Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration.
Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration.
复制标题
DOI：
--
复制
发表时间：
1996-02
影响因子：
3.6
通讯作者：
J. L. Venero;F. Hefti;B. Knusel
中科院分区：
文献类型：
--
作者：
J. L. Venero;F. Hefti;B. Knusel
在神经营养因子用于治疗脑神经变性的药理学用途中，渗透入脑是一个重要的考虑因素，老年痴呆症患者。此外，已经发现用神经生长因子（NGF）进行脑室内治疗会引起副作用，包括异常交感神经发芽和体重减轻。这些发现表明，直接脑实质内应用最少量的营养因子可能是治疗上可取的。我们比较了成年大鼠纹状体内和侧脑室注射NGF对纹状体胆碱能神经元的影响。每日纹状体内给予>或= 50 ng的NGF，持续1周，导致纹状体胆碱能细胞中胆碱乙酰转移酶（ChAT）的mRNA水平增加至对照组的约2倍。每天脑室内注射4.5微克的神经生长因子才能产生类似的反应。5和50 ng/天的NGF均未能诱导对跨膜蛋白酪氨酸激酶trkA mRNA水平的影响，但注射750或1500 ng/天的NGF使trkA mRNA表达上调至对照的约2倍。即使在4.5微克NGF/天的剂量下，侧脑室内递送的NGF也未能诱导纹状体trkA mRNA的可观察到的变化。这些数量上的差异反映在神经生长因子受体的水平。使用Western印迹程序，我们发现显着的酪氨酸磷酸化的Trk型蛋白质2小时后，纹状体内注射50 ng的神经生长因子。在150或750 ng的NGF下观察到最大反应。为了通过脑室内注射NGF最大程度地激活Trks，需要4.5微克的NGF。两者合计，我们的研究结果强烈支持脑实质内注射或输注的神经生长因子，并可能其他营养因子，用于治疗应用，以最大限度地提高对目标神经元群体的影响，并尽量减少不良副作用。
Penetration into the brain is an important consideration in the pharmacological use of neurotrophic factors for the treatment of brain neurodegeneration, e.g., in Alzheimer's disease. Furthermore, intracerebroventricular treatment with nerve growth factor (NGF) has been found to induce side effects, including aberrant sympathetic sprouting and weight loss. Such findings suggest that direct intraparenchymal application of minimal amounts of trophic factors might be therapeutically desirable. We compared the effectiveness of intrastriatal and intracerebroventricular administrations of NGF on striatal cholinergic neurons in adult rats. Daily intrastriatal administration for 1 week of > or = 50 ng of NGF resulted in an increase in mRNA levels for choline acetyltransferase (ChAT) in striatal cholinergic cells to approximately 2-fold over control. A daily intraventricular dose of 4.5 micrograms of NGF was required for a similar response. Both 5 and 50 ng of NGF/day failed to induce an effect on transmembrane protein tyrosine kinase trkA mRNA levels, but injections of 750 or 1500 ng/day of NGF up-regulated trkA mRNA expression to approximately 2-fold of control. NGF delivered intracerebroventricularly failed to induce an observable change in striatal trkA mRNA, even at a dosage of 4.5 micrograms of NGF/day. These quantitative differences in NGF actions were reflected at the level of NGF receptors. Using Western blotting procedures, we found pronounced tyrosine phosphorylation of Trk-type proteins 2 hr after intrastriatal injection of 50 ng of NGF. Maximal responses were seen with either 150 or 750 ng of NGF. For maximal activation of Trks by intraventricular NGF injection, 4.5 micrograms of NGF was required. Taken together, our results strongly favor intraparenchymal injections or infusions of NGF, and possibly other trophic factors, for therapeutical applications to maximize the effects on the targeted neuronal populations and to minimize undesirable side effects.