Yan Q, Matheson C, Sun J, Radeke M J, Feinstein S C, Miller J A
Department of Neurobiology, Amgen, Inc., Amgen Center, Thousand Oaks, California 91320.
Exp Neurol. 1994 May;127(1):23-36. doi: 10.1006/exnr.1994.1076.
To assess the potential effectiveness by which injected neurotrophins can diffuse throughout the brain, we used autoradiographic and immunohistochemical techniques to examine the brain distributions of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) after a single injection into the lateral cerebral ventricle (ICV) in rats. As described previously, ICV-injected NGF labeled cholinergic neurons in the basal forebrain. Injection of BDNF resulted in few or no labeled neurons in the basal forebrain or in the substantia nigra. However, very intense labeling was associated with the ventricular walls and immediate parenchyma. The distribution of NT-3 after ICV injection was intermediate between that of NGF and BDNF. In the basal forebrain, similar neurotrophin distributions were observed in neonate versus adult animals. Our in situ hybridization analysis has shown that mRNA encoding the BDNF receptor(s) (trkB) is highly expressed by ependymal cells as well as by many neurons and glia. On the other hand, expression of the high-affinity NGF receptor (trkA) is restricted to cholinergic neurons in basal forebrain and striatum. In addition, staining with antisera specific for the trkA or trkB receptors demonstrated that their expression patterns closely reflect their mRNA distributions. Taken together, these data suggest that the presence of the trkB receptor on the ependymal layer of the ventricle and its expression throughout the brain parenchyma represents a significant impediment to the adequate diffusion of ICV-injected BDNF into the brain for delivery to target neurons.
为评估注射的神经营养因子在全脑扩散的潜在效果，我们采用放射自显影和免疫组化技术，检测大鼠侧脑室单次注射神经生长因子（NGF）、脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）后在脑内的分布情况。如前所述，侧脑室注射的NGF标记了基底前脑的胆碱能神经元。注射BDNF后，基底前脑或黑质中标记的神经元很少或没有。然而，脑室壁和紧邻的实质出现了非常强烈的标记。侧脑室注射后NT-3的分布介于NGF和BDNF之间。在基底前脑，新生动物与成年动物的神经营养因子分布相似。我们的原位杂交分析表明，编码BDNF受体（trkB）的mRNA在室管膜细胞以及许多神经元和胶质细胞中高度表达。另一方面，高亲和力NGF受体（trkA）的表达局限于基底前脑和纹状体的胆碱能神经元。此外，用trkA或trkB受体特异性抗血清染色表明，它们的表达模式与其mRNA分布密切相关。综上所述，这些数据表明，脑室室管膜层上trkB受体的存在及其在全脑实质中的表达，对侧脑室注射的BDNF充分扩散到脑内并传递给靶神经元构成了重大障碍。
