Cheng Xi, Wang Zhaolu, Yang Jiping, Ma Minmin, Lu Tingting, Xu Gelin, Liu Xinfeng
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Neurol Res. 2011 Sep;33(7):675-80. doi: 10.1179/1743132810Y.0000000004.
Enhancing angiogenesis and neurogenesis is a novel therapeutic strategy for stroke treatment. Acidic fibroblast growth factor (aFGF) has been shown to have both angiogenesis and neurogenesis effects in animals with cerebral ischemia. But aFGF can not enter the brain freely after system administration due to the filtration of the blood-brain barrier (BBB). Intranasal administration of aFGF as a noninvasive method can bypass the BBB and enter the central nervous system directly without systemic adverse effects.
To investigate the therapeutic effects of intranasally delivered aFGF, adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO) and intranasally administrated with aFGF or saline starting at 24 hours and once daily for the subsequent 6 days. BrdU (50 mg/kg) was intraperitoneally injected daily for 13 days. A modified neurological severity scores test was performed before and at 1, 7, 14 days after MCAO. Infarct volumes were evaluated after hematoxylin and eosin staining. Immunohistochemistry was performed to detect BrdU immunoreactive cells and BrdU / DCX double labeled cells. Microvessels were labeled by FITC-dextran and the numbers, length and diameters of vessels were also measured.
Intranasal aFGF did not significantly reduce the lesion size, but did improve neurological functional recovery. In the subventricular zone and the striatum, numbers of BrdU immunoreactive cells were significantly increased in aFGF group at day 14, and the majority of BrdU positive cells were co-labeled with DCX. At 14 days after ischemia, the percentage of BrdU positive endothelial cells around the ischemic lesions were significantly increased in aFGF group, compared with control. Quantitative analysis of FITC-dextran perfusing vessels revealed a significant increase of vessels in the boundary regions of ischemia in the rats treated with aFGF. But there were no significant differences concerning the length and the diameter of the vessels between groups.
In summary, aFGF may enhance neurogenesis and angiogenesis after focal cerebral ischemia. Intranasal administration of aFGF may be a feasible approach for ischemic stroke treatment.
增强血管生成和神经发生是一种治疗中风的新型策略。酸性成纤维细胞生长因子（aFGF）已被证明在脑缺血动物中具有血管生成和神经发生作用。但全身给药后，由于血脑屏障（BBB）的滤过作用，aFGF不能自由进入大脑。鼻内给予aFGF作为一种非侵入性方法可以绕过血脑屏障，直接进入中枢神经系统且无全身不良反应。
为研究鼻内给予aFGF的治疗效果，成年雄性Sprague Dawley大鼠接受大脑中动脉闭塞（MCAO），并在24小时后开始鼻内给予aFGF或生理盐水，随后6天每天给药一次。连续13天每天腹腔注射BrdU（50mg/kg）。在MCAO前及MCAO后1、7、14天进行改良神经功能缺损评分测试。苏木精-伊红染色后评估梗死体积。进行免疫组织化学检测BrdU免疫反应性细胞和BrdU/DCX双标细胞。用FITC-葡聚糖标记微血管，并测量血管的数量、长度和直径。
鼻内给予aFGF并未显著减小梗死灶大小，但确实改善了神经功能恢复。在脑室下区和纹状体，aFGF组在第14天时BrdU免疫反应性细胞数量显著增加，且大多数BrdU阳性细胞与DCX共标记。缺血14天后，与对照组相比，aFGF组缺血灶周围BrdU阳性内皮细胞百分比显著增加。对FITC-葡聚糖灌注血管的定量分析显示，接受aFGF治疗的大鼠缺血边界区域的血管显著增加。但两组之间血管的长度和直径无显著差异。
总之，aFGF可能增强局灶性脑缺血后的神经发生和血管生成。鼻内给予aFGF可能是一种治疗缺血性中风的可行方法。
