Laboratory of Molecular Therapeutics, Department of Neurosurgery, University of California San Francisco, CA 94103, USA.
Neuropharmacology. 2010 Jun;58(7):1114-21. doi: 10.1016/j.neuropharm.2010.02.002. Epub 2010 Feb 11.
Convection-enhanced delivery (CED) of GDNF and NTN was employed to determine the tissue clearance of these factors from the rat striatum and the response of the dopaminergic system to a single infusion. Two doses of GDNF (15 and 3 microg) and NTN (10 microg and 2 microg) were infused into the rat striatum. Animals were euthanized 3, 7, 14, 21, and 28 days post-infusion. Brains were processed for ELISA, HPLC, and immunohistochemistry (IHC). Both doses of the infused GDNF resulted in a sharp increase in striatal GDNF levels followed by a rapid decrease between day 3 and 7. Interestingly, IHC revealed GDNF in the septum and the base of the brain 14 days after GDNF administration. Dopamine (DA) turnover was significantly increased in a dose-dependent manner for more than 7 days after a single GDNF infusion. NTN persisted in the brain for at least two weeks longer than GDNF. It also had more persistent effects on DA turnover, probably due to its precipitation in the brain at neutral pH after infusion. Our data suggest that daily or continuous dosing may not be necessary for delivering growth factors into the CNS.
通过对流增强递送 (CED) 技术将 GDNF 和 NTN 递送至大鼠纹状体，以确定这些因子从大鼠纹状体中的组织清除率，以及多巴胺能系统对单次输注的反应。将两种剂量的 GDNF（15 和 3μg）和 NTN（10μg 和 2μg）输注到大鼠纹状体中。动物在输注后 3、7、14、21 和 28 天被安乐死。对大脑进行 ELISA、HPLC 和免疫组织化学 (IHC) 分析。两种剂量的输注 GDNF 导致纹状体 GDNF 水平急剧增加，随后在第 3 天至第 7 天迅速下降。有趣的是，在 GDNF 给药后 14 天，IHC 显示 GDNF 在隔室和大脑基底。单次 GDNF 输注后，多巴胺 (DA) 周转率呈剂量依赖性显著增加，持续时间超过 7 天。NTN 在大脑中的持续时间比 GDNF 长至少两周。这可能是由于输注后在中性 pH 值下在大脑中沉淀，因此对 DA 周转率的持续作用也更长。我们的数据表明，每天或连续给药可能不是将生长因子递送至中枢神经系统所必需的。
