DIFFUSION NGF & BIOLOGICAL RESPONSE FROM BASAL FOREBRAIN CHOLINERGIC NEURONS

神经生长因子对基底前脑表型的调节意义 胆碱能神经元(BFCN)并能促进BFCN存活 损伤或与年龄相关的退化。因此，NGF可能在 治疗阿尔茨海默病神经元丢失的胆碱能成分 疾病。然而，脑室内输注NGF会导致 来自非目标系统的重大不利影响；因此，当地和 实质内向BFCNs输送NGF是必要的。目标为 确定实质内(IP)注射NGF是否扩散到 距离足以从广泛的 BFCNs在灵长类、成年恒河猴(n=4)中的数量介于 7岁和19岁的儿童连续输注NGF[1.0 Mg/mlx12ml/天]进入纹状体或核内3天 基底大细胞(NBM)。对脑部切片进行免疫标记 神经生长因子[Mufson等人，1994]，脑脊液和血清样本检测 NGF蛋白含量采用双点酶联免疫吸附试验。结果NGF提供IP 在6-10毫米的球形分布中扩散，并访问 大多数NBM神经元。仅检测到微量的NGF 腹腔注射后给予脑脊液。因此，脑实质内的未来方向 NGF输注广泛扩散，仅提高脑脊液水平 稍微有点。这些结果进一步支持了将IP 输液可以提供一种替代ICV输液的方法 营养因子长期进入中枢神经系统。关键词老化， 阿尔茨海默氏症，神经营养因子资助NIH Grant AG10435

Significance NGF regulates the phenotype of basal forebrain cholinergic neurons (BFCN) and can promote BFCN survival following injury or age-related degeneration. NGF may therefore be useful in treating the cholinergic component of neuronal loss in Alzheimer's disease. However, intracerebroventricular infusions of NGF cause substantial adverse effects from non-targeted systems; thus, local and intraparenchymal delivery of NGF to BFCNs is necessary. Objectives To determine whether intraparenchymal (IP) infusions of NGF diffuse for distances sufficient to elicit neurotrophic effects from the extensive population of BFCNs in the primate, adult rhesus monkeys (n=4) between the ages of 7 and 19 years received continuous infusions of NGF [1.0 mg/ml x 12 ml/day] for 3 days into either the striatum or nucleus basalis magnocellularis (NBM). Brain sections were immunolabeled for NGF [Mufson et al., 1994], and CSF and serum samples were assayed for NGF protein content using a two-site ELISA. Results NGF delivered IP diffused in a spherical distribution over 6-10 mm and accessed a majority of NBM neurons. Only slight amounts of NGF were detected in the CSF after IP. Future Directions Thus, intraparenchymal brain infusions of NGF diffuse extensively while raising CSF levels only slightly. These results further support the concept that direct IP infusions may provide an alternative to ICV infusions for delivering trophic factors chronically into the CNS. KEY WORDS aging, Alzheimer's, neurotrophic factor FUNDING NIH Grant AG10435