DIFFUSION NGF & BIOLOGICAL RESPONSE FROM BASAL FOREBRAIN CHOLINERGIC NEURONS

神经生长因子调节基底前脑表型的意义 胆碱能神经元（BFCN），并可以促进BFCN的生存 损伤或与年龄相关的退化。 因此，NGF可能有助于 治疗阿尔茨海默氏症中神经元损失的胆碱能成分 疾病 然而，侧脑室注射神经生长因子， 非目标系统的重大不利影响;因此， 需要将NGF实质内递送到BFCN。 目的 确定脑实质内（IP）输注的NGF是否扩散， 距离足以引起广泛的神经营养作用， 灵长类、成年恒河猴（n=4）中的BFCN群体 7岁和19岁接受持续输注NGF [1.0 mg/ml x 12 ml/天]持续3天，注入纹状体或核中 大细胞基底层（NBM）。 对脑切片进行免疫标记， NGF [Mufson等人，1994]，并对CSF和血清样本进行检测 使用双位点ELISA测定NGF蛋白含量。 结果NGF递送IP 在6-10 mm范围内以球形分布扩散， 大部分NBM神经元。 只有少量的神经生长因子被检测到， IP后的CSF。 因此，脑实质内 输注NGF广泛扩散，而仅升高CSF水平 微微 这些结果进一步支持了直接IP 输注可提供ICV输注的替代方案， 营养因子长期进入中枢神经系统。 关键词老龄化， 阿尔茨海默氏症，神经营养因子基金NIH Grant AG 10435

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