Rao Muddanna S, Hattiangady Bharathi, Shetty Ashok K
Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham NC 27705, USA.
Neurobiol Dis. 2006 Feb;21(2):276-90. doi: 10.1016/j.nbd.2005.07.009. Epub 2005 Aug 15.
Cell transplants that successfully replace the lost neurons and facilitate the reconstruction of the disrupted circuitry in the injured aging hippocampus are invaluable for treating acute head injury, stroke and status epilepticus in the elderly. This is because apt graft integration has the potential to prevent the progression of the acute injury into chronic epilepsy in the elderly. However, neural transplants into the injured middle-aged or aged hippocampus exhibit poor cell survival, suggesting that apt graft augmentation strategies are critical for robust integration of grafted cells into the injured aging hippocampus. We examined the efficacy of pre-treatment and grafting of donor fetal CA3 cells with a blend of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) for lasting survival and integration of grafted cells in the injured middle-aged (12 months old) hippocampus of F344 rats. Grafts were placed at 4 days after the kainic-acid-induced hippocampal injury and were analyzed at 6 months post-grafting. We demonstrate that 80% of grafted cells exhibit prolonged survival and 71% of grafted cells differentiate into CA3 pyramidal neurons. Grafts also receive a robust afferent input from the host mossy fibers and project efferent axons into the denervated zones of the dentate gyrus and the CA1 subfield. Consequently, the aberrant sprouting of the dentate mossy fibers, an epileptogenic change that typically ensues after the hippocampal injury, was suppressed. Thus, grafts of fetal CA3 cells enriched with FGF-2 and BDNF exhibit robust integration and dampen the abnormal mossy fiber sprouting in the injured middle-aged hippocampus. Because the aberrantly sprouted mossy fibers contribute to the generation of seizures, the results suggest that the grafting intervention using FGF-2 and BDNF is efficacious for suppressing epileptogenesis in the injured middle-aged hippocampus.
能够成功替代受损神经元并促进受伤老化海马体中受损神经回路重建的细胞移植，对于治疗老年人的急性头部损伤、中风和癫痫持续状态具有重要价值。这是因为合适的移植物整合有可能防止老年人急性损伤进展为慢性癫痫。然而，将神经移植到受伤的中年或老年海马体中时，细胞存活率较低，这表明合适的移植物增强策略对于将移植细胞稳固整合到受伤老化海马体中至关重要。我们研究了用成纤维细胞生长因子-2（FGF-2）和脑源性神经营养因子（BDNF）混合物对供体胎儿CA3细胞进行预处理和移植，以实现移植细胞在F344大鼠受伤中年（12个月大）海马体中的持久存活和整合。在 kainic 酸诱导海马体损伤后4天进行移植，并在移植后6个月进行分析。我们证明80%的移植细胞存活时间延长，71%的移植细胞分化为CA3锥体神经元。移植物还从宿主苔藓纤维接收强大的传入输入，并将传出轴突投射到齿状回和CA1子区域的去神经支配区域。因此，海马体损伤后通常会出现的致痫性变化——齿状苔藓纤维异常发芽受到了抑制。因此，富含FGF-2和BDNF的胎儿CA3细胞移植物表现出强大的整合能力，并抑制了受伤中年海马体中异常的苔藓纤维发芽。由于异常发芽的苔藓纤维会导致癫痫发作，结果表明使用FGF-2和BDNF的移植干预对于抑制受伤中年海马体中的癫痫发生是有效的。
