Tobinick Edward
100 UCLA Medical Plaza, Suites 205-210, Los Angeles, California 90095, USA.
Curr Alzheimer Res. 2007 Dec;4(5):550-2. doi: 10.2174/156720507783018217.
Increasing basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of Alzheimer's Disease. Excess TNF-alpha, a cytokine with pleotropic effects in the CNS, has been suggested to be involved in the pathogenesis of AD. In addition to its pro-inflammatory effects, TNF-alpha affects synaptic transmission; and glutamate, NMDA, and amyloid pathways. More specifically, TNF-alpha, produced by glia, has been shown to affect both synaptic strength and to mediate synaptic scaling, a homeostatic mechanism important to the control of neural networks. A recently published small, open-label pilot study suggested that inhibition of the inflammatory cytokine TNF-alpha utilizing the perispinal administration of etanercept may lead to sustained cognitive improvement for six months in patients with mild, moderate, and severe Alzheimer's disease.
Continued open-label clinical experience with this new treatment modality, now for more than two years, suggests that weekly maintenance treatment with perispinal etanercept may have a sustained positive effect. In addition, rapid clinical improvement, within minutes of dosing, has been observed on a repeated basis in multiple patients.
It is hypothesized that perispinal administration of etanercept may enable rapid delivery to the CNS via the cerebrospinal venous system, resulting in improvement in synaptic mechanisms which have been dysregulated by excess TNF-alpha. TNF-alpha modulation in Alzheimer's disease may also act by influencing glutamate, NMDA, amyloid and other inflammatory pathways. Methods of perispinal administration, as described in the pilot study, may prove useful for delivering other therapeutics, particularly large molecules, to the CNS. Further study in randomized, placebo-controlled clinical trials and in basic science studies is merited.
越来越多的基础科学和临床证据表明，炎症过程以及由此导致的胶质细胞激活与阿尔茨海默病的发病机制有关。过量的肿瘤坏死因子-α（TNF-α）是一种在中枢神经系统中具有多种效应的细胞因子，被认为参与了阿尔茨海默病的发病机制。除了其促炎作用外，TNF-α还影响突触传递以及谷氨酸、N-甲基-D-天冬氨酸（NMDA）和淀粉样蛋白途径。更具体地说，由胶质细胞产生的TNF-α已被证明既能影响突触强度，又能介导突触缩放，这是一种对神经网络控制很重要的稳态机制。最近发表的一项小型开放标签试验研究表明，通过脊柱旁注射依那西普抑制炎性细胞因子TNF-α可能会使轻度、中度和重度阿尔茨海默病患者的认知能力持续改善六个月。
这种新治疗方式持续两年多的开放标签临床经验表明，脊柱旁注射依那西普进行每周维持治疗可能具有持续的积极效果。此外，在多名患者中多次重复观察到给药后几分钟内临床症状迅速改善。
据推测，脊柱旁注射依那西普可能通过脑脊液静脉系统实现向中枢神经系统的快速递送，从而改善因TNF-α过量而失调的突触机制。阿尔茨海默病中TNF-α的调节也可能通过影响谷氨酸、NMDA、淀粉样蛋白和其他炎症途径起作用。正如试验研究中所描述的脊柱旁给药方法，可能被证明对向中枢神经系统递送其他治疗药物，特别是大分子药物有用。值得在随机、安慰剂对照临床试验和基础科学研究中进一步开展研究。
