Bäckman C, Rose G M, Hoffer B J, Henry M A, Bartus R T, Friden P, Granholm A C
Department of Basic Science, University of Colorado Health Sciences Center, Denver 80262, USA.
J Neurosci. 1996 Sep 1;16(17):5437-42. doi: 10.1523/JNEUROSCI.16-17-05437.1996.
Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration of NGF is necessary because NGF will not cross the blood-brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. In our experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.
在大鼠脑室内给予神经生长因子（NGF）已被证明可减少与年龄相关的中枢胆碱能神经元萎缩及伴随的记忆障碍。脑室内给予NGF是必要的，因为NGF不能穿过血脑屏障（BBB）。在此，我们使用了一种新型载体系统，该系统由与抗转铁蛋白受体抗体（OX-26）共价连接的NGF组成，用于将具有生物活性的NGF转运穿过血脑屏障。在我们的实验中，24月龄的老年Fischer 344大鼠每周静脉注射两次OX-26-NGF偶联物或对照溶液（未偶联的OX-26和NGF的混合物），持续6周。OX-26-NGF注射使先前受损大鼠的空间学习能力有显著改善，但破坏了先前未受损大鼠的学习能力。神经解剖学分析表明，OX-26-NGF偶联物处理使最初在空间学习方面受损的大鼠内侧隔区胆碱能细胞大小显著增加。这些结果表明转铁蛋白受体抗体递送系统在使用神经营养蛋白治疗中枢神经系统疾病方面具有潜在用途。
