，将胎儿 VM 或皮质组织移植到动物的损伤纹状体中，此后每天接受 PFT-α 或载体注射，持续 5 天。在移植后 2、6、9 和 12 周检查阿扑吗啡诱导的旋转行为。移植后 5 天或 4 个月进行 TUNEL 或酪氨酸羟化酶 (TH) 免疫染色分析。将胎儿 VM 组织移植到受损纹状体中可减少旋转行为。在接受 PFT-α 和 VM 移植的动物中，旋转进一步减少是明显的。相比之下，在接受皮质移植物或皮质移植物+ PFT-α 的动物中，旋转没有明显减少。 PFT-α 治疗减少了 VM 移植物中的 TUNEL 标记并增加了 TH (+) 细胞和纤维密度。总之，我们的数据表明，PFT-α 的早期移植后治疗可提高多巴胺细胞移植物的存活率并增强帕金森病动物的行为恢复。
A key limiting factor impacting the success of cell transplantation for Parkinson’s disease is the survival of the grafted cells, which are often short-lived. The focus of this study was to examine a novel strategy to optimize the survival of exogenous fetal ventromesencephalic (VM) grafts by treatment with the p53 inhibitor, pifithrin-α (PFT-α), to improve the biological outcome of Parkinsonian animals. Adult male Sprague-Dawley rats were given 6-hydroxydopamine into the left medial forebrain bundle to induce a hemi-Parkinsonian state. At 7 weeks after lesioning, animals were grafted with fetal VM or cortical tissue into the lesioned striatum and, thereafter, received daily PFT-α or vehicle injections for 5 days. Apomorphine–induced rotational behavior was examined at 2, 6, 9, and 12 weeks after grafting. Analysis of TUNEL or tyrosine hydroxylase (TH) immunostaining was undertaken at 5 days or 4 months after grafting. The transplantation of fetal VM tissue into the lesioned striatum reduced rotational behavior. A further reduction in rotation was apparent in animals receiving PFT-α and VM transplants. By contrast, no significant reduction in rotation was evident in animals receiving cortical grafts or cortical grafts + PFT-α. PFT-α treatment reduced TUNEL labeling and increased TH (+) cell and fiber density in the VM transplants. In conclusion, our data indicate that early post-grafting treatment with PFT-α enhances the survival of dopamine cell transplants and augments behavioral recovery in Parkinsonian animals.