Croll S D, Chesnutt C R, Rudge J S, Acheson A, Ryan T E, Siuciak J A, DiStefano P S, Wiegand S J, Lindsay R M
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, New York, 10591, USA.
Exp Neurol. 1998 Jul;152(1):20-33. doi: 10.1006/exnr.1998.6836.
Fusion proteins comprising the Fc domain of human IgG and extracellular domains of receptor tyrosine kinases can neutralize the activity of their cognate ligands when administered in molar excess. We have generated a fusion protein using the ectodomain of TrkB (TrkB-Fc). Although the ability of TrkB-Fc to neutralize the activity of brain-derived neurotrophic factor (BDNF) in vitro has been demonstrated, there have been no conclusive demonstrations of its ability to neutralize the activity of BDNF in vivo. We co-infused TrkB-Fc with BDNF into the cortex and hippocampus of adult rats to determine whether TrkB-Fc would interfere with the ability of BDNF to upregulate neuropeptide Y (NPY). We report here that rather than neutralizing the activity of exogenous BDNF, co-infusion with the TrkB-Fc fusion protein greatly increased the volume of tissue in which neuropeptide Y immunostaining was upregulated. In addition, TrkB-Fc greatly enhanced BDNF's distribution through adult brain parenchyma. TrkB-Fc also markedly increased the otherwise limited diffusion of BDNF into brain parenchyma following intraventricular infusion. These results show that rather than neutralizing or sequestering BDNF, the TrkB-Fc, at close to molar equivalence to BDNF, can function as a carrier for BDNF and thus enhance the delivery or penetration of this polypeptide into the brain.
包含人IgG的Fc结构域和受体酪氨酸激酶胞外结构域的融合蛋白在以摩尔过量给药时可中和其同源配体的活性。我们利用TrkB的胞外结构域（TrkB-Fc）生成了一种融合蛋白。尽管已经证明TrkB-Fc在体外具有中和脑源性神经营养因子（BDNF）活性的能力，但尚无确凿证据表明其在体内具有中和BDNF活性的能力。我们将TrkB-Fc与BDNF共同注入成年大鼠的皮质和海马体，以确定TrkB-Fc是否会干扰BDNF上调神经肽Y（NPY）的能力。我们在此报告，与TrkB-Fc融合蛋白共同注入非但没有中和外源性BDNF的活性，反而极大地增加了神经肽Y免疫染色上调的组织体积。此外，TrkB-Fc极大地增强了BDNF在成体脑实质中的分布。在脑室内注入后，TrkB-Fc还显著增加了BDNF向脑实质中原本有限的扩散。这些结果表明，TrkB-Fc在与BDNF接近摩尔当量时，非但不会中和或隔离BDNF，反而可以作为BDNF的载体，从而增强该多肽向脑内的递送或渗透。
