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Brain-derived neurotrophic factor (BDNF) bound with lecithin derivative in order to prolong plasma-half and permeate through blood brain barrier (BBB)

脑源性神经营养因子（BDNF）与卵磷脂衍生物结合，以延长血浆半衰期并透过血脑屏障（BBB）

基本信息

批准号：
13672329
负责人：
IGARASHI Rie
金额：
$ 1.98万
依托单位：
St Marianna University, School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We synthesized lecithinized brain-derived neurotrophic factor (lecithinized-BDNF), in which several molecules of a lecithin derivative were bound to recombinant human BDNF. We evaluated its pharmacological activity in C57BL/KsJ-db/db mice, and assessed its targetability and affinity for the nervous system. When administered subcutaneously, lecithinized-BDNF markedly reduced the plasma glucose level, food intake, and body weight in C57BL/KsJ-db/db diabetic mice. Its potency was over 20 times greater than that of unmodified BDNF. We studied the mechanism of marked enhancement of pharmacological activity. In vitro cell growth activity of lecithinized-BDNF using MTT assay was lower than unmodified BDNF, steric hindrance of lecithine moieties. Moreover, the plasma BDNF level after subcutaneous administration of lecithinized-BDNF was not higher, compared with unmodified BDNF. The accumulated lecithinized-BDNF in the cerebrum, cerebellum, and spinal cord were higher than that of unmodified BDNF. We found finally that in vitro binding of lecithinized-BDNF for PC-pAB1 neural cells was much higher than that of unmodified BDNF. Moreover, lecithinized-BDNF bound to PC-pAB1 cells didn't change with even excess unmodified BDNF or even excess lecithinized-BDNF. PC-pAB1 cells treated with lecithinized-BDNF showed a sustained MAP kinase (ERK1/2) activation. These data would indicate that the high affinity of lecithinized-BDNF for the target cells followed by prolonged MAPK activation would play an important role on its more potent pharmacological activity.

我们合成了卵磷脂化脑源性神经营养因子（lecithinized-BDNF），其中几个分子的卵磷脂衍生物结合到重组人BDNF。我们在C57 BL/KsJ-db/db小鼠中评价了其药理活性，并评估了其对神经系统的靶向性和亲和力。当皮下给药时，卵磷脂化BDNF显著降低C57 BL/KsJ-db/db糖尿病小鼠的血糖水平、食物摄入量和体重。其效力比未修饰的BDNF高20倍以上。我们研究了药理活性显著增强的机制。MTT法检测卵磷脂化BDNF的体外细胞生长活性低于未修饰的BDNF，卵磷脂部分的空间位阻。此外，与未修饰的BDNF相比，皮下施用卵磷脂化的BDNF后的血浆BDNF水平并不更高。卵磷脂化的BDNF在大脑、小脑和脊髓中的积累高于未修饰的BDNF。结果表明，卵磷脂化的BDNF与PC-pAB 1神经细胞的体外结合率明显高于未修饰的BDNF。此外，即使过量的未修饰BDNF或过量的卵磷脂化BDNF，与PC-pAB 1细胞结合的卵磷脂化BDNF也没有改变。卵磷脂化BDNF处理的PC-pAB 1细胞显示持续的MAP激酶（ERK 1/2）激活。这些数据表明，卵磷脂化的BDNF对靶细胞的高亲和力，随后延长MAPK活化，将在其更有效的药理活性中发挥重要作用。