Olson L
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Exp Neurol. 1993 Nov;124(1):5-15. doi: 10.1006/exnr.1993.1167.
Issues related to the possible treatment of Alzheimer's disease with nerve growth factor (NGF) are discussed. Animal research has demonstrated that the ascending cholinergic projections in the brain express low- and high-affinity receptors for NGF and are NGF-sensitive as well as probably NGF-dependent. Cholinergic lesions lead to cognitive disturbances, and treatment with NGF can improve cognitive behavior in animals. It thus seems reasonable to attempt to counteract the degeneration of cholinergic systems known to occur in patients with Alzheimer's disease by treatment with NGF. There are several different possible ways of stimulating NGF receptors such as NGF infusion, implantation of slow-release biodegradable pellets, using carrier-mediated transport across the blood-brain barrier, grafting NGF-producing cells, transferring genes directly to the brain, developing NGF receptor agonists, or controlling the endogenous NGF production. The first clinical trial of NGF infusion is described in some detail. Based on background information from intracerebral infusion of NGF in parkinsonian patients, attempting to support intraputaminal chromaffin tissue grafts, a study was initiated using a radio-controlled fully implantable pumping device delivering NGF to the lateral ventricle. Several transient or more long-lasting "improvements" were noted in the pilot case. These involved increases of blood flow and nicotine binding as evaluated by positron-emission tomography as well as improvement of the EEG and certain psychological tests, tapping verbal episodic memory. Negative effects of NGF or formation of antibodies against NGF were not noted. In discussing the pilot case, the one conclusion which appears warranted is that it is reasonable to continue the clinical research with NGF treatment of a low number of patients with Alzheimer's disease. The question of whether neurotrophin-mediated mechanisms are disturbed in Alzheimer's disease is discussed. While this issue cannot be settled at present, it is argued that NGF can be used as a pharmacological agent, whether or not there are any primary disturbances of neurotrophin-mediated mechanisms in Alzheimer's disease. Finally, the possibility that NGF might have other positive or negative effects is discussed. In particular, the increase in blood flow noted in the Alzheimer patient suggests that data from clinical research may also generate a feedback to basic science, thus aiding in attempts to find new treatment strategies for neurodegenerative diseases.
本文讨论了与神经生长因子（NGF）治疗阿尔茨海默病可能性相关的问题。动物研究表明，大脑中上行胆碱能投射表达NGF的低亲和力和高亲和力受体，对NGF敏感且可能依赖于NGF。胆碱能损伤会导致认知障碍，而用NGF治疗可改善动物的认知行为。因此，尝试通过用NGF治疗来对抗已知在阿尔茨海默病患者中发生的胆碱能系统退化似乎是合理的。刺激NGF受体有几种不同的可能方法，如NGF输注、植入缓释可生物降解微丸、利用载体介导的转运穿过血脑屏障、移植产生NGF的细胞、将基因直接导入大脑、开发NGF受体激动剂或控制内源性NGF的产生。详细描述了NGF输注的首次临床试验。基于帕金森病患者脑内输注NGF以支持脑内嗜铬组织移植的背景信息，启动了一项研究，使用无线电控制的完全可植入泵装置将NGF输送到侧脑室。在试点病例中注意到了一些短暂或更持久的“改善”。这些包括通过正电子发射断层扫描评估的血流增加和尼古丁结合增加，以及脑电图和某些心理测试（涉及言语情景记忆）的改善。未注意到NGF的负面影响或抗NGF抗体的形成。在讨论试点病例时，有一个似乎合理的结论是，继续对少数阿尔茨海默病患者进行NGF治疗的临床研究是合理的。讨论了神经营养因子介导的机制在阿尔茨海默病中是否受到干扰的问题。虽然目前这个问题无法解决，但有人认为，无论阿尔茨海默病中神经营养因子介导的机制是否存在任何原发性干扰，NGF都可以用作一种药物。最后，讨论了NGF可能产生其他正面或负面影响的可能性。特别是，阿尔茨海默病患者中注意到的血流增加表明，临床研究数据也可能为基础科学提供反馈，从而有助于寻找神经退行性疾病的新治疗策略。
