Emerich D F, Plone M, Francis J, Frydel B R, Winn S R, Lindner M D
Cyto Therapeutics, Inc., Providence, RI 02906, USA.
Brain Res. 1996 Oct 14;736(1-2):99-110.
The present study examined the effects of encapsulated cells which were genetically modified to secrete human glail-derived neurotrophic factor (hGDNF) on the motor deficits in aged rodents. Prior to implantation, animals were tested on a battery of motor tasks. Spontaneous locomotion and motor coordination was evaluated in young (5 month) and aged (20 months) rats. Aged animals tested for spontaneous locomotor activity were found to be hypoactive relative to young animals. Compared to the young animals the aged animals also: (1) were impaired on a bar pressing task, (2) were unable to descend a wooden pole covered with wire mesh in a coordinated manner, (3) fell more rapidly from a rotating rod and (4) were unable to maintain their balance on a series of wooden beams of varying widths. Following baseline testing, aged animals received either no implant, encapsulated baby hamster kidney fibroblast cells that were modified to produce hGDNF (BHK-hGDNF) or encapsulated BHK cells which were not modified to produce hGDNF (BHK-Control) implanted bilaterally into the striatum. Following surgery, a significant increase in locomotor activity and bar pressing was observed in those aged animals receiving BHK-hGDNF implants. Bar pressing in aged animals receiving BHK-Control cells was improved to a lesser extent and reached the level of performance seen in young rats. No recovery was observed in the animals receiving BHK-Control cell-loaded capsules on any of the other motor tasks. Histological analysis revealed that implants of hGDNF-producing cells produced a marked increase in the density of tyrosine hydroxylase staining in the striatum adjacent to the implant site. This increased staining was not seen in animals receiving BHK-Control cells. Histological analysis also revealed the presence of viable BHK-hGDNF cells within the capsules that continued to produce hGDNF as measured by ELISA. These results indicate that polymer-encapsulated hGDNF-secreting cells survive following implantation into aged rats and may be useful for treating some of the behavioral consequences of aging or disorders characterized by dopaminergic hypofunction.
本研究检测了经基因改造可分泌人胶质细胞源性神经营养因子（hGDNF）的封装细胞对老年啮齿动物运动功能缺陷的影响。在植入前，对动物进行了一系列运动任务测试。评估了年轻（5个月）和老年（20个月）大鼠的自发运动和运动协调性。发现接受自发运动活动测试的老年动物相对于年轻动物活动不足。与年轻动物相比，老年动物还：（1）在压杆任务中受损；（2）无法以协调的方式从覆盖有金属丝网的木杆上下来；（3）从旋转杆上掉落得更快；（4）无法在一系列不同宽度的木梁上保持平衡。在基线测试后，老年动物双侧纹状体植入物分别为：未植入、经改造可产生hGDNF的封装幼仓鼠肾成纤维细胞（BHK-hGDNF）或未改造以产生hGDNF的封装BHK细胞（BHK-对照）。手术后，接受BHK-hGDNF植入物的老年动物的运动活动和压杆行为有显著增加。接受BHK-对照细胞的老年动物的压杆行为有较小程度的改善，并达到了年轻大鼠的表现水平。在接受装有BHK-对照细胞胶囊的动物的任何其他运动任务中均未观察到恢复。组织学分析显示，植入产生hGDNF的细胞使植入部位附近纹状体中酪氨酸羟化酶染色密度显著增加。在接受BHK-对照细胞的动物中未观察到这种染色增加。组织学分析还显示，胶囊内存在存活的BHK-hGDNF细胞，通过酶联免疫吸附测定法（ELISA）测量，这些细胞继续产生hGDNF。这些结果表明，聚合物封装的分泌hGDNF的细胞在植入老年大鼠后能够存活，并且可能有助于治疗衰老的一些行为后果或以多巴胺能功能减退为特征的疾病。
