Tuszynski M H
Department of Neurosciences, University of California-San Diego, La Jolla 92093-0626, USA.
Cell Transplant. 2000 Sep-Oct;9(5):629-36. doi: 10.1177/096368970000900508.
Nerve growth factor (NGF) exerts both trophic (cell survival) and tropic (axonal growth-promoting) effects on several neuronal populations. In particular, its robust ability to prevent lesion-induced and spontaneous age-related basal forebrain cholinergic neuronal degeneration, and to promote mnemonic recovery, has suggested its potential use as a therapeutic agent in Alzheimer's disease. When infused intracerebroventricularly, however, NGF is associated with several adverse effects that make this delivery route impractical. The present study examined whether intraparenchymal infusions of NGF adjacent to cholinergic neuronal soma are an effective and well-tolerated means of providing NGF to degenerating cholinergic neurons. Cholinergic neuronal rescue together with axonal sprouting responses and local tissue damage in the brain were assessed in adult rats that underwent complete unilateral fornix transections, followed by intraparenchymal infusions of recombinant human NGF for a 2-week period. Intraparenchymal NGF infusions prevented the degeneration of 94.7+/-6.6% of basal forebrain cholinergic neurons compared to 21.7+/-2.6% in vehicle-infused animals (p < 0.0001). Cholinergic axons sprouted toward the intraparenchymal NGF source in an apparent gradient-dependent manner. Glial responses to intraparenchymal infusions were minimal, and no apparent toxic effects of the infusions were observed. Thus, when infused intraparenchymally, NGF rescues basal forebrain cholinergic neurons, alters the topography of axonal sprouting responses, and does not induce adverse affects over a 2-week infusion period. Intraparenchymal NGF delivery merits further study at longer term time points as a means of treating the cholinergic component of neuronal loss in Alzheimer's disease.
神经生长因子（NGF）对多个神经元群体发挥营养（细胞存活）和向性（促进轴突生长）作用。特别是，它具有强大的能力来预防损伤诱导的和与年龄相关的自发性基底前脑胆碱能神经元变性，并促进记忆恢复，这表明它有可能作为治疗阿尔茨海默病的药物。然而，当通过脑室内注射时，NGF会产生多种不良反应，使得这种给药途径不切实际。本研究考察了在胆碱能神经元胞体附近进行脑实质内注射NGF是否是向退化的胆碱能神经元提供NGF的一种有效且耐受性良好的方法。在成年大鼠中评估了胆碱能神经元的挽救情况以及轴突发芽反应和脑内局部组织损伤，这些大鼠先进行了完全单侧穹窿横断，然后进行为期2周的脑实质内注射重组人NGF。与注射赋形剂的动物相比，脑实质内注射NGF可预防94.7±6.6%的基底前脑胆碱能神经元变性，而注射赋形剂的动物中这一比例为21.7±2.6%（p<0.0001）。胆碱能轴突以明显的梯度依赖方式向脑实质内NGF来源方向发芽。脑实质内注射引起的胶质反应最小，且未观察到注射有明显的毒性作用。因此，当进行脑实质内注射时，NGF可挽救基底前脑胆碱能神经元，改变轴突发芽反应的拓扑结构，并且在2周的注射期内不会引起不良反应。作为治疗阿尔茨海默病中神经元丢失的胆碱能成分的一种方法，脑实质内递送NGF在更长时间点值得进一步研究。
