神经营养因子
神经保护
神经营养素
血脑屏障
药理学
医学
脑源性神经营养因子
缺血
内科学
内分泌学
受体
中枢神经系统
作者
Yun Zhang,William M. Pardridge
出处
期刊:Brain Research
[Elsevier]
日期:2001-01-01
卷期号:889 (1-2): 49-56
被引量:156
标识
DOI:10.1016/s0006-8993(00)03108-5
摘要
Neurotrophins such as brain-derived neurotrophic factor (BDNF) are potential neuroprotective agents that could be used in the treatment of acute stroke, should these proteins be made transportable through the blood-brain barrier (BBB) in vivo. One approach to the BBB problem is to attach the nontransportable peptide to a brain targeting vector, which is a peptide or peptidomimetic monoclonal antibody (MAb), that is transported into brain from blood via an endogenous BBB transport system. The present studies describe a conjugate of BDNF and the OX26 monoclonal antibody (MAb) to the transferrin receptor. Avidin-biotin technology is used to link the BDNF and the MAb. The surface of the BDNF is conjugated with 2000 Da polyethylene glycol at carboxyl residues to optimize the plasma pharmacokinetics of the neurotrophin. Adult rats subjected to 24 h of permanent middle cerebral artery occlusion (MCAO) were treated intravenously with either unconjugated BDNF, unconjugated MAb, or the BDNF-OX26 conjugate at a dose of 1, 5 and 50 microg/rat of the BDNF. These doses decreased the infarct volume by 6% (not significant), 43% (P<0.01), and 65% (P<0.01), respectively. Significant reduction in stroke volume was still observed if the administration of the BDNF conjugate was delayed for 1-2 h after MCAO, although the pharmacological effect was progressively diminished in proportion to the time delay between MCAO and treatment. In conclusion, these studies demonstrate that large reductions in stroke volume can be achieved with the noninvasive intravenous administration of neurotrophins such as BDNF, providing the peptide is conjugated to a BBB drug targeting system.
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