Clarkson Andrew N, Parker Kim, Nilsson Michael, Walker F Rohan, Gowing Emma K
1] Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand [2] Department of Psychology, University of Otago, Dunedin, New Zealand [3] Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia.
Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
J Cereb Blood Flow Metab. 2015 Aug;35(8):1272-9. doi: 10.1038/jcbfm.2015.33. Epub 2015 Mar 11.
Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke. Mice that received a local delivery of BDNF via hydrogel implanted into the stroke cavity also showed a small gain of function from 4 to 6 weeks after stroke. Combining both treatments, however, resulted in a marked improvement in motor function from 2 weeks after insult. Assessment of peri-infarct tissue 2 weeks after stroke revealed a significant increase in p-AKT and p-CREB after the combined drug treatment. Using the pan-AKT inhibitor, GSK-690693, or deletion of CREB from forebrain neurons using the CREB-flox/CAMKii-cre mice, we were able to block the recovery of motor function. These data suggest that combined CX1837 and local delivery of BDNF are required to achieve maximal functional recovery after stroke in aged mice, and is occurring via the AKT-GSK3-CREB signaling pathway.
脑缺血会导致神经回路受损和功能的持久损伤。我们之前报道过，用安帕金CX1837刺激α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体可提高脑源性神经营养因子（BDNF）水平，并使年轻小鼠中风后运动功能得到显著恢复。在此，我们研究了在老年（24月龄）小鼠中给予CX1837是否同样有效。在局灶性缺血模型中，中风后5天开始给予CX1837，到中风后第6周运动功能有小幅改善。通过植入中风腔的水凝胶进行局部递送BDNF的小鼠在中风后4至6周也显示出功能的小幅改善。然而，联合两种治疗方法，在损伤后2周运动功能有显著改善。中风后2周对梗死灶周围组织的评估显示，联合药物治疗后p-AKT和p-CREB显著增加。使用泛AKT抑制剂GSK-690693，或使用CREB-flox/CAMKii-cre小鼠从前脑神经元中删除CREB，我们能够阻断运动功能的恢复。这些数据表明，联合使用CX1837和局部递送BDNF是老年小鼠中风后实现最大功能恢复所必需的，并且是通过AKT-GSK3-CREB信号通路发生的。
