Bix Gregory J, Gowing Emma K, Clarkson Andrew N
Anatomy and Neurobiology, University of Kentucky College of Medicine, Sanders Brown Center for Aging, Lexington, KY, 40536, USA.
Transl Stroke Res. 2013 Oct;4(5):515-23. doi: 10.1007/s12975-013-0266-1. Epub 2013 Jun 7.
With the failure of so many pre-clinical stroke studies to translate into the clinic, there is a need to find new therapeutics to minimize the extent of cellular damage and aid in functional recovery. Domain V (DV), the c-terminal protein fragment of the vascular basement membrane component, perlecan, was recently shown to afford significant protection in multiple transient middle cerebral artery occlusion stroke models. We sought here to determine whether DV might have similar therapeutic properties in a focal photothrombosis stroke model in both young and aged mice. Young (3-month old) and aged (24-month old) mice underwent photothrombotic stroke to the motor cortex and were then treated with DV or phosphate buffered saline vehicle at different initial time points up to 7 days. Stroke volume was analyzed histologically using cresyl violet and functional recovery assessed behaviorally on both the grid-walking and cylinder tasks. In young mice, DV administration resulted in a significant decrease in infarct volume when treatment started 3 or 6 h post-stroke. In aged mice, DV administration was only protective when started 3 h post-stroke. In addition to a decrease in the area of infarction, DV treatment was effective in significantly decreasing the number of foot-faults on the grid-walking task and improving use of the stroke-affected limb in the cylinder task in both young and aged. Previously, we have shown that DV can alter the expression profile of various astroglial markers. Consistent with our previous finding, treatment groups that showed therapeutic potential in both young and aged mice also showed an elevation in glial fibrillary acidic protein (GFAP) expression in peri-infarct regions. We conclude that DV is neuroprotective and affords significant improvements in functional recovery in both young and aged mice after focal ischemia. These data also highlight a therapeutic time-window shift that is narrower in aged compared with young mice and is associated with an elevation in GFAP expression and heightened astrogliosis.
由于许多临床前中风研究未能转化为临床应用，因此需要寻找新的治疗方法，以尽量减少细胞损伤的程度并促进功能恢复。结构域V（DV）是血管基底膜成分核心蛋白聚糖的C末端蛋白片段，最近在多个短暂性大脑中动脉闭塞性中风模型中显示出显著的保护作用。我们在此研究DV在年轻和老年小鼠的局灶性光血栓性中风模型中是否具有类似的治疗特性。年轻（3个月大）和老年（24个月大）小鼠的运动皮层接受光血栓性中风，然后在长达7天的不同初始时间点用DV或磷酸盐缓冲盐水载体进行治疗。使用甲酚紫对脑梗死体积进行组织学分析，并通过网格行走和圆筒任务对功能恢复进行行为评估。在年轻小鼠中，中风后3或6小时开始给予DV可导致梗死体积显著减小。在老年小鼠中，仅在中风后3小时开始给予DV才有保护作用。除了梗死面积减小外，DV治疗还能有效减少年轻和老年小鼠在网格行走任务中的失足次数，并改善其在圆筒任务中对中风侧肢体的使用。此前，我们已表明DV可以改变各种星形胶质细胞标志物的表达谱。与我们之前的发现一致，在年轻和老年小鼠中均显示出治疗潜力的治疗组在梗死周围区域的胶质纤维酸性蛋白（GFAP）表达也有所升高。我们得出结论，DV具有神经保护作用，并且在局灶性缺血后能显著改善年轻和老年小鼠的功能恢复。这些数据还突出了一个治疗时间窗的变化，与年轻小鼠相比，老年小鼠的治疗时间窗更窄，并且与GFAP表达升高和星形胶质细胞增生加剧有关。
